RU2831159C2 - N-(phenylsulphonyl) benzamides and related compounds as bcl-2 inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula II and formula VII, and pharmaceutically acceptable salts thereof. In formula II: Y is -O-; R² is -NO₂; R^4a is selected from a group consisting of unsubstituted C1-6 alkyl and (heterocyclo)alkyl. In formula VII: Y is selected from a group consisting of -CH₂- and -O-; X¹, X², and X³ each independently represents -CR⁸=; R² is -NO₂; R^4a is selected from the group consisting of unsubstituted C1-6 alkyl and (heterocyclo)alkyl; and R⁸ is hydrogen. (Heterocyclo)alkyl is C1-4 alkyl substituted with one heterocyclyl group, where the heterocyclyl group is 6-member cyclic group containing one ring and one or two oxygen atoms.

EFFECT: disclosed compounds inhibit Bcl-2 proteins and are used in treating a disease, disorder or condition susceptible to Bcl-2 protein inhibition, such as cancer.

4 cl, 4 dwg, 7 tbl, 20 ex

Description

AREA OF TECHNOLOGY

This description relates to inhibitors of Bcl-2 protein and therapeutic methods for the treatment of diseases, disorders or conditions in which inhibition of Bcl-2 proteins results in a beneficial effect.

LEVEL OF TECHNOLOGY

Apoptosis, the process of programmed cell death, is an essential biological process for tissue homeostasis. In mammals, it has been shown to regulate early embryonic development. Later in life, cell death is a standard mechanism by which potentially dangerous cells, such as those bearing malignant defects, are eliminated. Several apoptotic pathways are recognized. One of the most important apoptotic pathways involves the Bcl-2 family of proteins, which are key regulators of the mitochondrial (also called "intrinsic") apoptotic pathway. See Danial and Korsmeyer, Cell 116:205-219 (2004). The structural homology domains BH1, BH2, BH3, and BH4 are characteristic of the Bcl-2 family of proteins. The Bcl-2 protein family can be further classified into three subfamilies, depending on how many homology domains each protein contains and its biological activity, i.e. whether it has a pro- or anti-apoptotic function.

The first subgroup of Bcl-2 proteins contains proteins that have all four homology domains, i.e. BH1, BH2, BH3, and BH4. Their overall effect is antiapoptotic, which means they prevent the cell from initiating the cell death process. Proteins such as Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1/A1 are members of this first subgroup. Proteins belonging to the second subgroup of Bcl-2 proteins contain three homology domains, BH1, BH2, and BH3, and have a proapoptotic effect. The two main representative proteins of this second subgroup are Bax and Bak. The third subgroup of Bcl-2 proteins consists of proteins that contain only the BH3 domain, and members of this subgroup are commonly referred to as "BH3-only proteins." Their biological effect on the cell is proapoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, and Puma are examples of this third subfamily of proteins. The precise mechanism by which Bcl-2 family proteins regulate cell death is not fully known. In one hypothesis for the regulation of cell death by Bcl-2 family proteins, BH3-only proteins are further classified as "activators," such as Bim and Bid, or "sensitizers," such as Bad, Bik, Noxa, Hrk, Bmf, and Puma proteins, depending on their regulatory function.

One of the keys to tissue homeostasis is achieving a balance in the interactions between the three subsets of Bcl-2 proteins in cells. Studies have elucidated the mechanisms by which pro-apoptotic and anti-apoptotic subsets of Bcl 2 family proteins interact to allow the cell to undergo programmed cell death. Upon receipt of intracellular or extracellular signals in cells, post-translational or transcriptional activation of BH3-only proteins occurs. BH3-only proteins are the primary inducers of the apoptotic cascade, which includes, as one step, the activation of the pro-apoptotic proteins Bax and Bak on the mitochondrial membrane in cells. Following activation of Bax and/or Bak that are already anchored to the mitochondrial membrane or migrate to this membrane, Bax and/or Bak oligomerize, leading to mitochondrial outer membrane permeabilization (MOMP), release of cytochrome C, and subsequent activation of effector caspases, ultimately leading to cell apoptosis. Some researchers hypothesize that some BH3-only proteins, such as Puma, Bim, Bid, are “activators” because these proteins directly recruit the pro-apoptotic proteins Bax and Bak to initiate MOMP, whereas other BH3-only proteins, such as Bad, Bik, and Noxa, are “sensitizers” and induce Bax and Bak oligomerization indirectly by binding anti-apoptotic proteins, such as Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and displacing and “releasing” BH3-only proteins “activators,” which subsequently bind to and activate pro-apoptotic proteins, such as Bax, Bak, to induce cell death. Other research suggests that antiapoptotic proteins recruit and block Bax and Bak directly, and all BH3-only proteins regulate this interaction by binding to antiapoptotic proteins such as Bcl-2, Bcl-xL, Bcl-w, Mcl-1, resulting in the release of Bax and Bak. See Adams and Cory, Oncogene 26: 1324–1337 (2007) and Willis et al., Science 315: 856–859 (2007). Although the precise interactions by which anti- and pro-apoptotic Bcl-2 family proteins regulate apoptosis remain a subject of investigation, there is a large body of evidence that compounds that inhibit the binding of BH3-only proteins to antiapoptotic Bcl-2 family proteins promote apoptosis in cells.

Dysregulation of apoptotic pathways is observed in the pathology of many important diseases, such as neurodegenerative conditions (activated apoptosis), such as Alzheimer's disease; and proliferative diseases (inhibited apoptosis), such as cancer, autoimmune diseases and prothrombotic states.

Inhibited apoptosis (and in particular the Bcl-2 family of proteins) may be involved in malignancy. Research has shown, for example, that the antiapoptotic proteins, Bcl-2 and Bcl-xL, are overexpressed in many types of cancer cells. See Zhang, Nature Reviews Drug Discovery 1: 101 (2002); Kirkin et al., Biochimica et Biophysica Acta 1644: 229–249 (2004); and Amundson et al., Cancer Research 60: 6101–6110 (2000). The effect of this deregulation is to result in the survival of altered cells that would otherwise undergo apoptosis under normal conditions. Recapitulation of these defects in unregulated proliferation is thought to be the starting point of cancer evolution. Furthermore, research has shown that BH3-only proteins can act as tumor suppressors when expressed in diseased animals.

These results have opened the door to new strategies in cancer drug discovery. If a small molecule that could mimic the effect of BH3-only proteins could enter the cell and overcome the overexpression of the antiapoptotic protein, the apoptotic process could be restored. This strategy may have the advantage of alleviating the problem of drug resistance that is usually a consequence of apoptotic deregulation (abnormal survival). Therapeutic strategies targeting Bcl-2 and Bcl-XL in cancer have been explored to restore cancer cell sensitivity and overcome cancer cell resistance to apoptosis. See Adams et al., Science 281:1322 (1998) and Reed, Adv. Pharmacol. 41:501 (1997); Reed et al., J. Cell. Biochem. 60:23 (1996).

Platelets also contain essential apoptotic machinery, such as Bax, Bak, Bcl-xL, Bcl-2, cytochrome c, caspase-9, caspase-3, and APAF-1, to mediate programmed cell death via the intrinsic apoptotic pathway. Although the production of circulating platelets is a normal physiological process, a number of diseases are caused or complicated by excess or unwanted platelet activation. This suggests that therapeutic agents that can inhibit anti-apoptotic proteins in platelets and reduce platelet counts in mammals may be useful in the treatment of prothrombotic conditions and diseases that are characterized by excess or unwanted platelet activation.

Small molecule mimetics of BH3-only proteins, such as ABT-737 and ABT-263, bind strongly to a subset of antiapoptotic Bcl-2 proteins, including Bcl-2, Bcl-w, and Bcl-xL, and weakly to Mcl-1 and A1. These small molecules have been tested in animal studies and have demonstrated cytotoxic activity in several xenograft models as single agents and have potentiated the effects of several chemotherapeutic agents in other xenograft models when used in combination. See Tse, C., et al., Cancer Res 68:3421–3428 (2008) and van Delft, M. F., et al., Cancer Cell 10:389–399 (2006). These in vivo studies suggest potential utility of inhibitors of the Bcl-2 family of anti-apoptotic proteins for the treatment of diseases in which the apoptotic pathway is dysregulated. ABT-199 (Venetoclax) is a highly active Bcl-2 inhibitor approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukemia. See Cang et al., Journal of Hematology & Oncology 8:129 (2015) and Souers et al., Nature Medicine 19:202–208 (2013).

Natural expression levels of anti-apoptotic Bcl-2 family proteins vary across cell types. For example, in young platelets, Bcl-xL protein is highly expressed and plays an important role in regulating platelet cell death (survival). Furthermore, in some cancer cell types, cancer cell survival is attributed to dysregulation of the apoptotic pathway caused by overexpression of one or more anti-apoptotic Bcl-2 family proteins. In view of the important role of the Bcl-2 family of proteins in the regulation of apoptosis in both cancer and normal, i.e., non-malignant cells, and the recognized variability in the cell-to-cell expression pattern of the Bcl-2 family protein, it would be advantageous to have a small molecule inhibitor that selectively targets and preferentially binds to one type or subset of the anti-apoptotic Bcl-2 protein(s), such as an anti-apoptotic Bcl-2 family member that is overexpressed in a particular cancer type. Such a selective compound may also confer certain advantages in the clinical setting, such as flexibility in dosing, reduced toxicity to the target in normal cells, among others, such as the lymphopenia observed in Bcl-2 deficient mice. See Nakayama, K. et al. PNAS 91:3700-3704 (1994).

There is an ongoing need for small molecules that selectively inhibit the activity of one type or subset of Bcl-2 proteins for the treatment of hyperproliferative diseases such as cancer.

BRIEF DESCRIPTION OF THE ESSENCE OF THE INVENTION

In one aspect, this disclosure relates to compounds represented by any of Formulas I-A or I-VIII, below, and their pharmaceutically acceptable salts and solvates, such as hydrates thereof, which are collectively referred to herein as “Compounds of this Disclosure.”

In another aspect, this disclosure relates to a pharmaceutical composition comprising a Compound of this disclosure and one or more pharmaceutically acceptable carriers.

In another aspect, this disclosure relates to a method of inhibiting Bcl-2 proteins, such as Bcl-2, Bcl-w, Bcl-xL, Mcl-1, and Bfl-1/A1, or any combination thereof, in a subject, such as a human, comprising administering to the subject an effective amount of at least one Compound of this disclosure.

In another aspect, this disclosure relates to methods for treating or preventing diseases, disorders, or conditions, e.g., a hyperproliferative disease, e.g., a cancer, e.g., small cell lung cancer, non-Hodgkin's lymphoma (NHL), acute myelogenous leukemia (AML), chronic lymphoid (or lymphocytic) leukemia (CLL), or acute lymphoblastic leukemia (ALL), in a subject susceptible to inhibition of Bcl-2 proteins, e.g., Bcl-2 and/or Bcl-xL, comprising administering to the subject a therapeutically effective amount of a Compound of this disclosure.

In another aspect, this disclosure relates to the use of the Compounds of this disclosure as inhibitors of one or more Bcl-2 proteins, such as Bcl-2 and/or Bcl-xL.

In another aspect, this disclosure relates to the use of the Compounds of this disclosure as Bcl-2 inhibitors.

In another aspect, this disclosure relates to the use of the Compounds of this disclosure as Bcl-xL inhibitors.

In another aspect, this disclosure relates to a pharmaceutical composition for the treatment of diseases, disorders, or conditions responsive to inhibition of Bcl-2 proteins, such as Bcl-2 and/or Bcl-xL, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of this disclosure, optionally admixed with one or more pharmaceutically acceptable carriers.

In another aspect, this disclosure relates to Compounds of this disclosure for use in the treatment or prevention of a disease, disorder, or condition, such as a hyperproliferative disease, such as cancer, in a subject, such as a human.

In another aspect, this disclosure relates to a Compound of this disclosure for use in the manufacture of a medicament for the treatment of a disease, disorder, or condition, such as a hyperproliferative disease, such as cancer, in a subject, such as a human.

In another aspect, this description relates to a kit comprising a Compound of this Description.

In another aspect, this disclosure relates to a kit comprising a Compound of this disclosure and a second therapeutic agent used to treat a disease, disorder, or condition of interest, and a package insert containing instructions for use in treating the disease, disorder, or condition.

In another aspect, this disclosure relates to a composition comprising: (a) a Compound of this disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or a pharmaceutically acceptable carrier.

Additional embodiments and advantages of the invention will be set forth in part in the following description, and will be apparent from the description, or may be learned in practicing the invention. The embodiments and advantages of the invention will be realized and achieved by means of the elements and combinations particularly indicated in the appended claims.

It should be understood that both the above summary and the following detailed description are merely exemplary and explanatory and do not limit the claimed invention.

DETAILED DESCRIPTION OF GRAPHIC MATERIALS

Figure 1 is an illustration (Western blot analysis) showing the expression of PARP, cleaved caspase-3, and Bcl-2 in RS4;11 xenograft tumor tissues obtained from mice after administration of the Compounds of this Description and ABT-199.

Figure 2 is an illustration (Western blot analysis) showing the expression of PARP and caspase-3 in RS4;11 xenograft tumor tissues obtained from mice after administration of the Compounds of this Description.

Figure 3 is a line graph showing the antitumor activity of Compound No. 6 in the RS4:11 xenograft leukemia model.

Figure 4 is a line graph showing the mouse weight after administration of Compound No. 6 into the RS4:11 xenograft leukemia model.

DETAILED DESCRIPTION OF THE ESSENCE OF THE INVENTION

The compounds of this Description inhibit Bcl-2 proteins, such as Bcl-2 and/or Bcl-xL. In view of this property, the Compounds of this Description can be used to treat or prevent diseases, disorders, or conditions, such as a hyperproliferative disease, such as a cancer, that are susceptible to inhibition of Bcl-2 proteins in a subject. Cancers susceptible to inhibition of Bcl-2 proteins include, but are not limited to, small cell lung cancer, NHL, AML, CLL, and ALL.

