BCL-2 inhibitors

Abstract

The present invention is generally directed to inhibitors of BCL-2 proteins useful in the treatment of diseases and disorders modulated by said enzyme and having the Formula (A):

Description

Attorney Docket No.: Eil.23.0001 BCL-2 INHIBITORS Cross-Reference to Related Inventions

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application Ser. No. 63 / 584,850 filed September 22, 2023 and entitled “BCL-2 Inhibitors,” the entire content of which is incorporated by reference herein, for all purposes. Field of Invention

[0002] The present invention is directed to inhibitors of B-cell lymphoma 2 (BCL-2) proteins. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with BCL-2. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting BCL-2, methods of treating diseases or disorders associated with BCL-2, and methods of synthesizing these compounds. Background of the Invention

[0003] Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis.

[0004] Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischaemia. Conversely, deficits in the implementation of apoptosis play a significant role in the development of cancers and their chemoresistance, in auto-immune diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan, D. et al., Cell, 2000, 100, 57–70).

[0005] The BCL-2 family of proteins plays a major role in tumorogenesis. BCL-2 proteins are characterized based on the presence of BCL-2 homology (BH) domains. The anti- apoptotic proteins contain all the BH1-4 domains; the pro-apoptotic proteins contain either the BH3 domain only or multiple BH domains. The BH3 domain is necessary in executing the pro apoptotic function of these proteins. In anti-apoptotic proteins, the BH3 domain remains hidden or buried inside other BH domains and hence they exclusively function as protectors of cell survival. The BCL-2 proteins use BH domains to interact with each other. The anti-apoptotic BCL-2 proteins interact with pro-apoptotic members and inhibit their function to maintain cellular homeostasis. It is the shift in balance between anti-apoptotic and pro-apoptotic BCL-2 proteins that may decide the fate of cancer cells. 1 ASBAttorney Docket No.: Eil.23.0001

[0006] Cancer therapeutics targeting the BCL-2 family mainly have focused on neutralizing one or more anti-apoptotic members by inhibiting their function using small molecule inhibitors or by suppressing their expression utilizing anti-sense oligonucleotides. The concept was to inhibit the anti-apoptotic BCL-2 members' function and thus allowing pro-apoptotic members to induce cell death in cancer cells. However, cancer cells treated with Bcl-2 inhibitors were found to upregulate other anti-apoptotic BCL-2 or non-BCL-2 family proteins involved in cell survival, resulting in therapeutic resistance.

[0007] There is a need for therapeutic agents that can induce cell death in tumors or cancers with increased expression of BCL-2. This invention is intended to fill this unmet needs associated with current BCL-2 inhibition therapy. Summary of the Invention

[0008] In general the invention relates to compound of Formula (A): , andor tautomers thereof, wherein: A is selected from CH and N; 2 ASBAttorney Docket No.: Eil.23.0001cycloalkyl, or aryl is optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6alkyl; 3 ASBAttorney Docket No.: Eil.23.0001 R5is selected from H, halogen, -OH, -NH2, -CN, C1–C6alkyl, and C1–C6alkoxy; or R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered cycloalkyl or a 5-8 membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, C1-C6 alkyl, C1-C6 alkoxy; each R6is independently selected from H, halogen, -CN, -NO2, -NH2, -OR7, -COOR7, C1– C6alkyl, C3-C8cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen; each R7is independently selected from H, and C1–C6 alkyl; k is an integer selected from 0, 1, and 2; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 1, 2, and 3; o is an integer selected from 0, 1, 2, and 3; p is an integer selected from 1, 2, and 3; r is an integer selected from 0, 1, and 2.

[0009] A first aspect of the invention relates to compounds of Formula (I): (I),tautomers thereof, wherein: A is selected from CH and N; ;ASBAttorney Docket No.: Eil.23.0001 R3is selected ; R4is selected C3-C7 cycloalkyl, C6-C10 aryl, wherein alkyl,cycloalkyl, or aryl is one or more substitutients selected from -OH, -CN, halogen, C1–C6alkyl; R5is selected from H, halogen, -OH, -NH2, -CN, C1–C6 alkyl, and C1–C6 alkoxy; or R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered cycloalkyl or a 5-8 membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, C1-C6alkyl, C1-C6alkoxy; k is an integer selected from 0, 1, and 2; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 1, 2, and 3; o is an integer selected from 0, 1, 2, and 3; p is an integer selected from 1, 2, and 3.