In one embodiment of the invention, the Compounds of this Description are compounds having Formula I-A:

I.A.,

or a pharmaceutically acceptable salt or solvate thereof, wherein:

A is selected from the group consisting of:

, , , , , , , , , And ;

E represents a carbon atom and represents a double bond; or

E is -C(H)- and represents a simple connection; or

E represents a nitrogen atom and represents a simple connection;

X1, X2, and X3 are each independently selected from the group consisting of -CR8= and -N=;

R1a and R1b, taken together with the carbon atom to which they are attached, form a 3-, 4-, or 5-membered optionally substituted cycloalkyl; or

R1a and R1b, taken together with the carbon atom to which they are attached, form a 4- or 5-membered optionally substituted heterocycle;

R2 is selected from the group consisting of -NO2, -SO2CH3, and -SO2CF3;

R2a is selected from the group consisting of hydrogen and halogen;

R3 is selected from the group consisting of hydrogen, -CN, -C≡CH, and -N(R4a)(R4b);

R4a is selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, heterocycle, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;

R4b is selected from the group consisting of hydrogen and C1-4 alkyl;

R5 is selected from the group consisting of optionally substituted C1-6 alkyl, heterocycle, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;

R6a, R6c, R6e, R6f, and R6g are each independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocycle, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl;

R6b and R6d are each independently selected from the group consisting of hydrogen, C1-4 alkyl, and halogen;

R7 is selected from the group consisting of optionally substituted C1-6 alkyl, heterocycle, heteroalkyl, (cycloalkyl)alkyl and (heterocyclo)alkyl; and

R8 is selected from the group consisting of hydrogen and halogen.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula I-A, wherein:

A is selected from the group consisting of A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, and A-9;

R4a is selected from the group consisting of optionally substituted C1-6 alkyl, heterocycle, heteroalkyl, (cycloalkyl)alkyl and (heterocyclo)alkyl; and

R6a, R6c, R6e, R6f, and R6g are each independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, heterocycle, heteroalkyl, (cycloalkyl)alkyl, and (heterocyclo)alkyl.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula I:

I,

or a pharmaceutically acceptable salt or solvate thereof, wherein:

E represents a carbon atom and represents a double bond; or

E is -C(H)- and represents a simple connection; or

E represents a nitrogen atom and represents a simple connection;

R1a and R1b, taken together with the carbon atom to which they are attached, form a 3-, 4-, or 5-membered optionally substituted cycloalkyl; or

R1a and R1b, taken together with the carbon atom to which they are attached, form a 4- or 5-membered optionally substituted heterocycle;

R2 is selected from the group consisting of -NO2, -SO2CH3, and -SO2CF3;

R3 is selected from the group consisting of hydrogen, -CN, -C≡CH, and -N(R4a)(R4b);

R4a is selected from the group consisting of optionally substituted C1-6 alkyl, heterocycle, (cycloalkyl)alkyl, and (heterocyclo)alkyl; and

R4b is selected from the group consisting of hydrogen and C1-4 alkyl.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula II:

II,

or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of -CH2- and -O-, and R2 and R4a are as defined in relation to Formula I.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula III:

III,

or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of -CH2- and -O-, and R2 and R4a are as defined in relation to Formula I.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula IV:

IV,

or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of -CH2- and -O-, and R2 and R4a are as defined in relation to Formula I.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula V:

V,

or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of -CH2- and -O-, and A, X1, X2, and X3 are as defined in relation to Formula I-A.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula VI:

VI,

or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of -CH2- and -O-, and A is as defined in relation to Formula I-A.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-1.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-2.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-3.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-4.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-5.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-6.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-7.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-8.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-9.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-10.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula VII:

VII,

or a pharmaceutically acceptable salt or solvate thereof, wherein Y is selected from the group consisting of -CH2- and -O-, and X1, X2, X3, R2, and R4a are as defined in relation to Formula I-A.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, and X3 are each -CH=.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is -CF=, and X2 and X3 are each -CH=.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X3 are each -CH=, and X2 is -CF=.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X2 are each -CH=, and X3 is -CF=.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is -N=, and X2 and X3 are each -CH=.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X3 are each -CH=, and X2 is -N=.

In another embodiment of the invention, the Compounds of this Description are compounds of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X2 are each -CH=, and X3 is -N=.

In another embodiment of the invention, the Compounds of this Description are compounds having any of Formulas II-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O-.

In another embodiment of the invention, the Compounds of this Description are compounds having any of Formulas II-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is CH2-.

In another embodiment of the invention, the Compounds of this Description are compounds having any of Formulas I-A or I-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -NO2.

In another embodiment of the invention, the Compounds of this Description are compounds having any of Formulas I-IV, or a pharmaceutically acceptable salt or solvate thereof, wherein R4a is selected from the group consisting of:

, , , , , , , , , , , , And .

In another embodiment of the invention, the Compounds of this Description are compounds having any of Formulas I-A or V-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein R4a, R5, R6a, and R7 are each independently selected from the group consisting of:

, , , , , , , , , , , , , , , And .

In another embodiment of the invention, the Compounds of this Description are compounds having Formula VIII:

VIII,

or a pharmaceutically acceptable salt or solvate thereof, wherein R2a is hydrogen or fluoro and R4a is as defined in relation to Formula I-A.

In another embodiment of the invention, the Compounds of this Description are compounds having Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R4a is selected from the group consisting of:

, , , , , , , , , , , , , , , And .

In another embodiment of the invention, the Compounds of this Description are compounds selected from one or more compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

Table 1

Conn. No. Structure Name 1 (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide 2 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 3 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 4 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitrophenyl)sulfonyl)benzamide 5 (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide 6 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide 7 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 8 (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide 9 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 10 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-(methylamino)-3-nitrophenyl)sulfonyl)benzamide 11 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-(dimethylamino)-3-nitrophenyl)sulfonyl)benzamide 12 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 13 (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl) piperazin-1-yl)benzamide 14 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)phenyl)sulfonyl)benzamide 15 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((piperidin-4-yl-methyl)amino)phenyl)sulfonyl)benzamide 16 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 17 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 18 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 19 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((oxetan-3-yl)methyl)amino)phenyl)sulfonyl)benzamide 20 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-cyano-3-nitrophenyl)sulfonyl)benzamide 21 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-ethynyl-3-nitrophenyl)sulfonyl)benzamide

In another embodiment of the invention, the Compounds of the invention are compounds selected from one or more compounds of Table 1-A, or a pharmaceutically acceptable salt or solvate thereof.

Table 1-A

Conn. No. Structure Name 22 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-fluoro-2-(2-(2-methoxyethoxy)ethyl)-4-nitro-2H-indazol-6-yl)sulfonyl)benzamide 23 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-3-oxo-2-(tetrahydro-2H-pyran-4-yl)-2,3,3a,7a-tetrahydro-1H-isoindol-5-yl)sulfonyl)benzamide 24 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((5-nitro-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrrol-3-yl)sulfonyl)benzamide 25 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((5-nitro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrol-3-yl)sulfonyl)benzamide 26 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-5-fluorobenzamide 27 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)picolinamide 28 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)nicotinamide 29 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-fluoro-5-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 30 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)picolinamide 31 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-((2-(2-methoxyethoxy)ethyl)amino)-3-nitrophenyl)sulfonyl)picolinamide 32 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)nicotinamide 33 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-6-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-((2-(2-methoxyethoxy)ethyl)amino)-3-nitrophenyl)sulfonyl)nicotinamide 34 3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-((2-(2-methoxyethoxy)ethyl)amino)-3-nitrophenyl)sulfonyl)picolinamide 35 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((1-(2-methoxyethyl)-5-nitro-1H-pyrrol-3-yl)sulfonyl)benzamide 36 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-3-fluorobenzamide 37 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-5-fluoro-N-((4-((2-(2-methoxyethoxy)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide 38 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-3-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-2,3,3a,7a-tetrahydro-1H-isoindol-5-yl)sulfonyl)benzamide 39 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-5-fluorobenzamide 40 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide 41 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 42 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide 43 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-3-fluoro-N-((4-((2-(2-methoxyethoxy)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide 44 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-2-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide 45 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-2-fluoro-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide 46 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-methyl-7-nitro-2H-indazol-5-yl)sulfonyl)benzamide 47 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide 48 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)sulfonyl)benzamide 49 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((1-methyl-7-nitro-1H-indazol-5-yl)sulfonyl)benzamide 50 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2H-indazol-5-yl)sulfonyl)benzamide 51 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-nitro-2H-indazol-6-yl)sulfonyl)benzamide 52 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((1-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)sulfonyl)benzamide 53 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide 54 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-(2-(2-methoxyethoxy)ethyl)-4-nitro-2H-indazol-6-yl)sulfonyl)benzamide 55 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-(2-methoxyethyl)-4-nitro-2H-indazol-6-yl)sulfonyl)benzamide 56 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-(naphthalen-2-ylsulfonyl)benzamide

In another embodiment of the invention, the Compound of this Description is a compound of Table 1-B, or a pharmaceutically acceptable salt or solvate thereof.

Table 1-B

Conn. No. Structure Name 57 (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-5-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)picolinamide

In another embodiment of the invention, the Compounds of the invention are compounds selected from one or more compounds of Table 1-C, or a pharmaceutically acceptable salt or solvate thereof.

Table 1-C

Conn. No. Structure Name 58 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-isopropyl-7-nitro-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide 59 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-cyclopropyl-7-nitro-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide 60 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazol-5-yl)sulfonyl)benzamide 61 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazol-5-yl)sulfonyl)benzamide 62 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-nitro-1-((tetrahydro-2H-pyran-4-yl)methyl)-3a,7a-dihydro-1H-indazol-6-yl)sulfonyl)benzamide 63 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-nitro-2-((tetrahydro-2H-pyran-4-yl)methyl)-2H-indazol-6-yl)sulfonyl)benzamide 64 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-nitro-1-(tetrahydro-2H-pyran-4-yl)-3a,7a-dihydro-1H-indazol-6-yl)sulfonyl)benzamide 65 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-6-yl)sulfonyl)benzamide 66 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2-(pyridin-4-yl)-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide

In another embodiment of the invention, the Compounds of this Description are selected from the group consisting of:

.

or their pharmaceutically acceptable salts or solvates.

In another embodiment of the invention, the Compounds of this Description are selected from the group consisting of:

.

or their pharmaceutically acceptable salts or solvates.

In another embodiment of the invention, the Compound of this Description is:

.

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the invention, this disclosure relates to a pharmaceutical composition comprising a Compound of this disclosure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

DEFINITIONS

In this description, the term "halogen", whether used alone or as part of another group, refers to -Cl, -F, -Br, or -I.

In this description, the term "nitro", used by itself or as part of another group, refers to -NO2.

In this description, the term "cyano", whether used by itself or as part of another group, refers to -CN.

In this description, the term "hydroxy" used by itself or as part of another group refers to -OH.

In this description, the term "amino", whether used alone or as part of another group, refers to -NH2.

As used herein, the term "alkyl" whether used alone or as part of another group refers to unsubstituted straight or branched aliphatic hydrocarbons having from one to twelve carbon atoms, i.e., C1-12 alkyl, or alkyl of the indicated number of carbon atoms, for example, C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, C1-3 alkyl such as methyl, ethyl, propyl, or isopropyl, etc. In one embodiment, the alkyl group is a straight C1-6 alkyl group. In another embodiment, the alkyl group is a branched C3-6 alkyl group. In another embodiment, the alkyl group is a straight C1-4 alkyl group. In another embodiment, the alkyl group is a branched C3-4 alkyl group. In another embodiment, the alkyl group is a straight or branched C3-4 alkyl group. In another embodiment, the alkyl group is partially or fully deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms. Non-limiting examples of C1-12 alkyl groups include methyl, -CD3, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting examples of C1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl. Non-limiting examples of C1-4 groups include methyl, ethyl, propyl, isopropyl, and tert-butyl.

As used herein, the term "optionally substituted alkyl," whether used alone or as part of another group, refers to alkyl that is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, and optionally substituted aryl. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. In another embodiment, the optionally substituted alkyl is unsubstituted. Non-limiting examples of optionally substituted alkyl groups include -CH2Ph, -CH2CH2NO2, -CH2CH2OH, -CH2CH2OCH3, and CH2CH2F.

As used herein, the term "cycloalkyl" whether used alone or as part of another group refers to unsubstituted saturated or partially unsaturated, e.g., containing one or two double bonds, cyclic aliphatic hydrocarbons containing one to three rings having three to twelve carbon atoms, i.e., C3-12 cycloalkyl, or cycloalkyl of the indicated number of carbon atoms. In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is C3-8 cycloalkyl. In another embodiment, the cycloalkyl group is C3-6 cycloalkyl. In another embodiment, the cycloalkyl group is C3-5 cycloalkyl. The term "cycloalkyl" is intended to include groups in which the -CH2- unit is replaced with -C(=O)-. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, cyclopentanone, spiro[3.3]heptane, and bicyclo[3.3.1]nonane.

As used herein, the term "optionally substituted cycloalkyl," whether used alone or as part of another group, refers to a cycloalkyl that is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocycle. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In another embodiment, the optionally substituted cycloalkyl is unsubstituted.

As used herein, the term "haloalkyl" when used alone or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two, or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl group is a C1-4 haloalkyl group. Non-limiting examples of haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

As used herein, the term "alkoxy" used alone or as part of another group refers to an optionally substituted alkyl attached to a terminal oxygen atom. In one embodiment, an alkoxy group is a C1-6 alkyl attached to a terminal oxygen atom. In another embodiment, an alkoxy group is a C1-4 alkyl attached to a terminal oxygen atom. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy groups.

As used herein, the term "aryl" used alone or as part of another group refers to unsubstituted monocyclic or bicyclic aromatic ring systems having six to fourteen carbon atoms, i.e., C6-14 aryl. Non-limiting examples of aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl.

As used herein, the term "optionally substituted aryl," as used herein by itself or as part of another group, refers to an aryl that is unsubstituted or substituted with one to five substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocycle. In one embodiment, the optionally substituted aryl is optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl is unsubstituted. Non-limiting examples of substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, and 4-chlorophenyl.

As used herein, the term "heterocycle" whether used alone or as part of another group refers to unsubstituted saturated and partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two or three rings having from three to fourteen ring members, i.e., from 3- to 14-membered heterocycles, wherein at least one carbon atom of one of the rings is replaced by a heteroatom. The term "heterocycle" is intended to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as β-lactam, γ-lactam, δ-lactam and ε-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one. In one embodiment, the heterocyclyl group is a 4-, 5-, 6-, 7-, or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclyl group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclyl group is an 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. In one embodiment, the heterocyclyl group is a 4- or 5-membered cyclic group containing one ring and one oxygen atom. The heterocycle may optionally be bonded to the remainder of the molecule through a carbon or nitrogen atom. Non-limiting examples of heterocyclyl groups include 1,4-dioxane, 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, and 1,3-dihydro-2H-benzo[d]imidazol-2-one.

As used herein, the term "optionally substituted heterocycle," as used herein by itself or as part of another group, refers to a heterocycle that is unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, and heterocycle. Non-limiting examples of optionally substituted heterocyclyl groups include:

.