[0010] A second aspect of the invention relates to compounds of Formula (II): ,thereof, wherein: A is selected from CH and N; ;ASBAttorney Docket No.: Eil.23.0001 R2is selected from -NO2, -SO2CH3, -SO2CF3; R3is selected ; R6is selected -NH2, -OR7, -COOR7, C1–C6alkyl, C3-C8cycloalkyl, wherein the or substituted with one or more halogen; each R7is independently selected from H, and C1–C6 alkyl; k is an integer selected from 0, 1, and 2; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 1, 2, and 3; o is an integer selected from 0, 1, 2, and 3; p is an integer selected from 1, 2, and 3; and r is an integer selected from 0, 1, and 2.

[0011] A third aspect of the invention relates to compounds of Formula (III): ,tautomers thereof, wherein: A is selected from CH and N; 6 ASBAttorney Docket No.: Eil.23.0001 , ,C1– C6alkyl, C3-C8cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen; each R7is independently selected from H, and C1–C6 alkyl; k is an integer selected from 0, 1, and 2.

[0012] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0013] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0014] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, 7 ASBAttorney Docket No.: Eil.23.0001 or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0015] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0016] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0017] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0018] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof. 8 ASBAttorney Docket No.: Eil.23.0001

[0020] Another aspect of the invention is directed to a method of inhibiting BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0021] Another aspect of the invention is directed to a method of inhibiting BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0022] Another aspect of the invention is directed to a method of inhibiting BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0023] Another aspect of the invention is directed to a method of inhibiting BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0025] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0026] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0027] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a 9 ASBAttorney Docket No.: Eil.23.0001 patient in need thereof an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0028] Another aspect of the present invention relates to compounds of Formula (A), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting BCL-2 proteins, such as Isoform 1 and Isoform 2.

[0029] Another aspect of the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting BCL-2 proteins, such as Isoform 1 and Isoform 2.

[0030] Another aspect of the present invention relates to compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting BCL-2 proteins, such as Isoform 1 and Isoform 2.

[0031] Another aspect of the present invention relates to compounds of Formula (III), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting BCL-2 proteins, such as Isoform 1 and Isoform 2.

[0032] Another aspect of the present invention relates to compounds of Formula (A), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0033] Another aspect of the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0034] Another aspect of the present invention relates to compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein. 10 ASBAttorney Docket No.: Eil.23.0001

[0035] Another aspect of the present invention relates to compounds of Formula (III), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0036] Another aspect of the present invention relates to the use of compounds of Formula (A), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting BCL- 2 proteins, such as Isoform 1 and Isoform 2.

[0037] Another aspect of the present invention relates to the use of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting BCL- 2 proteins, such as Isoform 1 and Isoform 2.

[0038] Another aspect of the present invention relates to the use of compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting BCL- 2 proteins, such as Isoform 1 and Isoform 2.

[0039] Another aspect of the present invention relates to the use of compounds of Formula (III), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting BCL- 2 proteins, such as Isoform 1 and Isoform 2.

[0040] Another aspect of the present invention relates to the use of compounds of Formula (A), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0041] Another aspect of the present invention relates to the use of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0042] Another aspect of the present invention relates to the use of compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein. 11 ASBAttorney Docket No.: Eil.23.0001

[0043] Another aspect of the present invention relates to the use of compounds of Formula (III), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0044] The present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0045] The present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0046] The present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0047] The present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0048] The present invention provides inhibitors of BCL-2 proteins that are therapeutic agents in the treatment of diseases such as cancer and metastasis.