As used herein, the term "alkylamino" used alone or as part of another group refers to -NHR10, wherein R10 is C1-6 alkyl. In one embodiment, R10 is C1-4 alkyl. Non-limiting examples of alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

As used herein, the term "dialkylamino," whether used alone or as part of another group, refers to -NR11aR11b, wherein R11a and R11b are each independently C1-6 alkyl. In one embodiment, R11a and R11b are each independently C1-4 alkyl. Non-limiting examples of dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

As used herein, the term "(cycloalkyl)alkyl," whether used alone or as part of another group, refers to alkyl substituted with one optionally substituted cycloalkyl group. In one embodiment, the (cycloalkyl)alkyl is C1-4 alkyl substituted with one optionally substituted C3-6 cycloalkyl. In one embodiment, the optionally substituted cycloalkyl group is substituted with a heterocyclyl group. Non-limiting examples of (cycloalkyl)alkyl groups include:

.

As used herein, the term "(heterocyclo)alkyl" used alone or as part of another group refers to alkyl substituted with one optionally substituted heterocyclyl group. In one embodiment, (heterocyclo)alkyl is C1-4 alkyl substituted with one optionally substituted 4-6 membered heterocyclyl group. The heterocycle may be bonded to the alkyl group through a carbon or nitrogen atom. Non-limiting examples of (heterocyclo)alkyl groups include:

, , , , , , , , , , And .

As used herein, the term "heteroalkyl" whether used alone or as part of another group refers to unsubstituted straight or branched aliphatic hydrocarbons having six to twelve chain atoms, i.e., 6- to 12-membered heteroalkyl, or heteroalkyl of the indicated number of chain atoms, wherein at least two -CH2- groups are independently replaced with -O-, -N(H)-, or -S-. The -O-, -N(H)-, or -S- groups may be independently placed at any internal position on the aliphatic hydrocarbon chain, so long as each -O-, -N(H)-, or -S- group is separated by at least two -CH2- groups. In one embodiment, two -CH2- groups are replaced by two -O- groups. In another embodiment, three -CH2- groups are replaced by three -O- groups. Non-limiting examples of heteroalkyl groups include -CH2CH2OCH2CH2 OCH3, -CH2CH2OCH2CH2N(H)CH3, and -CH2CH2OCH2CH2OCH2CH2OCH3.

This disclosure encompasses any of the Compounds of this disclosure that is isotopically labeled (i.e., labeled with a radioactive isotope) by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of isotopes that can be introduced into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H (or deuterium (D)), 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively, such as 3H, 11C, and 14C. In one embodiment, the invention provides a composition in which substantially all of the atoms within a Compound of this disclosure are replaced with an atom having a different atomic mass or mass number. In another embodiment of the invention, a composition is provided in which a portion of the atoms within a Compound of this Description are replaced, i.e., the Compound of this Description is enriched at a position with an atom having a different atomic mass or mass number. Isotopically labeled Compounds of this Description can be prepared by methods known in the art.

The compounds of this disclosure may contain one or more centers of asymmetry and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms. This disclosure is intended to cover the use of all such possible forms, including racemic and resolved forms, as well as mixtures thereof. Individual stereoisomers, for example enantiomers, may be separated according to methods known in the art in light of this disclosure. When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, this is meant to include both E and Z geometric isomers. All tautomers are also intended to be included in this disclosure.

As used in this document, the term "stereoisomers" or "stereoisomeric forms" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereomers).

The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and is therefore optically active, with the enantiomer rotating the plane of polarized light in one direction and its mirror image rotating the plane of polarized light in the opposite direction.

The term "racemic" refers to a mixture of equal parts of enantiomers that is optically inactive.

The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral chemical compound (or group) and its stereochemical description, such as R or S.

Stereochemical terms and conventions used in the description of the invention are intended to correspond to those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

The term "enantiomeric excess" or "ee" refers to a measure of how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│*100, where R and S are the respective mole or weight fractions of the enantiomers in the mixture, such that R+S=1. When the optical rotation of a chiral substance is known, the percent enantiomeric excess is defined as ([α]obs/[α]max)*100, where [α]obs is the optical rotation of the mixture of enantiomers, and [α]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry.

The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance in which all molecules (within the limits of detection) have the same chirality. In one embodiment, the Compounds of this disclosure that have one or more chiral centers are enantiopure.

The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance that has an enantiomeric excess of greater than 50%, such as about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more. Enantiomerically enriched compounds may be enantiomerically pure. In one embodiment, the Compounds of this disclosure that have one or more chiral centers are enantioenriched.

The use of terms in the singular also implies the plural for these terms.

As used herein, the term "about" includes the given number ± 10%. Thus, "about 10" means from 9 to 11.

This disclosure covers the preparation and use of salts of the Compounds of this disclosure, including non-toxic pharmaceutically acceptable salts. Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and base salts. Pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt, and the like; alkaline earth metal salts such as calcium, magnesium salt, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; and amino acid salts such as arginate, aspartate, glutamate, etc. The term "pharmaceutically acceptable salt" as used herein refers to any salt, such as that formed by reaction with an acid or base, of the Compound of this disclosure that is physiologically tolerable to the intended patient (e.g., a mammal, such as a human).

Acid addition salts can be prepared by mixing a solution of a particular Compound of this Description with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like. Basic salts can be prepared by mixing a solution of a compound of this Description with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like.

This disclosure encompasses the preparation and use of solvates of the Compounds of this disclosure. Solvates generally do not substantially alter the physiological activity or toxicity of the compounds and, as such, can function as pharmacological equivalents. As used herein, the term "solvate" means a combination, physical association, and/or solvation of a compound of this disclosure with a solvent molecule, such as, for example, a disolvate, monosolvate, or hemisolvate, wherein the ratio of solvent molecules to the compound of this disclosure is about 2:1, about 1:1, or about 1:2, respectively. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both the solution phase and solvates that can be isolated. The compounds of this Description may be present as solvated forms with a pharmaceutically acceptable solvent such as water, methanol, ethanol, etc., and the description is intended to include both solvated and unsolvated forms of the Compounds of this Description.

In one embodiment, the solvate is a hydrate. "Hydrate" refers to a particular subgroup of solvates wherein the solvent molecule is a water molecule. Solvates can generally function as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of fluconazole solvates with ethyl acetate and water. Similar preparations of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting method for preparing the solvate comprises dissolving the Compound of this Description in the desired solvent (organic, water, or mixtures thereof) at a temperature of 20 to 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, such as filtration. Analytical methods such as infrared spectroscopy can be used to confirm the presence of solvent in the solvate crystal.

The compounds of this Description are inhibitors of Bcl-2 proteins, such as Bcl-2 and/or Bcl-XL, and thus treatment or prevention of a number of diseases, conditions or disorders mediated by Bcl-2 proteins is possible by administering these compounds to a subject. This Description is therefore generally directed to a method of treating or preventing a disease, condition or disorder responsive to inhibition of Bcl-2 proteins, such as Bcl-2 and/or Bcl-XL, in an animal suffering from or at risk of the disease, condition or disorder. This method comprises administering to the animal an effective amount of one or more Compounds of this Description.

This description is further directed to a method of inhibiting Bcl-2 proteins in an animal, such as a human, in need thereof, which method comprises administering to the animal a therapeutically effective amount of at least one Compound of this Description.

This disclosure is further directed to a method of inhibiting Bcl-2 in an animal, such as a human, in need thereof, which method comprises administering to the animal a therapeutically effective amount of at least one Compound of this disclosure.

This disclosure is further directed to a method of inhibiting Bcl-XL in an animal, such as a human, in need thereof, which method comprises administering to the animal a therapeutically effective amount of at least one Compound of this disclosure.

As used herein, the terms "treat", "treatment" and the like refer to the elimination, reduction or amelioration of a disease or condition and/or its associated symptoms. Although not excluded, treatment of a disease or condition does not require the complete elimination of the disease, condition or its associated symptoms. The term "treat" and synonyms include the administration of a therapeutically effective amount of a Compound of this Description to a subject in need of such treatment. Treatment may be symptomatic, such as symptom suppression. It may be short-term, medium-term, or may be a long-term treatment, such as in the context of maintenance therapy.

As used herein, the terms "prevent," "prevention," and "prophylaxis" refer to a method of preventing the occurrence of a disease or condition and/or its associated symptoms or protecting a subject from contracting a disease. As used herein, the terms "prevent," "prevention," and "prophylaxis" also include delaying the onset of a disease and/or its associated symptoms and reducing the risk of a subject contracting a disease. The terms "prevent," "prevention" may include "prophylactic treatment," which refers to reducing the likelihood of a recurrence of a disease or condition, or a relapse of a previously controlled disease or condition, in a subject who is not ill but is at risk or susceptible to a recurrence of the disease or condition or a relapse of the disease or condition.

As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of active ingredient(s) that is/are sufficient, when administered by the method described herein, to effectively deliver the active ingredient(s) to treat the condition or disease of interest to a person in need thereof. In the case of cancer or other proliferative disorder, a therapeutically effective amount of the agent can reduce (i.e., slow to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow to some extent and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in target cells; and/or relieve, to some extent, one or more symptoms associated with the cancer. To the extent that the administered compound or composition prevents the growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.

The term "container" means any container or vessel suitable for storing, transporting, dispensing and/or handling a pharmaceutical product.

The term "package insert" means information included with a pharmaceutical product that describes how to administer the product and provides safety and efficacy information necessary to enable the physician, pharmacist, and patient to make an informed decision regarding the use of the product. A package insert is generally considered the "label" for a pharmaceutical product.

As used herein, the term “Bcl-2 proteins” or “Bcl-2 family of proteins” refers to any one or more of the following proteins: Bax, Bak, Bid, Bcl-2, Bcl-xL, Mcl-1, Bcl-w, Bfl-1/A1, Bim, Puma, Bad, Bik/Blk, Noxa, Bmf, Hrk/DP5, and Beclin-1. See Cold Spring Harb Perspect Biol 2013;5:a008714.

The term "disease" or "condition" or "disorder" refers to disorders and/or abnormalities that are generally considered pathological conditions or functions, and which may manifest as specific signs, symptoms and/or dysfunctions. The compounds of this Description inhibit Bcl-2 proteins, such as Bcl-2 and/or Bcl-xL, and can be used to treat or prevent diseases, conditions or disorders, such as hyperproliferative diseases, in which inhibition of Bcl-2 proteins results in a beneficial effect.

The term "hyperproliferative disease" refers to any condition in which a localized population of proliferating cells in an animal is not regulated by the normal constraints of normal growth. In one embodiment, the hyperproliferative disease is cancer.

In some embodiments, the Compounds of this disclosure may be used to treat a "Bcl-2-mediated disorder," such as a Bcl-2-mediated disorder and/or a Bcl-xL-mediated disorder. A Bcl-2-mediated disorder is any pathological condition in which Bcl-2 is known to play a role. In one embodiment, the Bcl-2-mediated disorder is a hyperproliferative disorder. In one embodiment, the Bcl-2-mediated disorder is cancer.

In one embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 10 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 5 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 1 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.5 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.1 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.05 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.025 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.010 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.005 μM. In another embodiment, the Compounds of this disclosure have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.0025 μM. In another embodiment of the invention, the Compounds of this Description have an IC50 for Bcl-2 and/or Bcl-xL of less than about 0.001 μM.

In one embodiment of the invention, this disclosure relates to a method of treating or preventing a hyperproliferative disease in a subject, such as a human, comprising administering a therapeutically effective amount of a Compound of this disclosure.

In another embodiment, the disclosure relates to a method of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of a Compound of the disclosure. While not limited to a particular mechanism, in some embodiments, the Compounds of the disclosure may treat or prevent cancer by inhibiting Bcl-2 proteins, such as Bcl-2 and/or Bcl-xL. Examples of treatable cancers include, but are not limited to, one or more of the cancers in Table 2.

Table 2

adrenal cancer lymphoepithelioma acinar cell tumor lymphoma acoustic neuroma acute lymphocytic leukemia acral lentiginous melanoma acute myeloid leukemia acrospiroma chronic lymphocytic leukemia acute eosinophilic leukemia liver cancer acute erythroid leukemia small cell lung cancer acute lymphoblastic leukemia non-small cell lung cancer acute megakaryoblastic leukemia MALT lymphoma acute monocytic leukemia malignant fibrous histiocytoma acute promyelocytic leukemia malignant tumor of the peripheral nerve sheaths adenocarcinoma malignant newt tumor adenoid cystic carcinoma mantle cell lymphoma adenoma Marginal zone B-cell lymphoma adenomatoid odontogenic tumor mast cell leukemia adenosquamous carcinoma mediastinal germ cell tumor adipose tissue neoplasms medullary breast cancer adrenocortical cancer medullary thyroid cancer, adult T-cell leukemia/lymphoma medulloblastoma aggressive NK cell leukemia melanoma, AIDS-associated lymphoma meningioma, alveolar rhabdomyosarcoma Merkel cell cancer alveolar soft tissue sarcoma mesothelioma ameloblastic fibroma metastatic urothelial carcinoma anaplastic large cell lymphoma mixed Müllerian tumor anaplastic thyroid cancer mucinous tumor angioimmunoblastic T-cell lymphoma, multiple myeloma angiomyolipoma muscle tissue neoplasms angiosarcoma fungal mycosis astrocytoma myxoid liposarcoma atypical teratoid rhabdoid tumor cardiac myxoma B-cell chronic lymphocytic leukemia malignant myxoma of the heart B-cell prolymphocytic leukemia nasopharyngeal carcinoma B-cell lymphoma neurinoma basalioma neuroblastoma bile duct cancer neurofibroma bladder cancer neuroma blastoma nodular melanoma bone cancer eye cancer Brenner's tumor oligoastrocytoma Brown tumor oligodendroglioma Burkitt's lymphoma oncocytoma breast cancer optic nerve sheath meningioma brain cancer optic nerve tumor carcinoma oral cancer preinvasive cancer osteosarcoma carcinosarcoma ovarian cancer cartilage tumor Pancoast tumor cementoma papillary thyroid cancer myeloid sarcoma paraganglioma chondroma pineoblastoma chordoma pineocytoma choriocarcinoma pituicytoma choroid papilloma pituitary adenoma clear cell sarcoma of the kidney pituitary tumor craniopharyngioma plasmacytoma cutaneous T-cell lymphoma polyembryoma cervical cancer T-lymphoblastic progenitor cell lymphoma colorectal cancer primary central nervous system lymphoma Degos disease primary effusion lymphoma desmoplastic small round cell tumor primary peritoneal cancer diffuse large B-cell lymphoma prostate cancer dysembryoplastic neuroepithelial tumor, pancreatic cancer dysgerminoma pharyngeal cancer embryonal carcinoma pseudomyxoma peritonei neoplasms of the endocrine system renal cell carcinoma endodermal sinus tumor medullary renal carcinoma Enteropathy-associated T-cell lymphoma retinoblastoma esophageal cancer rhabdomyoma fetus in fetus rhabdomyosarcoma fibroma Richter transform fibrosarcoma rectal cancer follicular lymphoma sarcoma follicular thyroid cancer Schwannomatosis ganglioneuroma seminoma gastrointestinal cancer Sertoli cell tumors gonocytoma sex cord stromal tumor gestational choriocarcinoma signet ring cell carcinoma giant cell fibroblastoma skin cancer giant cell tumor of bone small round cell tumors glial tumor small cell carcinoma glioblastoma multiforme soft tissue sarcoma glioma somatostatinoma gliomatosis cerebri scrotal cancer glucagonoma spinal cord tumor gonadoblastoma splenic marginal zone lymphoma granulosa cell tumor squamous cell carcinoma gynandroblastoma synovial sarcoma gallbladder cancer Sezary disease stomach cancer small bowel cancer hairy cell leukemia squamous cell carcinoma hemangioblastoma stomach cancer head and neck tumors T-cell lymphoma hemangiopericytoma testicular cancer hemoblastosis tekoma hepatoblastoma thyroid cancer hepatosplenic T-cell lymphoma transitional cell carcinoma Hodgkin's lymphoma throat cancer non-Hodgkin's lymphoma urachus cancer invasive lobular carcinoma cancer of the genitourinary system bowel cancer urothelial carcinoma kidney cancer uveal melanoma laryngeal cancer uterine cancer lentiginous melanoma verrucous carcinoma lethal median carcinoma optic tract glioma leukemia vulvar cancer Leydig cell tumor vaginal cancer liposarcoma Waldenstrom's macroglobulinemia lung cancer Warthin's tumor lymphangioma Wilms tumor lymphangiosarcoma

In another embodiment of the invention, the cancer is breast, cervical, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.