[0049] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known BCL-2 protein inhibitors. The present disclosure also provides agents with novel mechanisms of action toward BCL-2 protein in the treatment of various types of diseases including cancer and metastasis. 12 ASBAttorney Docket No.: Eil.23.0001

[0050] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedures A–D).

[0051] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Examples 1–11).

[0052] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0053] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0055] Other features and advantages of the disclosure will be apparent from the following detailed description and claims Detailed Description of the Invention

[0056] The present disclosure relates to compounds and compositions that are capable of inhibiting the activity BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The disclosure features methods of treating, preventing or ameliorating a disease or disorder in which BCL-2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the 13 ASBAttorney Docket No.: Eil.23.0001 treatment of a variety of BCL-2 mediated diseases and disorders by inhibiting the activity of BCL- 2 proteins. Inhibition of BCL-2 can be an effective approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis. Decreasing BCL-2 activity can suppress cancer mutagenesis, dampen tumor evolution, and / or decrease the probability of adverse outcomes, such as drug resistance and / or metastases.

[0057] In particular, the present disclosure relates to compounds and compositions that are capable of inhibiting the activity BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The disclosure features methods of treating, preventing or ameliorating a disease or disorder in which BCL-2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of BCL-2 mediated diseases and disorders by inhibiting the activity of BCL- 2 proteins. Inhibition of BCL-2 can be an effective approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis. Decreasing BCL-2 activity can suppress cancer mutagenesis, dampen tumor evolution, and / or decrease the probability of adverse outcomes, such as drug resistance and / or metastases.

[0058] In particular the present disclosure relates to compounds and compositions that are capable of inhibiting the activity BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The disclosure features methods of treating, preventing or ameliorating a disease or disorder in which BCL-2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of BCL-2 mediated diseases and disorders by inhibiting the activity of BCL- 2 proteins. Inhibition of BCL-2 can be an effective approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis. Decreasing BCL-2 activity can suppress cancer mutagenesis, dampen tumor evolution, and / or decrease the probability of adverse outcomes, such as drug resistance and / or metastases.

[0059] In particular the present disclosure relates to compounds and compositions that are capable of inhibiting the activity BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2. The disclosure features methods of treating, preventing or ameliorating a disease or disorder in 14 ASBAttorney Docket No.: Eil.23.0001 which BCL-2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of BCL-2 mediated diseases and disorders by inhibiting the activity of BCL- 2 proteins. Inhibition of BCL-2 can be an effective approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis. Decreasing BCL-2 activity can suppress cancer mutagenesis, dampen tumor evolution, and / or decrease the probability of adverse outcomes, such as drug resistance and / or metastases.

[0060] The present invention relates to the compounds of Formula (A): , andand tautomers thereof, wherein A, G, R1, R2, R3, and k are described herein.

[0061] It is understood that, for a compound of Formula (A), A, G, R1, R2, R3, and k can each be, where applicable, selected from the groups described herein, and any group described herein for any A, G, R1, R2, R3, and k can be combined, where applicable, with any group described herein for one or more of the remainders of A, G, R1, R2, R3, and k.

[0062] In a first aspect of the invention, the compounds of Formula (I) are described: ,ASBAttorney Docket No.: Eil.23.0001 and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein A, R1, R2, R3, R4, R5, k, m, n, o and p are described herein.

[0001] It is understood that, for a compound of Formula (I), A, R1, R2, R3, R4, R5, k, m, n, o and p can each be, where applicable, selected from the groups described herein, and any group described herein for any A, R1, R2, R3, R4, R5, k, m, n, o and p can be combined, where applicable, with any group described herein for one or more of the remainders of A, R1, R2, R3, R4, R5, k, m, n, o and p.

[0002] In a second aspect of the invention, the compounds of Formula (II) are described: , andthereof, wherein A, R1, R2, R3, R6, R7, k, m, n, o, p and r are described herein.

[0003] It is understood that, for a compound of Formula (II), A, R1, R2, R3, R6, R7, k, m, n, o, p and r can each be, where applicable, selected from the groups described herein, and any group described herein for any A, R1, R2, R3, R6, R7, k, m, n, o, p and r can be combined, where applicable, with any group described herein for one or more of the remainders of A, R1, R2, R3, R6, R7, k, m, n, o, p and r.