In another embodiment of the invention, the cancer is a hematological malignancy, such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).

In another embodiment, the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.

In another embodiment, the cancer is a leukemia, such as a leukemia selected from acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and undifferentiated leukemia (MLL). In another embodiment, the cancer is a midline carcinoma having a NUT rearrangement. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is a lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is a neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment of the invention, the cancer is prostate cancer. In another embodiment of the invention, the cancer is breast cancer.

In another embodiment of the invention, the cancer is adrenocortical cancer, urothelial carcinoma of the bladder, invasive breast carcinoma, colorectal adenocarcinoma, diffuse large B-cell lymphoma, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, lung adenocarcinoma, squamous cell lung cancer, serous cystadenocarcinoma of the ovary, pancreatic adenocarcinoma, prostate adenocarcinoma, clear cell carcinoma of the kidney, cutaneous melanoma, gastric adenocarcinoma, uterine carcinosarcoma, or endometrial and uterine carcinoma.

In another embodiment of the invention, this disclosure relates to a therapeutic method for modulating gene expression, cell proliferation, cell differentiation, and/or apoptosis in vivo in cancer, such as the cancers mentioned above, by administering a therapeutically effective amount of a Compound of this disclosure to a subject in need of such therapy.

The compounds of this Description may be administered to a subject in the form of the pure compound without containing other components. The compounds of this Description may also be administered to a subject as part of a pharmaceutical composition containing the compound, in combination with one or more suitable pharmaceutically acceptable carriers. Such carriers may be selected from pharmaceutically acceptable excipients and excipients. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable carriers include aqueous carriers and non-aqueous carriers. Standard pharmaceutical carriers and techniques for their preparation are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

Pharmaceutical compositions within the scope of this disclosure include all compositions in which a Compound of this disclosure is in combination with one or more pharmaceutically acceptable carriers. In one embodiment, a Compound of this disclosure is present in the composition in an amount that is effective to achieve the intended therapeutic application. Although individual needs may vary, determination of optimal ranges of effective amounts of each compound is within the skill of the art. Typically, a Compound of this disclosure, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, can be administered to a mammal, such as a human, orally at a dose of about 0.0025 to about 1500 mg per kg of body weight of the mammal, per day to treat a particular disorder. A useful oral dose of the Compound of this Description, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, administered to a mammal is from about 0.0025 to about 50 mg per kg of body weight of the mammal. For intramuscular injection, the dose is typically about half the oral dose.

A single oral dose may contain from about 0.01 mg to about 1 g of the Compound of this Description, for example, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 100 mg, from 0.01 mg to about 50 mg, for example, from about 0.1 mg to about 10 mg of the compound. The single dose may be administered one or more times per day, for example, in the form of one or more tablets or capsules each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.

A compound of this Description or a pharmaceutical composition comprising a Compound of this Description may be administered to any patient or subject that can experience the beneficial effects of a Compound of this Description. Preferably, such patients or subjects are mammals, such as humans and domestic animals, although the description is not intended to be so limiting. In one embodiment, the patient or subject is a human.

The Compound of this Description or a pharmaceutical composition comprising the Compound of this Description may be administered by any route that achieves the intended area of application. For example, administration may be by oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal routes, or by inhalation. The dose administered and the route of administration will vary with the circumstances of the particular subject and take into account such factors as the age, sex, health and weight of the recipient, the condition or disorder being treated, the type of concurrent treatment, if any, the frequency of treatment and the nature of the effect desired.

In one embodiment of the invention, the Compound of this Description or a pharmaceutical composition comprising the Compound of this Description can be administered orally. In another embodiment of the invention, the pharmaceutical composition of this Description can be administered orally in the form of tablets, pills, capsules or a liquid dosage form. In one embodiment of the invention, the oral composition comprises a plurality of extruded particles comprising the Compound of this Description.

According to another embodiment, the Compound of this Description or a pharmaceutical composition containing the Compound of this Description may be administered rectally in the form of suppositories.

According to another embodiment, the Compound of this Description or a pharmaceutical composition containing the Compound of this Description may be administered by injection.

According to another embodiment, the Compound of this Description or a pharmaceutical composition comprising the Compound of this Description may be administered transdermally.

According to another embodiment, the Compound of this Description or a pharmaceutical composition comprising the Compound of this Description may be administered by inhalation or by an intranasal or transmucosal route of administration.

According to another embodiment, the Compound of this Description or a pharmaceutical composition containing the Compound of this Description can be administered intravaginally.

The pharmaceutical composition of this disclosure may contain from about 0.01 to 99 percent by weight, such as from about 0.25 to 75 percent by weight, of the Compound of this disclosure, such as about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of the Compound of this disclosure.

The pharmaceutical composition according to this description is produced by a process which will be known per se in the context of this description, for example by means of standard processes of mixing, granulation, dragee preparation, dissolution, extrusion or lyophilization. Thus, pharmaceutical compositions for oral use can be prepared by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliary substances, if desired or necessary, to obtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (e.g. lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (e.g. tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, corn starch, wheat starch, rice starch or potato starch), gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

Excipients are generally flow regulators and lubricants, such as, for example, silicon dioxide, talc, stearic acid or its salts (for example, magnesium stearate or calcium stearate), and polyethyleneglycol. The dragee cores are provided with suitable coatings resistant to gastric juice. For this field of application, concentrated solutions of saccharides can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium dioxide, varnish solutions and suitable organic solvents or solvent mixtures. For the preparation of coatings resistant to gastric juice, solutions of suitable cellulose preparations can be used, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the coatings of tablets or dragees, for example for identification or to characterize combinations of doses of the active compound.

Examples of other pharmaceutical preparations that can be administered orally include hard capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Hard capsules may contain the compound in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of a plurality of extruded particles. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids such as fatty oils or liquid paraffin. In addition, stabilizers may be added.

Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base. Suitable suppository bases include, among others, natural and synthetic triglycerides and paraffin hydrocarbons. It is also possible to use gelatin rectal capsules, which consist of a combination of an active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol or a paraffin hydrocarbon.

Suitable compositions for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, an alkaline solution, or an acidic solution. According to another embodiment, a suspension of the active compound can be prepared as an oil suspension. Suitable lipophilic solvents or vehicles for such a suspension can include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or polyethylene glycol, such as polyethylene glycol-400 (PEG-400). The aqueous suspension can contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethylcellulose, sorbitol, and/or dextran. The suspension can optionally contain stabilizers.

In another embodiment, this disclosure relates to kits that contain a Compound of this disclosure (or a pharmaceutical composition comprising a Compound of this disclosure) packaged in a manner that facilitates their use in carrying out the methods of this disclosure. In one embodiment, a kit includes a Compound of this disclosure (or a pharmaceutical composition comprising a Compound of this disclosure) packaged in a container, such as a sealed bottle or jar, with a label affixed to the container or included in the kit that describes the use of the compound or composition in carrying out the methods of this disclosure. In one embodiment, the compound or composition is packaged in a single-dose dosage form. Additionally, the kit may include a device suitable for administering the composition according to the intended route of administration.

In another embodiment of the invention, the Compound of this Description is administered to a subject in combination with a second therapeutic agent. The second therapeutic agent is different from the Compound of this Description. The Compound of this Description and the second therapeutic agent may be administered simultaneously or sequentially to achieve the desired effect. In addition, the Compound of this Description and the second therapeutic agent may be administered from a single composition or two separate compositions.

The second therapeutic agent is administered in an amount that provides its desired therapeutic effect. The range of effective doses for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to a subject in need thereof within such established ranges.

The compound of this Description and the second therapeutic agent may be administered together as a single dose or separately as multiple doses, with the Compound of this Description being administered before the second therapeutic agent or vice versa. One or more doses of the Compound of this Description and/or one or more doses of the second therapeutic agent may be administered. The compound of this Description may therefore be used in combination with one or more second therapeutic agents, such as, but not limited to, anticancer agents.

In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drug" refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

In another embodiment of the invention, chemotherapeutic agents or other antiproliferative agents can be combined with a Compound of this Description to treat proliferative diseases and cancer. Examples of treatments and anticancer agents that can be used in combination with the Compounds of this Description include surgery, radiation therapy (e.g., gamma radiation, neutron radiation therapy, electron beam therapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biological response modifier (e.g., interferon, interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved chemotherapeutic agent.

Examples of antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an antiestrogen; an antiandrogen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule-active agent; an alkylating agent; a retinoid, carotenoid, or tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platinum compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematological malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; a MEK inhibitor; an antitumor antibiotic; a nitrosourea; a compound that specifically targets/reduces the activity of a protein kinase or lipid kinase, a compound that specifically targets/reduces the activity of a protein phosphatase or lipid phosphatase, or any other antiangiogenic compound.

Non-limiting examples of aromatase inhibitors include, but are not limited to, steroids such as atamestane, exemestane, and formestane, and non-steroids such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole.

Non-limiting antiestrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Antiandrogens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

Typical topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones such as mitoxantrone and losoxantrone; and podophyllotoxins such as etoposide and teniposide.

Microtubule-active substances include microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubule polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine, vinblastine sulfate, vincristine and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and their derivatives.

Non-limiting examples of alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosourea derivatives such as carmustine and lomustine.

Non-limiting examples of cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives thereof such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid and derivative thereof such as lumiracoxib.

Non-limiting examples of matrix metalloproteinase inhibitors ("MMP inhibitors") include peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12 9566, TAA211, MMI2996, and MMI299B.

Non-limiting examples of mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus, everolimus, CCI-779, and ABT578.

Non-limiting examples of antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed.

Non-limiting examples of platinum compounds include carboplatin, cis-platin, cisplatin, and oxaliplatin.

Non-limiting examples of methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.

Non-limiting examples of bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

Non-limiting examples of antiproliferative antibodies include trastuzumab, trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term "antibody" is intended to include intact monoclonal antibodies, polyclonal antibodies, polyspecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

Non-limiting examples of heparanase inhibitors include compounds that specifically target, reduce, or inhibit the degradation of heparin sulfate, such as PI-88 and OGT2115.

As used herein, the term "inhibitor of oncogenic Ras isoforms" such as H-Ras, K-Ras or N-Ras refers to a compound that specifically targets, reduces or inhibits the oncogenic activity of Ras, such as a farnesyl transferase inhibitor such as L-744832, DK8G557, tipifarnib and lonafarnib.

Non-limiting examples of telomerase inhibitors include compounds that specifically target, reduce, or inhibit telomerase activity, such as compounds that inhibit the telomerase receptor, such as telomestatin.

Non-limiting examples of proteasome inhibitors include compounds that specifically target, reduce, or inhibit the activity of the proteasome, including, but not limited to, bortezomid.

As used herein, the phrase "compounds used to treat hematological malignancies" includes FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, β-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase.

Non-limiting examples of Flt-3 inhibitors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.

Non-limiting examples of HSP90 inhibitors include compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; or degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 include, but are not limited to, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino-17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

The phrase "a compound that targets/reduces protein kinase or lipid kinase activity, or protein phosphatase or lipid phosphatase activity, or any other antiangiogenic compound" as used herein includes a protein tyrosine kinase and/or serine kinase and/or threonine kinase inhibitor, or a lipid kinase inhibitor, such as a) a compound that targets, reduces, or inhibits platelet-derived growth factor receptors (PDGFR) activity, such as a compound that targets, reduces, or inhibits PDGFR activity, such as N-phenyl-2-pyrimidineamine derivatives such as imatinib, SU101, SU6668, and GFB-111; b) a compound that targets, reduces, or inhibits fibroblast growth factor receptors (FGFR) activity; c) a compound that targets, reduces, or inhibits the activity of the insulin-like growth factor I receptor (IGF-IR), such as a compound that targets, reduces, or inhibits the activity of IGF-IR; d) a compound that targets, reduces, or inhibits the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) a compound that targets, reduces, or inhibits the activity of the Axl receptor tyrosine kinase family; f) a compound that targets, reduces, or inhibits the activity of the Ret receptor tyrosine kinase; g) a compound that targets, reduces, or inhibits the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) a compound that targets, reduces, or inhibits the activity of c-Kit receptor tyrosine kinases, such as imatinib; i) a compound that targets, reduces, or inhibits the activity of members of the c-Abl family, their gene fusion products (e.g., Bcr-Abl kinase), and mutants such as an N-phenyl-2-pyrimidineamine derivative such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound that targets, reduces, or inhibits the activity of members of the protein kinase C (PKC) family and the Raf family of serine/threonine kinases, members of MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and members of the Ras/MAPK family, and/or members of the cyclin-dependent kinase (CDK) family, such as a staurosporine derivative described in U.S. Patent No. 5,093,330, such as midostaurin; Examples of other compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; an isoquinoline compound; a farnesyl transferase inhibitor; PD184352 or QAN697 or AT7519; k) a compound that targets, reduces or inhibits protein tyrosine kinase activity such as imatinib mesylate or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; (+) enantiomer of Tyrphostin B44; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid adamantyl ester); NSC 680410, adaphostin); l) a compound that specifically targets, reduces or inhibits the activity of the epidermal growth factor receptor family of tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and 7H-pyrrolo[2,3-d]pyrimidine derivatives; and m) a compound that targets, reduces or inhibits c-Met receptor activity.