[0004] In a third aspect of the invention, the compounds of Formula (III) are described: 16 ASBAttorney Docket No.: Eil.23.0001 , andtautomers thereof, wherein A, W, R1, R2, R3, R6, R7, and k are described herein.

[0005] It is understood that, for a compound of Formula (III), A, W, R1, R2, R3, R6, R7, and k can each be, where applicable, selected from the groups described herein, and any group described herein for any A, W, R1, R2, R3, R6, R7, and k can be combined, where applicable, with any group described herein for one or more of the remainders of A, W, R1, R2, R3, R6, R7, and k.

[0006] The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions

[0007] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0008] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. 17 ASBAttorney Docket No.: Eil.23.0001

[0009] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2- C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1- C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1- C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0010] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0011] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0012] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, - H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2- 18 ASBAttorney Docket No.: Eil.23.0001 C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, - OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, - S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings, the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0013] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3- c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3- c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2- a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ2-pyrrolo[2,1- b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo 19 ASBAttorney Docket No.: Eil.23.0001 [1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4- dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2- b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3- e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4- dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl.

[0014] “Halogen” or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0015] “Alkyl” refers to a straight or branched chain saturated hydrocarbon containing 1–12 carbon atoms. Examples of a (C1–C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0016] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1–12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0017] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2–12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. 20 ASBAttorney Docket No.: Eil.23.0001 Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

[0018] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2–12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

[0019] The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above- mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C1–C6alkylene. An alkylene may further be a C1–C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, - C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0020] “Cycloalkyl” means a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4- tetrahydronaphthalenyl, octahydropentalenyl, 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a- tetrahydropentalenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6- methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, adamantyl, and derivatives thereof. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0021] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” refers to a saturated or partially unsaturated 3–10 membered monocyclic, 7–12 membered bicyclic (fused, bridged, or spiro rings), or 11–14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, Se, or B), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. ¸1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, 21 ASBAttorney Docket No.: Eil.23.0001 oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H- spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2- azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa- azaspiro[3.4]octan-6-yl, and the like.

[0022] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0023] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0024] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.

[0025] The term “amine” as used herein refers to primary (R-NH2, R ^ H), secondary (R2-NH, R2^ H) and tertiary (R3-N, R ^ H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent.

[0026] The term “amino” as used herein means a substituent containing at least one nitrogen atom. Specifically, -NH2, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “amino”. 22 ASBAttorney Docket No.: Eil.23.0001

[0027] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0028] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0029] The present invention also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with2H and14C). Deuterated (i.e.,2H or D) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0030] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, 23 ASBAttorney Docket No.: Eil.23.0001 methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2- hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0031] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

[0032] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease or disorder in a subject as described herein.

[0033] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0034] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0035] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0036] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0037] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0038] The present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting BCL-2 proteins, such as Isoform 1 and Isoform 2, which are useful for the treatment of diseases and disorders associated with modulation of an BCL-2 protein. The invention further relates to compounds, or 24 ASBAttorney Docket No.: Eil.23.0001 pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which can be useful for inhibiting BCL-2.

[0039] In some embodiments, the compound of Formula (A) have the structure of Formula (I): (I), and tautomersthereof.

[0040] In some embodiments, the compound of Formula (A) have the structure of Formula (II): , andthereof.

[0041] In some embodiments, the compound of Formula (A) have the structure of Formula (III): ,ASBAttorney Docket No.: Eil.23.0001 and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0042] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A): , andthereof.

[0043] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1): Cl 1), andthereof. 26 ASBAttorney Docket No.: Eil.23.0001

[0044] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a): Cl R3a),thereof.

[0045] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a-I): Cl I),thereof.

[0046] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a-I-A): 27 ASBAttorney Docket No.: Eil.23.0001 Cl ,thereof.

[0047] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a-I-A-1): Cl Oand pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0048] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a-I-A-2): 28 ASBAttorney Docket No.: Eil.23.0001 Cl Oand pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0049] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a-I-A-3): Cl Oand pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0050] In some embodiments, the compounds of Formula (I) have the structure of Formula (I-A- 1-a-I-A-4): 29 ASBAttorney Docket No.: Eil.23.0001and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, stereoisomers, or tautomers thereof.

[0051] In some embodiments, A is CH. In some embodiments, A is N.

[0052] In some embodiments, R1is H. In some .

[0053] In some embodiments, R2is -NO2. In someIn some embodiments, R2is -SO2CF3.

[0054] In some embodiments, R3is H. In some embodiments, R3.

[0055] In some H.

[0056] In someC6-C10aryl, wherein alkyl, cycloalkyl, or aryl is optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6 alkyl. 30 ASBAttorney Docket No.: Eil.23.0001

[0057] In some embodiments, R4is C1–C6alkyl optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6 alkyl.

[0058] In some embodiments, R4is C1–C6 alkyl.

[0059] In some embodiments, R4is -CH3.

[0060] In some embodiments, R4is -CH2CH3.

[0061] In some embodiments, R4is -CH2CH2CH3.

[0062] In some embodiments, R4is -CH(CH3)2.

[0063] In some embodiments, R4is -CH2CH2CH2CH3.

[0064] In some embodiments, R4is -CHCH2(CH3)2.

[0065] In some embodiments, R4is -C(CH3)3.

[0066] In some embodiments, R4is C3-C7cycloalkyl optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6 alkyl.

[0067] In some embodiments, R4is C3-C7 cycloalkyl.

[0068] In some embodiments, R4is cyclopropyl.

[0069] In some embodiments, R4is cyclobutyl.

[0070] In some embodiments, R4is cyclopentyl.

[0071] In some embodiments, R4is cyclohexyl.

[0072] In some embodiments, R4is cycloheptyl.

[0073] In some embodiments, R4is C6-C10 aryl optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6alkyl.

[0074] In some embodiments, R4is C6-C10aryl.

[0075] In some .

[0076] In somehalogen, -OH, -NH2, -CN, C1–C6 alkyl, and C1–C6alkoxy.

[0077] In some embodiments, R5is H.

[0078] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered cycloalkyl or a 5-8 membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, C1-C6 alkyl, C1-C6 alkoxy. 31 ASBAttorney Docket No.: Eil.23.0001

[0079] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5 membered cycloalkyl.

[0080] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form a 6 membered cycloalkyl.

[0081] In some embodiments, k is an integer selected from 0, 1, and 2.

[0082] In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2.

[0083] In some embodiments, m is an integer selected from 0, 1, 2, and 3.

[0084] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0085] In some embodiments, n is an integer selected from 1, 2, and 3.

[0086] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0087] In some embodiments, o is an integer selected from 0, 1, 2, and 3.

[0088] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3.

[0089] In some embodiments, p is an integer selected from 1, 2, and 3.

[0090] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0091] In some embodiments, m is 1, n is 1, o is 2 and p is 2.

[0092] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A): Cl O , or

[0093] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1): 32 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0094] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a): Cl Oor pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0095] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I): Cl Oor pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof. 33 ASBAttorney Docket No.: Eil.23.0001

[0096] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0097] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A-1):

[0098] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A-1-a): 34 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0099] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A-1-b):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0100] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A-2): 35 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0101] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A-2-a):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0102] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- A-1-a-I-A-2-b): 36 ASBAttorney Docket No.: Eil.23.0001 or

[0103] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B): B), or

[0104] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1): 37 ASBAttorney Docket No.: Eil.23.0001 1), or

[0105] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a): a), or

[0106] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I): 38 ASBAttorney Docket No.: Eil.23.0001 I),

[0107] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0108] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A-1): 39 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0109] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A-1-a):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0110] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A-2): 40 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0111] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A-2-a):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0112] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A-3): 41 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0113] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-1-a-I-A-3-a):or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0114] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-2): 42 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0115] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-2-a):, or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0116] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-2-a-I): 43 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0117] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-2-a-I-A):a- , or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0118] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-2-a-I-A-1): 44 ASBAttorney Docket No.: Eil.23.0001or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0119] In some embodiments, the compounds of Formula (II) have the structure of Formula (II- B-2-a-I-A-1-a):a- , or pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, or tautomers thereof.