Typical compounds that specifically target, reduce, or inhibit the activity of a protein or lipid phosphatase include phosphatase 1, phosphatase 2A, or CDC25 inhibitors such as okadaic acid or its derivative.

Other antiangiogenic compounds include compounds that have a mechanism of activity other than protein kinase or lipid kinase inhibition, such as thalidomide and TNP-470.

Additional non-limiting examples of chemotherapeutic compounds, one or more of which may be used in combination with a Compound of this disclosure include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H-isoindole-1,3-dione derivatives, 1-(4)-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors, FLT-3 inhibitors, IgG1 antibodies to VEGFR-2, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocortisone, cortexolone, 17a-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloid, hormonal compound and/or antagonist, biological response modifier such as a lymphokine or interferon, antisense oligonucleotide or oligonucleotide derivative, shRNA and siRNA.

Other examples of second therapeutic agents, with one or more of which the Compound of this Description may also be combined, include, but are not limited to: an agent for treating Alzheimer's disease, such as donepezil and rivastigmine; an agent for treating Parkinson's disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl and amantadine; an agent for treating multiple sclerosis (MS), such as beta-interferon (e.g., AVONEX® and REBIF®), glatiramer acetate and mitoxantrone; an agent for treating asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel and haloperidol; an anti-inflammatory agent such as a corticosteroid, TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent including immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor such as an acetylcholinesterase inhibitor, MAO inhibitor, interferon, anticonvulsant, ion channel blocker, riluzole, or an antiParkinson's disease agent; an agent for treating cardiovascular disease such as a beta blocker, ACE inhibitor, diuretic, nitrate, calcium channel blocker, or statin; an agent for treating liver disease such as a corticosteroid, cholestyramine, interferon, and an antiviral agent; a drug to treat a blood disorder, such as a corticosteroid, an antileukemia drug, or a growth factor; or a drug to treat an immunodeficiency disorder, such as gamma globulin.

The above-mentioned second therapeutically active agents, one or more of which may be used in combination with the Compound of this Description, are prepared and administered as described in the art.

GENERAL SCHEME OF SYNTHESIS OF COMPOUNDS

The compounds of this Description are prepared using methods known to those skilled in the art in view of this Description, or by the illustrative methods shown in the General Schemes below. In the General Schemes, R2 and R4a are as defined in connection with Formula I, and Y is as defined in connection with Formula II.

General Scheme 1

In General Scheme 1, Compound A is contacted with R4aNH2 in the presence of a base such as triethylamine to give Compound B.

General Scheme 2

In General Scheme 2, methyl 4-bromo-2-fluorobenzoate is contacted with Compound C to give Compound D, and the ester of Compound D is hydrolyzed to give Compound E. Compound E is cross-coupled with Compound B from General Scheme 1 to give Compound F.

General Scheme 3

In General Diagram 3, Connection G becomes Connection H.

General Scheme 4

In General Scheme 4, Compound H from General Scheme 3 is contacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine to provide Compound I. Compound I is cross-coupled with Compound F from General Scheme 2 to provide a compound having Formula IV.

General Scheme 5

In General Scheme 5, Compound H from General Scheme 3 is contacted with a Boc-protected piperidine to give Compound J, and the Boc group is removed to give Compound K. Compound K is contacted with methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate to give Compound L, and the ester of Compound L is hydrolyzed to give Compound M. Compound M is cross-coupled with Compound B from General Scheme 1 to give a compound having Formula II.

EXAMPLES

EXAMPLE 1

Synthetic intermediates

INTERMEDIATE 1: Synthesis of 1-cyclobutylidenepropan-2-one

To a solution of cyclobutanone (5.0 g, 71.4 mmol) in toluene (200 mL) was added 1-(triphenylphosphoranylidene)-2-propanone (22.7 g, 71.4 mmol), and the mixture was heated under reflux overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane 1/10-1/5) to give 1-cyclobutylidenepropan-2-one (5.0 g) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.95-5.93 (m, 1H), 3.19-3.13 (m, 2H), 2.91-2.84 (m, 2H), 2.21 (s, 3H), 2.21-2.11 (m, 2H).

INTERMEDIATE 2: Synthesis of Spiro[3,5]nonane-6,8-dione.

To a solution of 1-cyclobutylidenepropan-2-one (23.1 g, 0.21 mol) and methyl malonate (30.3 g, 0.23 mol) in methanol (150 mL) was added sodium methoxide (41.4 g, 30% in methanol). The mixture was refluxed under N2 for 4 h and concentrated. The resulting residue was hydrolyzed in 2N potassium hydroxide (200 mL) at 70 °C for 4 h. The mixture was extracted with ethyl acetate (100 mL) then titrated to pH 3-5 with 1N hydrochloric acid. The resulting solution was heated to 70 °C for 5 h and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over magnesium sulfate and concentrated to give spiro[3,5]nonane-6,8-dione (19.8 g, 62.3%) as a yellow solid. This product was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 5.17 (s, 1H), 2.50-2.35 (m, 4H), 1.92-1.79 (m, 2H), 1.79-1.72 (m, 4H).

INTERMEDIATE 3: 8-Isobutoxyspiro[3.5]non-7-en-6-one.

To a solution of spiro[3.5]nonane-6,8-dione (19.8 g, 0.13 mol) in toluene (150 ml) were added 4-toluenesulfonic acid (248 mg, 0.0013 mol) and isobutyl alcohol (14.5 g, 0.2 mol). The mixture was heated under reflux and water was removed by azeotropic distillation. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 1/10 to 1/3) to give 8-isobutoxyspiro[3.5]non-7-en-6-one (25.0 g, 92.7%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.31 (s, 1H), 3.59 (d, J=6.8 Hz, 2H), 2.51 (s, 2H), 2.45 (s, 2H), 2.12-1.96 (m, 1H), 1.93-1.83 (m, 6H), 0.99 (d, J=6.8 Hz, 6H).

INTERMEDIATE 4: Synthesis of Spiro[3.5]non-7-en-6-one.

To a solution of 8-isobutoxyspiro[3.5]non-7-en-6-one (25.0 g, 0.12 mol) in toluene (100 mL) was added Red-Al® (40 mL, 70% in toluene, 0.18 mol) dropwise at room temperature. The mixture was heated to 45 °C for 4 h, then quenched with 1 N hydrochloric acid. The mixture was filtered and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/10) to give spiro[3.5]non-7-en-6-one (9.0 g, 55%) as a light yellow oil.

INTERMEDIATE 5: Synthesis of Spiro[3.5]nonan-6-one.

Spiro[3.5]non-7-en-6-one (9.0 g) was hydrogenated under 1 atm H2 in the presence of 10% Pd/C (1.0 g) in methanol (80 mL) for 5.5 h. Pd/C was removed by filtration and the filtrate was concentrated to give spiro[3.5]nonan-6-one (8.8 g, 96.4%) as a colorless oil, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 2H), 2.23-2.20 (m, 2H), 1.89-1.75 (m, 10H).

INTERMEDIATE 6: Synthesis of Methyl 6-oxospiro[3.5]nonane-7-carboxylate.

To a suspension of sodium hydride (5.1 g, 0.13 mol) in tetrahydrofuran (150 ml) was added methyl carbonate (28.7 g, 0.32 mol) at room temperature, followed by spiro[3.5]nonan-6-one in tetrahydrofuran (30 ml). The mixture was heated under reflux for 2 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine and concentrated. The resulting residue was purified by column chromatography on silica gel to give methyl 6-oxospiro[3.5]nonane-7-carboxylate (4.0 g, 32%) as a light yellow oil.

INTERMEDIATE 7: Synthesis of Methyl 6-(((trifluoromethyl)sulfonyl)oxy)spiro[3.5]non-6-ene-7-carboxylate.

To a solution of methyl 6-oxospiro[3.5]nonane-7-carboxylate (4.0 g, 0.02 mol) in tetrahydrofuran (25 mL) were added potassium carbonate (5.6 g, 0.04 mol) and N,N-bis(trifluoromethylsulfonyl)aniline (7.9 g, 0.022 mol). The mixture was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/50-1/10) to give methyl 6-(((trifluoromethyl)sulfonyl)oxy)spiro[3.5]non-6-ene-7-carboxylate (5.0 g, 76%) as a light yellow oil.

INTERMEDIATE 8: Synthesis of Methyl 6-(4-chlorophenyl)spiro[3.5]non-6-ene-7-carboxylate.

A mixture of methyl 6-((((trifluoromethyl)sulfonyl)oxy)spiro[3.5]non-6-ene-7-carboxylate (5.0 g, 0.015 mol), 4-chlorophenylboronic acid (2.58 g, 0.017 mol), CsF (4.63 g, 0.03 mol) and Pd(PPh3)4 (173 mg, 0.15 mol) in 1,2-dimethoxyethane (30 mL) and methanol (15 mL) was heated to 70 °C under N2 for 2 h. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 1/10) to give methyl 6-(4-chlorophenyl)spiro[3.5]non-6-ene-7-carboxylate (4.0 g, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=8.5 Hz, 2H), 7.06 (d, J=8.5 Hz, 2H), 3.48 (s, 3H), 2.50-2.44 (m, 2H), 2.43 (t, J=2.3 (2.3 or 6.3?) Hz, 2H), 2.02-1.80 (m, 6H), 1.74 (t, J=6.3 Hz, 2H).

INTERMEDIATE PRODUCT 9: Synthesis of (6-(4-Chlorophenyl)spiro[3.5]non-6-en-7-yl)methanol.

To a solution of methyl 6-(4-chlorophenyl)spiro[3.5]non-6-ene-7-carboxylate (4.0 g, 0.014 mol) in tetrahydrofuran (20 mL) was added a solution of LiBH4 (910 mg, 0.042 mol) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature overnight, quenched with 1N aqueous hydrochloric acid, and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/10-1/3) to give (6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methanol (3.0 g, 81.7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 3.93 (d, J=4.2 Hz, 2H), 2.37-2.26 (m, 2H), 2.01-1.77 (m, 8H), 1.74 (t, J=6.3 Hz, 2H).

INTERMEDIATE 10: Synthesis of 7-(Chloromethyl)-6-(4-chlorophenyl)spiro[3.5]non-6-ene.

To a solution of (6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methanol (3.5 g, 0.013 mol) and trimethylamine (2.7 g, 0.026 mol) in dichloromethane (20 ml) was added dropwise methylsulfonyl chloride (3.0 g, 0.026 mol). The mixture was stirred at room temperature for 5 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 7-(chloromethyl)-6-(4-chlorophenyl)spiro[3.5]non-6-ene (2.75 g, 75.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 3.93 (s, 2H), 2.34-2.25 (m, 4H), 1.97-1.78 (m, 6H), 1.74 (t, J=6.3 Hz, 2H).

INTERMEDIATE 11: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate.

A mixture of 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.2 g), ethyl 2,4-difluorobenzoate (1.96 g), and K3PO4 (2.14 g) in diglyme (20 mL) was stirred at 115 °C for 1 h. The reaction mixture was cooled, diluted with ethyl acetate (100 mL), and washed with water, brine, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1/3) to give ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (1.9 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.13-10.08 (m, 1H), 8.23 (d, J=2.6 Hz, 1H), 7.98 (dd, J=8.8, 6.6 Hz, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.44 (dd, J=3.5, 2.5 Hz, 1H), 6.84 (dd, J=8.8, 7.6, 2.4 Hz, 1H), 6.55 (dd, J=10.3, 2.4 Hz, 1H), 6.52 (dd, J=3.5, 2.0 Hz, 1H), 4.38 (k, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

INTERMEDIATE 12: Synthesis of Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate.

A mixture of 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (1.91 g), methyl 4-bromo-2-fluorobenzoate (1.70 g) and K3PO4 (1.86 g) in diglyme (20 mL) was stirred at 115 °C for 1 h. The reaction mixture was cooled, diluted with ethyl acetate (100 mL) and washed with water, brine and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1/3) to give methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (1.8 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.18 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.62 (d, J=2.5 Hz), 1H), 7.40-6.96 (m, 2H), 6.96 (d, J=1.7 Hz, 1H), 6.51-6.48 (m, 1H), 3.89 (s, 3H).

INTERMEDIATE 13: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid.

To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoate (300 mg, 0.867 mmol) in dioxane (10 ml) was added 1N NaOH solution (2.2 ml, 2.2 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N HCl solution and extracted with ethyl acetate, washed with brine and dried over anhydrous MgSO4. After evaporation under reduced pressure, crude 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid was obtained as a colorless oil. This product was used directly in the next step without further purification.

INTERMEDIATE 14: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran )-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.

To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzoic acid (100 mg, 0.3 mmol) in DCM (10 mL) were added 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (95 mg, 0.3 mmol), DMAP (55 mg, 0.45 mmol) and EDCI (115 mg, 0.6 mmol), and the mixture was stirred at room temperature for 24 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (DCM/MeOH 95/5) to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide as a yellow oil (80 mg). MS m/z 630 [M+H]+.

INTERMEDIATE 15: Synthesis of (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2, 3-b]pyridin-5-yl)oxy)-4-bromobenzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.59-8.52 (m, 2H), 8.05 (d, J=2.6 Hz, 1H), 7.85 (dd, J=9.2, 2.4 Hz), 1H), 7.66 (d, J=2.6 Hz, 1H), 7.59-7.49 (m, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.34 (dd, J=8.2, 1.8 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 6.50-6.40 (m, 1H), 3.83-3.37 (m, 2H), 3.72-3.56 (m, 2H), 3.56-3.42 (m, 2H), 3.37-3.01 (m, 3H).

INTERMEDIATE 16: Synthesis of (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo [2, 3-b]pyridin-5-yl)oxy)-4-bromobenzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 8.59-8.52 (m, 2H), 8.05 (d, J=2.6 Hz, 1H), 7.85 (dd, J=9.2, 2.4 Hz), 1H), 7.66 (d, J=2.6 Hz, 1H), 7.59-7.49 (m, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.34 (dd, J=8.2, 1.8 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 6.50-6.40 (m, 1H), 3.83-3.37 (m, 2H), 3.72-3.56 (m, 2H), 3.56-3.42 (m, 2H), 3.37-3.01 (m, 3H).

INTERMEDIATE 17: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 685 [M+H]+.

INTERMEDIATE 18: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((4-(((4-morpholinocyclohexyl)methyl)amino)3-nitrophenyl)sulfonyl)benzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 713 [M+H]+.

INTERMEDIATE 19: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methyl)amino)phenyl)sulfonyl)benzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 713 [M+H]+.

INTERMEDIATE 20: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((3-nitro-4-(((tetrahydro-2H-pyran -3-yl)methyl)amino)phenyl)sulfonyl)benzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 630 [M+H]+.

INTERMEDIATE 21: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromo-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

The title compound was prepared using a procedure similar to that described for INTERMEDIATE 14 and purified by silica gel chromatography (DCM/MeOH 95/5). MS m/z 643 [M+H]+.

INTERMEDIATE 23: Synthesis of tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(ethoxycarbonyl)phenyl)piperazine-1-carboxylic acid.

A mixture of ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (2.1 g, 7 mmol), N-Boc-piperazine (2.61 g, 0.014 mol), and potassium hydrogen phosphate (2.44 g, 0.014 mol) in dimethyl sulfoxide was heated to 135 °C overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, concentrated and purified by silica gel column chromatography to give tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(ethoxycarbonyl)phenyl)piperazine-1-carboxylate (2.4 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.42 (br s, 1H), 8.20 (d, J=2.5 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.53 (d, J=2.5 Hz, 1H), 7.37 (dd, J=3.5, 2.5 Hz, 1H), 6.66 (dd, J=8.9, 2.5 Hz, 1H), 6.46 (dd, J=3.5, 2.0 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.55-3.50 (m, 4H), 3.21-3.17 (m, 4H), 1.47 (s, 9H), 1.26 (t, J=7.1 Hz, 3H).

INTERMEDIATE 24: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate.

Trifluoroacetic acid (6 ml) was added to a solution of tert-butyl 4-(3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(ethoxycarbonyl)phenyl)piperazine-1-carboxylate (2.1 g) in dichloromethane (10 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the crude ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (2.5 g) was directly used in the next step without further purification.

INTERMEDIATE 25: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate.

To a solution of 7-(chloromethyl)-6-(4-chlorophenyl)spiro[3.5]non-6-ene (851 mg, 3 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (1.26 g, 9 mmol), potassium iodide (100 mg, 0.6 mmol), and ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (1.53 g, 3.3 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, concentrated and purified by column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/1) to give ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate (1.3 g, 71%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.20 (d, J=2.6 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.51 (d, J=2.6 Hz, 1H), 7.38 (t, J=3.5 Hz, 1H), 7.28 (d, J=8.3 Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 6.62 (dd, J=9.0, 2.5 Hz, 1H), 6.45 (dd, J=3.5, 2.0 Hz, 1H), 6.32 (d, J=2.5 Hz, 1H), 4.26 (kv, J=7.1 Hz, 2H), 3.20-3.12 (m, 4H), 2.77 (s, 2H), 2.31-2.17 (m, 8H), 1.98-1.72 (m, 6H), 1.68 (t, J=6.3 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

INTERMEDIATE 26: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid.

A solution of ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate (1.3 g, 2.1 mmol) and 2N potassium hydroxide solution (12 mL, 0.042 mol) in dioxane (15 mL) was heated to 60 ℃ overnight. The mixture was neutralized with 1N aqueous hydrochloric acid to pH 7 and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid (1.1 g, 88.7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.19 (d, J=2.6 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.63 (d, J=2.6 Hz, 1H), 7.38-7.34 (m, 1H), 7.27 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 2H), 6.63 (dd, J=9.0, 2.4 Hz, 1H), 6.44 (dd, J=3.5, 1.5 Hz, 1H), 6.22 (d, J=2.4 Hz, 1H), 3.81 (s, 2H), 3.17-3.10 (m, 4H), 2.80 (s, 2H), 2.30-2.20 (m, 6H), 1.98-1.72 (m, 6H), 1.67 (t, J=6.3 Hz, 2H).

INTERMEDIATE 27: Synthesis of 1-(Oxetan-3-ylidene)propan-2-one.

To a solution of oxetan-3-one (20.6 g, 0.28 mol) in DCM (300 mL) was added 1-(triphenylphosphoranylidene)propan-2-one (98.6 g, 0.31 mol). The mixture was stirred at room temperature overnight. DCM was removed under reduced pressure until a solid precipitated. The solid was removed by filtration and the filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate/heptane 1/5~1/3) to give 1-(oxetan-3-ylidene)propan-2-one (23.3 g, 74.3%) as a yellow oil.

INTERMEDIATE 28: Synthesis of 2-Oxaspiro[3.5]nonane-6,8-dione.

To a solution of 1-(oxetan-3-ylidene)propan-2-one (23.3 g, 0.21 mol) and methyl malonate (30.2 g, 0.23 mol) in methanol (150 mL) was added sodium methoxide (41.3 g, 30% solution in MeOH). The mixture was refluxed under N2 for 1 h. The solvent was removed under reduced pressure to give methyl 6-hydroxy-8-oxo-2-oxaspiro[3.5]non-6-ene-5-carboxylate, which was used directly in the next step without purification. To an aqueous solution of KOH (2 mol/L, 200 mL) was added methyl 6-hydroxy-8-oxo-2-oxaspiro[3.5]non-6-ene-5-carboxylate. After stirring at room temperature for 30 min, the aqueous solution was extracted with ethyl acetate (150 ml × 3). The aqueous layer was adjusted to pH 3-5 with 1N hydrochloric acid and heated at 50 °C for 4 h. Water was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 2-oxaspiro[3.5]nonane-6,8-dione (2.5 g, 77.0%) as a light yellow solid. This product was used directly in the next step without further purification.

INTERMEDIATE 29: Synthesis of 8-Isobutoxy-2-oxaspiro[3.5]non-7-en-6-one.

To a solution of 2-oxaspiro[3.5]nonane-6,8-dione (25 g, 0.16 mol) in toluene (150 mL) were added TsOH (238 mg, 0.0016 mol) and isobutyl alcohol (18 g, 0.24 mol). The reaction was completed after stirring at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/5~1/3) to give 8-isobutoxy-2-oxaspiro[3.5]non-7-en-6-one (6 g, 43%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.34 (s, 1H), 4.47 (d, J=6.1 Hz, 2H), 4.45 (d, J=6.1 Hz, 2H), 3.60 (d, J=6.8 Hz, 2H), 2.80 (s, 2H), 2.68 (s, 2H), 2.09-2.01 (m, 1H), 0.98 (d, J=6.8 Hz, 6H).

INTERMEDIATE 30: Synthesis of 2-Oxaspiro[3.5]non-7-en-6-one.

To a solution of 8-isobutoxy-2-oxaspiro[3.5]non-7-en-6-one (14.7 g, 0.07 mol) in toluene (100 mL) was added Red-Al® (40.4 g, 70% in toluene) dropwise. The mixture was heated to 45°C for 2 h and quenched with 1N HCl solution. The mixture was concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/10~1/5) to give 2-oxaspiro[3.5]non-7-en-6-one (8.8 g, 91%) as a colorless oil. This product was used directly in the next step without further purification.

INTERMEDIATE 31: Synthesis of 2-Oxaspiro[3.5]nonan-6-one.

To a solution of 2-oxaspiro[3.5]non-7-en-6-one (8.8 g) in tetrahydrofuran (80 mL) was added Pd/C (1 g). The mixture was hydrogenated under 1 atm H2 at room temperature for 2 h. After completion of the reaction, Pd/C was removed by filtration and the solution was concentrated to give 2-oxaspiro[3.5]nonan-6-one (8.0 g, 89.6%) as a colorless oil. This product was used directly in the next step without further purification.

INTERMEDIATE 32: Synthesis of Methyl 6-oxo-2-oxaspiro[3.5]nonane-7-carboxylate.

To a suspension of sodium hydride (4.6 g, 0.11 mol) in tetrahydrofuran (150 mL) under N2 was added dropwise methyl carbonate (25.7 g, 0.28 mol). After complete addition, the mixture was heated under reflux. Then a solution of 2-oxaspiro[3.5]nonan-6-one (11.2 g, 0.057 mol) in tetrahydrofuran (30 mL) was added. The reaction mixture was refluxed for 2 h, quenched with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 6-oxo-2-oxaspiro[3.5]nonane-7-carboxylate (4.5 g, 69%) as a colorless oil. This product was used directly in the next step without further purification.

INTERMEDIATE 33: Synthesis of Methyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-oxaspiro[3.5]non-6-ene-7-carboxylate.

To a suspension of methyl 6-oxo-2-oxaspiro[3.5]nonane-7-carboxylate (4.5 g, 0.02 mol) and potassium carbonate (6.3 g, 0.046 mol) in DMF (30 mL) was added N,N-bis(trifluoromethylsulfonyl)aniline (8.9 g, 0.025 mol). The mixture was stirred at room temperature overnight, diluted with water and extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/10~1/3) to give methyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-oxaspiro[3.5]non-6-ene-7-carboxylate (6.6 g, 86%) as a light yellow oil. This product was used directly in the next step without further purification.

INTERMEDIATE 34: Synthesis of Methyl 6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-ene-7-carboxylate.

To a solution of methyl 6-(((trifluoromethyl)sulfonyl)oxy)-2-oxaspiro[3.5]non-6-ene-7-carboxylate (6.6 g, 0.02 mol) in 1,2-dimethoxyethane (30 mL) and methanol (10 mL) were added 4-chlorophenylboronic acid (3.13 g, 0.02 mol), CsF (6.08 g, 0.04 mol) and Pd(PPh3)4 (231 mg, 0.2 mmol) and the mixture was heated to 70 °C under N2 for 30 min. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 1/5-1/3) to give methyl 6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-ene-7-carboxylate (5.1 g, 87.3%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.54 (d, J=5.6 Hz, 2H), 4.48 (d, J=5.6 Hz, 2H), 3.48 (s, 3H), 2.74-2.70 (m, 2H), 2.55-2.50 (m, 2H), 2.04 (t, J=6.4 Hz, 2H).

INTERMEDIATE 35: Synthesis of (6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methanol.

To a solution of methyl 6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-ene-7-carboxylate (2.1 g, 0.0072 mol) in tetrahydrofuran (20 mL) was added LiBH4 (475 mg, 0.022 mol) in tetrahydrofuran (10 mL) dropwise at room temperature. The mixture was stirred at room temperature for 4 h, quenched with 1N HCl and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/1) to give (6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methanol (1.5 g, 78.9%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 2H), 7.07 (d, 2H, J=8.4 Hz), 4.54 (d, 2H, J=6.0 Hz), 4.46 (d, 2H, J=5.6 Hz), 3.93 (s, 2H), 2.62 (s, 2H), 2.40-2.33 (m, 2H), 2.03 (t, 2H, J=6.4 Hz).

INTERMEDIATE 36: Synthesis of 7-(Chloromethyl)-6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-ene.

To a solution of (6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methanol (1.5 g, 5.7 mmol) and triethylamine (836 mg, 8.6 mmol) in dichloromethane (15 mL) was added methylsulfonyl chloride (980 mg, 8.6 mmol), and the mixture was stirred at room temperature for 3.5 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 7-(chloromethyl)-6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-ene (1.4 g, 87.0%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, 2H, J=8.4 Hz), 7.16 (d, 2H, J=8.4 Hz), 4.53 (d, 2H, J=6.0 Hz), 4.45 (d, 2H, J=5.6 Hz), 3.86 (s, 2H), 2.64 (s, 2H), 2.40-2.33 (m, 2H), 2.03 (t, 2H, J=6.4 Hz).

INTERMEDIATE 37: Synthesis of Ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate.

To a solution of ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (382 mg, 0.82 mmol) in DMF (10 mL) were added 7-(chloromethyl)-6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-ene (200 mg, 0.75 mmol), potassium carbonate (310 mg, 2.25 mmol), DIPEA (290 mg, 2.25 mmol), and potassium iodide (24.9 mg, 0.15 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, concentrated and purified by silica gel column chromatography (ethyl acetate/petroleum ether 1/5-1/1) to give ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate (370 mg, 80.6%) as a white solid. MS m/z 613 [M+H]+.

INTERMEDIATE 38: Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid.

To a solution of ethyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate (370 mg, 0.6 mmol) in dioxane (10 mL) was added 2N potassium hydroxide solution (6 mL, 12 mmol), and the mixture was stirred at 60 ℃ overnight. The solution was neutralized with 1N hydrochloric acid to pH 7 and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid (1.1 g, 88.7%) as a white solid. MS m/z 585 [M+H]+.

INTERMEDIATE 55: Synthesis of Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)benzoate.

To a solution of 7-(chloromethyl)-6-(4-chlorophenyl)spiro[3.5]non-6-ene (850 mg, 3.04 mmol) in N,N-dimethylformamide (10 mL) were added potassium carbonate (1.26 g, 2.2 mmol), potassium iodide (100 mg, 0.61 mmol), and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperidin-4-yl)benzoate (1.0 g, 3.34 mmol), and the mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated. The resulting residue was purified by silica gel column chromatography to give methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)benzoate (1.0 g, 55.2%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.39 (w s, 1H), 8.19 (d, J=2.6 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.57 (d, J=2.6 Hz, 1H), 7.39 (dd, J=3.5, 2.5 Hz, 1H), 7.30-7.23 (m, 2H), 7.04-6.93 (m, 3H), 6.72 (d, J=1.6 Hz, 1H), 6.49 (dd, J=3.5, 2.0 Hz, 1H), 3.87 (s, 3H), 2.81-2.75 (m, 2H), 2.73-2.71 (m, 2H), 2.28 (s, 2H), 2.25-2.15 (m, 2H), 1.98-1.76 (m, 6H), 1.75-1.51 (m, 9H).

EXAMPLE 2

Synthesis (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine -5-il )oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide .

To a solution of (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzamide in 1,2-dimethoxyethane (10 mL) and water (1 mL) were added 1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine, Pd(dppf)Cl2 and K2CO3, and the mixture was stirred at 80°C for 12 h. The reaction mixture was cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate (30 mL × 3), dried over anhydrous MgSO4 and concentrated. The residue was purified by preparative C18 reverse phase HPLC to give (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide. 1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J=2.3 Hz, 1H), 7.97 (d, J=2.6 Hz, 1H), 7.88 (dd, J=9.3, 2.3 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.46 (d, J=3.5 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.16 (dd, J=8.2, 1.7 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.94 (d, J=9.3 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.41 (d, J=3.5 Hz, 1H), 5.94-5.90 (m, 1H), 3.95-3.40 (m, 14H), 3.15-3.03 (m, 1H), 2.68-2.45 (m, 2H), 2.43 (s, 2H), 2.30-2.20 (m, 2H), 2.03-1.77 (m, 8H).

EXAMPLE 3

2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 2. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.90 (dd, J=9.2, 2.3 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.20-7.10 (m, 3H), 6.96 (d, J=9.2 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.44 (d, J=3.5 Hz, 1H), 5.93-5.86 (m, 1H), 4.53 (d, J=5.9 Hz, 2H), 4.49 (d, J=5.9 Hz, 2H), 4.00-3.90 (m, 2H), 3.77-3.33 (m, 7H), 3.26 (d, J=7.0 Hz, 2H), 3.15-3.00 (m, 1H), 2.70-2.65 (m, 2H), 2.63-2.25 (m, 4H), 2.07 (t, J=6.3 Hz, 2H), 2.00-1.85 (m, 1H), 1.75-1.65 (m, 2H), 1.46-1.30 (m, 2H).

EXAMPLE 4

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7)yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 2. 1H NMR (400 MHz, Methanol-d4) δ 8.71 (t, J=1.9 Hz, 1H), 8.00-7.95 (m, 1H), 7.90 (dd, J=9.3, 1.9 Hz, 1H), 7.63 (dd, J=8.1, 1.4 Hz, 1H), 7.56-7.50 (m, 1H), 7.46 (dd, J=3.5, 1.4 Hz, 1H), 7.33-7.26 (m, 2H), 7.18-7.06 (m, 3H), 6.96 (dd, J=9.3, 1.4 Hz, 1H), 6.81 (s, 1H), 6.43 (dd, J=3.5, 1.5 Hz, 1H), 5.93-5.86 (m, 1H), 4.00-3.94 (m, 2H), 3.83-3.36 (m, 7H), 3.26 (d, J=7.0 Hz, 2H), 3.10-3.04 (m, 1H), 2.67-2.40 (m, 4H), 2.30-2.24 (m, 2H), 2.02-1.77 (m, 9H), 1.74-1.67 (m, 2H), 1.45-1.30 (m, 2H).

EXAMPLE 5

Synthesis of (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 1. 1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 7.89 (dd, J=9.2, 2.3 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.48 (d, J=3.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.21-7.16 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.95 (d, J=9.3 Hz, 1H), 6.86 (d, J=1.6 Hz, 1H), 6.43 (d, J=3.5 Hz, 1H), 5.94-5.90 (m, 1H), 4.60-4.43 (m, 4H), 3.95-3.40 (m, 14H), 3.15-3.00 (m, 1H), 2.80-2.60 (m, 4H), 2.38-2.25 (m, 2H), 2.08 (t, J=6.3 Hz, 2H).

EXAMPLE 6

Synthesis (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6)-en-7-yl)methyl)piperazin-1-yl)benzoic acid (290 mg, 0.5 mmol), (R)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide (236 mg, 0.75 mmol), EDCI (191 mg, 1 mmol), 4-(N,N-dimethylamino)pyridine (591 mg, 0.75 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the resulting residue was purified by silica gel column chromatography to give (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide (150 mg, 34.1%) as a yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 8.67 (d, J=2.3 Hz, 1H), 7.99 (d, J=2.3 Hz, 1H), 7.85 (dd, J=9.3, 2.3 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.45 (d, J=3.5 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.95 (d, J=9.3 Hz, 1H), 6.76 (dd, J=8.8, 2.4 Hz, 1H), 6.41 (d, J=3.5 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 4.48 (d, J=5.9 Hz, 2H), 3.93-3.35 (m, 19H), 2.70-2.65 (m, 2H), 2.33 (s, 2H), 2.08 (t, J=6.3 Hz, 2H).

EXAMPLE 7

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid (250 mg, 0.43 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (202 mg, 0.64 mmol), EDCI (164 mg, 0.86 mmol), 4-(N,N-dimethylamino)pyridine (78 mg, 0.64 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight, followed by concentration. The resulting residue was purified by silica gel column chromatography to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (150 mg, 39.6%) as a yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=2.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.87 (dd, J=9.2, 2.3 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.47 (d, J=3.5 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.2 Hz, 1H), 6.76 (dd, J=8.8, 2.4 Hz, 1H), 6.43 (d, J=3.5 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 4.54 (d, J=5.9 Hz, 2H), 4.48 (d, J=5.9 Hz, 2H), 4.03-3.94 (m, 2H), 3.67 (s, 2H), 3.55-3.27 (m, 12H), 2.69 (s, 2H), 2.35-2.25 (m, 2H), 2.08 (t, J=6.3 Hz, 2H), 2.05-1.93 (m, 1H), 1.76-1.69 (m, 2H), 1.45-1.35 (m, 2H).

EXAMPLE 8

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7)yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid (1.75 g, 3 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (1.43 g, 4.5 mmol), EDCI (1.15 g, 6 mmol), 4-(N,N-dimethylamino)pyridine (550 mg, 4.5 mmol) and dichloromethane (40 mL) was reacted at room temperature overnight, followed by the addition of water. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, concentrated and purified by silica gel column chromatography to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (1.7 g, 64.4%) as a yellow solid. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=2.3 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.87 (d, J=9.2, 2.3 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H), 7.55 (d, J=2.7 Hz, 1H), 7.47 (d, J=3.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.2 Hz, 1H), 6.77 (dd, J=8.9, 2.4 Hz, 1H), 6.44 (d, J=3.4 Hz, 1H), 6.34 (d, J=2.4 Hz, 1H), 4.02-3.94 (m, 3H), 3.66 (s, 3H), 3.49-3.38 (m, 2H), 3.41-3.25 (m, 7H), 2.42 (s, 3H), 2.26 (s, 3H), 2.00-1.67 (m, 4H), 1.45-1.38 (m, 2H).

EXAMPLE 9

Synthesis (R)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyr idin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 8. 1H NMR (400 MHz, Methanol-d4) δ 8.66 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.84 (dd, J=9.2, 2.4 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.51 (d, J=2.4 Hz, 2H), 7.45 (d, J=3.3 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.94 (d, J=9.2 Hz, 1H), 6.76 (dd, J=8.9, 2.3 Hz, 1H), 6.40 (d, J=3.3 Hz, 1H), 6.36 (d, J=2.3 Hz, 1H), 3.87 (dd, J=11.8, 4.2 Hz, 3H), 3.83-3.70 (m, 3H), 3.67 (s, 2H), 3.62 (dd, J=11.7, 2.9 Hz, 1H), 3.51-3.41 (m, 2H), 3.40-3.35 (m, 1H), 3.29 (dkv, J=3.2, 1.6 Hz, 1H), 2.41 (s, 2H), 2.26 (s, 2H), 2.00-1.77 (m, 6H).

EXAMPLE 10

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 8. 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 9.47 (s, 1H), 8.62 (d, J=2.2 Hz, 1H), 8.44 (d, J=8.3 Hz, 1H), 8.27 (d, J=7.9 Hz, 1H), 8.02-7.97 (m, 1H), 7.84-7.75 (m, 1H), 7.56-7.43 ( m, 3H), 7.40 (d, J=8.3 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 6.72 (d, J=8.9 Hz, 1H), 6.40-6.35 (m, 1H), 6.30 (s, 1H), 3.80-3.65 (m, 2H), 3.55 (s, 2H), 3.28-2, 95 (m, 4H), 2.82-2.65 (m, 2H), 2.31 (s, 2H), 2.22-2.15 (m, 2H), 1.93-1.60 (m, 8H).

EXAMPLE 11

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-(methylamino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 8. 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J=2.3 Hz, 1H), 8.05 (d, J=2.6 Hz, 1H), 7.96 (dd, J=9.2, 2.3 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.61 (d, J=2.6 Hz, 1H), 7.46 (d, J=3.5 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.90 (d, J=9.2 Hz, 1H), 6.68 (dd, J=8.9, 2.4 Hz, 1H), 6.46 (d, J=3.5 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 3.60 (s, 2H), 3.50-3.12 (m, 8H), 3.06 (s, 3H), 2.38 (s, 2H), 2.30-2.16 (m, 2H), 1.97-1.73 (m, 8H).

EXAMPLE 12

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7- yl)methyl)piperazin-1-yl)-N-((4-(dimethylamino)-3-nitrophenyl)sulfonyl)benzamide

The title compound was prepared using a procedure similar to that described for EXAMPLE 8. 1H NMR (400 MHz, Methanol-d4) δ 8.41 (d, J=2.2 Hz, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.91 (dd, J=9.4, 2.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.04 (d, J=9.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.71-6.63 (m, 1H), 6.51 (d, J=3.5 Hz, 1H), 6.15 (d, J=1.9 Hz, 1H), 3.59 (s, 2H), 3.52-3.20 (m, 8H), 2.98 (s, 6H), 2.38 (s, 2H), 2.25-2.17 (m, 2H), 1.96-1.72 (m, 8H).

EXAMPLE 13

Synthesis of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

A mixture of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)benzoic acid (200 mg, 0.34 mmol), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (162 mg, 0.52 mmol), EDCI (130 mg, 0.68 mmol), 4-(N,N-dimethylamino)pyridine (63.4 mg, 0.52 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight, followed by purification by silica gel column chromatography to give 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperidin-4-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide (170 mg, 57.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 11.64 (s, 1H), 8.50-8.42 (m, 2H), 7.97 (d, J=2.6 Hz, 1H), 7.76 (dd, J=9.2, 2.2 Hz, 1H), 7.52-7.36 (m, 5H), 7.11 (d, J=7.9 Hz, 2H), 6.99 (d, J=9.2 Hz, 1H), 6.91-6.86 (m, 1H), 6.55 (s, 1H), 6.37 (s, 1H), 3.89-3.79 (m, 2H), 3.35-2.90 (m, 10N), 2.32-2.10 (m, 5H), 1.95-1.15 (m, 17H).

EXAMPLE 14

The following Compounds described in this Description were prepared using the methodologies described in Examples 1-13:

Compound No. 40: (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.49-8.46 (m, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.70 (dd, J=13, 6, 2.3 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.45 (d, J=3.4 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.10 (d, J= 8.5 Hz, 2H), 6.79 (dd, J=8.8, 2.3 Hz, 1H), 6.41-6.37 (m, 2H), 3.83-2.70 (m, 19H), 2.42 (s, 2H), 2.30-2.22 (m, 2H), 2.00-1.78 (m, 8H).

Compound No. 44: (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-2-fluoro-5-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.75 (d, J=7.5 Hz, 1H), 8.08-8.02 (m, 1H), 7.68 (d, J=2, 4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.50 (d, J=3.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.80-6.72 (m, 2H), 6, 50 (d, J=3.4 Hz, 1H), 6.29 (d, J=2.2 Hz, 1H), 3.90-2.70 (m, 19H), 2.41 (s, 2H), 2.32-2.20 (m, 2H), 2.00-1.78 (m, 8H).

Comp. 45: (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-2-fluoro-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide

MS m/z=900 [M+H].

Compound No. 46: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-methyl-7-nitro-2H-indazol-5-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.80 (d, J=1.6 Hz, 1H), 8.73 (d, J=1.6 Hz, 1H), 8.69 (s, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.75 (dd, J=8.9, 2.3 Hz, 1H), 6.34 (d, J=2.3 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 4.35 (s, 3H), 3.67-2.70 (m, 8H), 3.66 (s, 2H), 2.41 (s, 2H), 2.32-2.22 (m, 2H), 2.02-1.75 (m, 8H).

Compound No. 47: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.70 (d, J=1.3 Hz, 1H), 8.64 (d, J=1.3 Hz, 1H), 8.57 (s, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.40 (d, J=3.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 6.74 (dd, J=8.9, 2.2 Hz, 1H), 6.35 (d, J=2.2 Hz, 1H), 6.33 (d, J=3.4 Hz, 1H), 3.72-2.72 (m, 8H), 2.40 (s, 2H), 2.34-2.20 (m, 2H), 2.00-1.77 (m, 8H).

Compound No. 48: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2-(tetrahydro-2H-pyran-4-yl)-2H-indazol-5-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.87 (d, J=1.6 Hz, 1H), 8.84 (s, 1H), 8.75 (d, J=1.6 Hz, 1H), 7.96 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.50 (d, J=2.6 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.75 (dd, J=8.9, 2.3 Hz, 1H), 6.35 (d, J=3.4 Hz, 1H), 6.31 (d, J=2.3 Hz, 1H), 4.20-4.14 (m, 2H), 3.75-2.70 (m, 13H), 2.41 (s, 2H), 2.32-1.76 (m, 14H).

Compound No. 49: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((1-methyl-7-nitro-1H-indazol-5-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.71 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.5 Hz, 1H), 8.33 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.42 (d, J=3.4 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 6.76 (dd, J=8.9, 1.7 Hz, 1H), 6.36 (d, J=3.4 Hz, 1H), 6.34 (d, J=1.7 Hz, 1H), 4.20 (s, 3H), 3.75-2.70 (m, 8H), 3.70 (s, 2H), 2.41 (s, 2H), 2.30-2.23 (m, 2H), 2.00-1.76 (m, 8H).

Compound No. 50: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2H-indazol-5-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.82 (s, 2H), 8.41 (s, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.64 (d , J=9.0 Hz, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.40-7.34 (m, 3H), 7.09 (d, J=8.4 Hz, 2H), 6.76 (dd, J=9.0, 2.3 Hz, 1H), 6 .36 (d, J=2.3 Hz, 1H), 6.29 (d, J=3.4 Hz, 1H), 3.70-2.70 (m, 8H), 3.66 (s, 2H), 2.41 (s, 2H), 2.30-2.20 (m, 2H), 2.02-1.77 (m, 8H).

Compound No. 51: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-nitro-2H-indazol-6-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 9.19 (s, 1H), 8.84 (s, 1H), 8.73 (d, J=1.2 Hz, 1H), 7.94 (d , J=2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.43-7.37 (m, 3H), 7.12 (d, J=8.4 Hz, 2H), 6.81 (dd, J=8.7 , 2.1 Hz, 1H), 6.41 (d, J=3.4 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 3.71-2.70 (m, 8H), 3.69 (s, 2H), 2.43 (s, 2H), 2.30-2.24 (m, 2H), 2.02-1.76 (m, 8H).

Compound No. 52: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((1-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.66 (d, J=1.6 Hz, 1H), 8.60 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.35 (d, J=2.6 Hz, 1H), 7.33 (d, J=3.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 6.77 (dd, J=8.9, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 6.27 (d, J=3.5 Hz, 1H), 4.01 (s, 3H), 3.70-2.70 (m, 8H), 3.66 (s, 2H), 2.42 (s, 2H), 2.32-2.23 (m, 2H), 2.03-1.80 (m, 8H).

Compound No. 53: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((7-nitro-2-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-5-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.67 (d, J=1.5 Hz, 1H), 8.56 (d, J=1.5 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.74 (dd, J=8.9, 2.3 Hz, 1H), 6.34 (d, J=3.4 Hz, 1H), 6.30 (d, J=2.3 Hz, 1H), 4.00-3.85 (m, 2H), 3.70-2.70 (m, 10H), 3.65 (s, 2H), 2.98 (d, J=7.3 Hz, 2H), 2.41 (s, 2H), 2.35-2.20 (m, 3H), 2.02-1.40 (m, 12H).

Compound No. 54: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-(2-(2-methoxyethoxy)ethyl)-4-nitro-2H-indazol-6-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.85 (s, 1H), 8.70 (s, 1H), 8.53 (d, J=1.2 Hz, 1H), 7.94 (d , J=2.5 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.10 (d, J=8.4 Hz, 2H), 6.79 (dd, J=8.9 , 2.3 Hz, 1H), 6.39 (d, J=2.3 Hz, 1H), 6.30 (d, J=3.4 Hz, 1H), 4.80 (t, J=5.0, 2H), 4.09 (t, J=5.0 Hz, 2H), 3.70-3.65 (m, 4H), 3.64-2.70 (m, 10H), 3.29 (s, 3H), 2, 42 (s, 2H), 2.30-2.25 (m, 2H), 2.02-1.76 (m, 8H).

Compound No. 55: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((2-(2-methoxyethyl)-4-nitro-2H-indazol-6-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.80 (d, J=0.8 Hz, 1H), 8.74-8.72 (m, 1H), 8.54 (d, J=1.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.40-7.35 (m, 3H), 7.10 (d, J=8.5 Hz, 2H), 6.78 (dd, J=8.9, 2.4 Hz, 1H), 6.36 (d, J=2.4 Hz, 1H), 6.30 (d, J=3.4 Hz, 1H), 4.79 (t, J=5.0 Hz, 2H), 3.99 (t, J=5.0 Hz, 2H), 3.70-2.70 (m, 8H), 3.67 (s, 2H), 3.38 (s, 3H), 2.42 (s, 2H), 2.32-2.25 (m, 2H), 2.02-1.76 (m, 8H).

Compound No. 25: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en)-7-yl)methyl)piperazin-1-yl)-N-((5-nitro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrol-3-yl)sulfonyl)benzamide

1H NMR (400 MHz, methanol-d4) δ 8.04 (d, J=2.5 Hz, 1H), 7.72-7.68 (m, 2H), 7.61 (d, J=2.5 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 6.80 (dd, J=8.9, 2.3 Hz, 1H), 6.47 (d, J=3.5 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 4.27 (d, J=7.2 Hz, 2H), 3.85-2.70 (m, 12H), 3.66 (s, 2H), 2.42 (s, 2H), 2.35-2.25 (m, 2H), 2.03-1.77 (m, 9H), 1.48-1.26 (m, 4H).

Compound No. 56: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-(naphthalen-2-ylsulfonyl)benzamide

1H NMR (400 MHz, methanol-d4+CDCl3) δ 8.61 (s, 1H), 8.07 (d, J=2.5 Hz, 1H), 7.92-7.70 (m, 4H), 7.78 (d, J=9.0 Hz, 1H), 7.68-7.57 (m, 3H), 7.47 (d, J=3.5 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 6.62 (dd, J=9.0, 2.3 Hz, 1H), 6.48 (d, J=3.5 Hz, 1H), 6.13 (d, J=2.3 Hz, 1H), 3.57 (s, 2H), 3.56-2.71 (m, 8H), 2.36 (s, 2H), 2.24-2.14 (m, 2H), 1.96-1.71 (m, 8H).

EXAMPLE 15

Inhibition of Bcl-2 and Bcl-xL: Fluorescein-labeled proteins BIM(81-106), BAK(72-87), and BID(79-99), designated Flu-BIM, Flu-BAK, and Flu-BID, respectively, were used as fluorescent probes in PF assays for Bcl-2, Bcl-xL, and Mcl-1, respectively. By monitoring the total fluorescence polarization values of mixtures consisting of fluorescent probes at fixed concentrations and proteins at increasing concentrations until saturation, the Kd values of Flu-BIM for Bcl-2, Flu-BAK for Bcl-xL, and Flu BID for Mcl-1 were determined to be 0.55 ± 0.15, 4.4 ± 0.8, and 6.9 ± 0.9 nM, respectively. Fluorescence polarization values were measured using an Infinite M-1000 plate reader (Tecan U.S., Research Triangle Park, NC) in 96-well black Microfluor 1 round-bottom plates (Thermo Scientific). To each well were added 1 nM Flu-BIM or 2 nM Flu-BAK or 2 nM Flu-BID and increasing concentrations of Bcl-2 or Bcl-xL or Mcl-1 to a final volume of 125 μL in assay buffer (100 mM potassium phosphate, pH 7.5, 100 μg/mL bovine γ-globulin, 0.02% sodium azide, Invitrogen, with 0.01% Triton X-100, and 4% DMSO). The plates were mixed and incubated at room temperature for 1 h with gentle shaking to ensure equilibration. Polarization values in millipolarization units (mP) were measured at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. Equilibrium dissociation constants (Kd) were then calculated by fitting the sigmoidal dose-dependent increase in PF as a function of protein concentration using Graphpad Prism 5.0 software (Graphpad Software, San Diego, CA).

Ki values of representative Compounds in this Description for Bcl-2, Bcl-xL, and Mcl-1 were determined from competition binding experiments in which serial dilutions of the inhibitors were added to 96-well plates containing fixed concentrations of fluorescent probes and proteins in each well. Mixtures of 5 μL of test inhibitors in DMSO and 120 μL of preincubated protein/probe complexes in assay buffer were added to the assay plates and incubated at room temperature for 2 h with gentle shaking. Final protein and probe concentrations were 1.5 nM and 1 nM for the Bcl-2 assay, 10 nM and 2 nM for the Bcl-xL assay, and 20 nM and 2 nM for the Mcl-1 assay, respectively. Negative controls containing only the protein/probe complex (equivalent to 0% inhibition) and positive controls containing only free probe (equivalent to 100% inhibition) were included in each assay plate. PF values were measured as described above. IC50 values were determined by nonlinear regression fitting of the competition curves. Ki values of the competitive inhibitors were calculated using the equation described in Nikolovska-Coleska et al., Analytical Biochemistry 332: 261–73 (2004), based on the measured IC50 values, Kd values of the protein probes, and the concentrations of proteins and probes in the competition assays. Ki values were also calculated using the Huang equation, Journal of Biomolecular Screening 8:34–38 (2003).

The inhibitory activities of representative Compounds of this Description against Bcl-2, Bcl-xL and Mcl-1 are presented in Table 4.

Table 4

Conn. No. Inhibitory activity
IC50 (nM) Bcl-2 Bcl-хL Mcl-1 1 1.4 9.2 2 0.76 10.6 3 1,2 13.7 4 3.1 8.6 5 2.1 14 6 2.0 5.9 >5000 7 2.4 15.7 8 2.4 6.4 >5000 9 1.9 20.6 10 3.3 14.0 11 11.9 77.8 12 4.4 139 13 1.3 14.8 58 3.8 19.2 59 5.0 20.7 60 2.1 67.5 61 2.1 13.1 62 1.6 4.0 63 1.3 7.1 64 2.4 8.7 65 1.4 9.9 66 2.7 12.0

EXAMPLE 16

RS4;11 inhibition

RS4;11 cells were obtained from the American Type Culture Collection (ATCC). They were used within three months after thawing new flasks. Cells were maintained in the recommended culture medium with 10% FBS at 37°C and 5% CO2.

The effect of representative Compounds described herein on cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay (Dojindo, Rockville, MD) according to the manufacturer's instructions. 200 μl of a suspension of RS4;11 cells (10,000 cells/well) in culture medium were seeded in 96-well plates and cultured overnight. Each test compound was serially diluted in culture medium, and 20 μl of the diluted compound was added to the appropriate well of the cell plate. After addition of the test compound, the cells were incubated at 37°C under 5% CO2 for 4 days. At the end of 4 days, 10 μl of the CCK-8 solution was added to each well of the plate and incubated for 1-4 h. The plates were read at 450 nm on a microplate spectrophotometer (Epoch2, BioTek). Readings were normalized to carrier cells and IC50 was calculated by nonlinear regression analysis using GraphPad Prism 5 software.

The inhibitory activities of typical Compounds of this Description against the RS4;11 cell line are presented in Table 5.

Table 5

Conn. No. RS4;11
IC50 (nM)
(depends on Bcl-2) 1 3 2 5.5 3 26 4 427 5 22 6 5.5 7 35 8 3.7 9 28 10 32 11 61 12 78 13 2.8 22 20 23 19 25 1,090 27 5.2 28 968 29 12 30 19 31 34 32 1,381 34 552 35 611 36 13 37 68 38 66 39 31 40 1.4 41 52 42 111 43 80 44 7,157 58 35 59 65 60 252 61 43 62 46 63 55 64 37 65 11 66 243

EXAMPLE 17

Inhibition of Molm13

Molm13 cells were obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ). They were used within three months after thawing new vials. Cells were maintained in the recommended culture medium with 10% FBS at 37°C and 5% CO2.

The effect of representative Compounds described herein on cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay (Dojindo, Rockville, MD) according to the manufacturer's instructions. 200 μl of Molm13 cell suspension (10,000 cells/well) in culture medium were seeded in 96-well plates and cultured overnight. Each test compound was serially diluted in culture medium, and 20 μl of the diluted compound was added to the appropriate well of the cell plate. After addition of the test compound, the cells were incubated at 37°C under 5% CO2 for 4 days. At the end of 4 days, 10 μl of CCK-8 solution were added to each well of the plate and incubated for 1-4 h. The plates were read at 450 nm on a microplate reader (Epoch2, BioTek). Readings were normalized to carrier cells and IC50 was calculated by nonlinear regression analysis using GraphPad Prism 5 software.

The inhibitory activities of typical Compounds of this Description against the Molm13 cell line are presented in Table 6.

Table 6

Conn. No. Molm13
IC50 (nM)
(depends on Bcl-2) 1 47 2 85 6 6.4 10 182 11 1024 12 253 13 1.8 58 250 59 468

EXAMPLE 18

RS4;11 xenograft model

RS4;11 xenograft tumor tissues from mice treated with the Compounds described herein or ABT-199 at 25 mg/kg orally were analyzed for expression of PARP (Cell Signaling Technology (CST), #9523), caspase-3 (CST, #9661), and Bcl-2 (CST, #4223) by Western blotting. GAPDH was used as a loading control. The results are shown in Fig. 1 and Fig. 2.

The antitumor activity of Compound #6 (Compound 6) was also studied in the RS4;11 xenograft leukemia model. Human RS4;11 tumor cells were injected into nude mice and treatment was started on day 11 when the tumor size reached approximately 100 mm3. Compound #6 was administered by gavage at the indicated doses and schedules. Compound #6 inhibited tumor growth (Fig. 3) and did not cause weight loss in mice (Fig. 4).

EXAMPLE 19

Pharmacokinetics

The pharmacokinetics of ABT-199 and representative Compounds of this Description were evaluated in rats at an intravenous dose of 2 mg/kg and an oral dose of 20 mg/kg. The results are shown in Table 3.

Table 3

Compound Tmax (h) Cmax (ng/ml) AUC0-t (ng h/ml) AUC0-∞ (ng h/ml) t 1/2 (h) CL (IV)
(l/h/kg) Vss (intravenous)
(l/
kg) SVUINF
(in/in)
(h) F(AUC0-t) i/v By i/v By i/v By i/v By i/v By ABT-199 0.083 1.67 8737 5999 5435 20786 5446 20812 4.32 3.22 0.394 0.496 1.23 38.2% Conn. No. 3 0.083 2.00 4202 1318 2656 7630 2683 7775 4.94 4.46 0.769 1.86 2.37 29.0% Conn. No. 6 0.083 2.67 4174 2623 2899 13424 2915 13475 4.39 3.12 0.695 1.44 2.09 46.2%

EXAMPLE 20

Inhibition of MV4;11

The inhibitory activities of typical Compounds of this Description against the MV4;11 cell line are presented in Table 7.

Table 7

Conn. No. MV4;11
IC50
(µm) 22 0.05894 23 0.05457 24 243.0 25 5,154 26 6,711 27 0.01694 28 1,295 29 0.04819 30 0.02249 31 0,1161 34 5,674 35 3,598 36 0,04444 37 0.1544 38 0,1030 39 0.03374 40 0.002455 41 0,01811 42 0,08810 43 0,1260 66 >1000

Having now fully described the present invention, it will be apparent to those of ordinary skill in the art that the same may be accomplished under a wide and equivalent range of conditions, compositions, and other parameters without affecting the scope of the invention or any embodiment thereof.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the description and practice of the invention described herein. It is intended that the description and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated in the following claims.

All patents and publications cited in this document are incorporated herein by reference in their entirety.

Claims (18)

1. A compound or a pharmaceutically acceptable salt thereof having Formula II II, where Y represents -O-; R ² is -NO ₂ ; R ^4a is selected from the group consisting of unsubstituted C1-6 alkyl and (heterocyclo)alkyl, where (heterocyclo)alkyl is C1-4 alkyl substituted with one heterocyclyl group, where the heterocyclyl group is a 6-membered cyclic group containing one ring and one or two oxygen atoms. 2. A compound or a pharmaceutically acceptable salt thereof having Formula VII VII, where Y is selected from the group consisting of _-CH2- and -O; X ¹ , X ² and X ³ each independently represent -CR ⁸ =; R ² is -NO ₂ ; R ^4a is selected from the group consisting of unsubstituted C1-6 alkyl and (heterocyclo)alkyl; and R ⁸ is hydrogen; where (heterocyclo)alkyl is C1-4 alkyl substituted with a heterocyclyl group, where the heterocyclyl group is a 6-membered cyclic group containing one ring and one or two oxygen atoms. 3. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^4a is selected from the group consisting of , , , , , , . 4. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R ^4a is .