[0120] In some embodiments, A is CH. In some embodiments, A is N. 45 ASBAttorney Docket No.: Eil.23.0001

[0121] In some embodiments, R1is H. In some .

[0122] In some embodiments, R2is -NO2. In some In some 2embodiments, R is -SO2CF3.

[0123] In some embodiments, R3is H. In some embodiments, R3.

[0124] In some embodiments, R6is selected from H, halogen, -7-COOR , C1–C6 alkyl, C3-C8 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen.

[0125] In some embodiments, R6is H.

[0126] In some embodiments, R6is C1–C6 alkyl.

[0127] In some embodiments, R6is methyl.

[0128] In some embodiments, each R7is independently selected from H and C1–C6alkyl.

[0129] In some embodiments, R7is H.

[0130] In some embodiments, R7is C1–C6 alkyl.

[0131] In some embodiments, R7is methyl.

[0132] In some embodiments, k is an integer selected from 0, 1, and 2.

[0133] In some embodiments, k is 0.

[0134] In some embodiments, k is 1.

[0135] In some embodiments, k is 2.

[0136] In some embodiments, m is an integer selected from 0, 1, 2, and 3.

[0137] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0138] In some embodiments, n is an integer selected from 1, 2, and 3.

[0139] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0140] In some embodiments, o is an integer selected from 0, 1, 2, and 3.

[0141] In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. 46 ASBAttorney Docket No.: Eil.23.0001

[0142] In some embodiments, p is an integer selected from 1, 2, and 3.

[0143] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0144] In some embodiments, r is an integer selected from 0, 1, and 2.

[0145] In some embodiments, r is 0.

[0146] In some embodiments, r is 1.

[0147] In some embodiments, r is 2.

[0148] In some embodiments, k is 0, m is 1, n is 1, o is 2, p is 1, r is 1.

[0149] In some embodiments, k is 0, m is 2, n is 2, o is 1, p is 1, r is 1.

[0150] In some embodiments, k is 0, m is 1, n is 1, o is 2, p is 2, r is 1.

[0151] In some embodiments, k is 2, m is 1, n is 1, o is 1, p is 2, r is 1.

[0152] In some embodiments, k is 2, m is 1, n is 1, o is 2, p is 2, r is 1.

[0153] In some embodiments, k is 2, m is 1, n is 1, o is 2, p is 2, r is 2.

[0154] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A): O , or

[0155] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1): 47 ASBAttorney Docket No.: Eil.23.0001 Cl R31), or

[0156] (III- A-1-a): Cl a), or

[0157] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I): 48 ASBAttorney Docket No.: Eil.23.0001 Cl R3I), or(III- A-1-a-I-A): Cl , or

[0159] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-1): 49 ASBAttorney Docket No.: Eil.23.0001 or(III- A-1-a-I-A-1-a): or

[0161] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-1-b): 50 ASBAttorney Docket No.: Eil.23.0001 or

[0162] (III- A-1-a-I-A-2): or

[0163] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-2-a): 51 ASBAttorney Docket No.: Eil.23.0001 or(III- A-1-a-I-A-2-b): or

[0165] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-3): 52 ASBAttorney Docket No.: Eil.23.0001 or

[0166] (III- A-1-a-I-A-3-a): or

[0167] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-3-b): 53 ASBAttorney Docket No.: Eil.23.0001 or

[0168] (III- A-1-a-I-A-4): Cl O or

[0169] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-4-a): 54 ASBAttorney Docket No.: Eil.23.0001 Cl O or(III- A-1-a-I-A-4-b): Cl O or

[0171] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-5): 55 ASBAttorney Docket No.: Eil.23.0001 or(III- A-1-a-I-A-5-a): or

[0173] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-5-b): 56 ASBAttorney Docket No.: Eil.23.0001 or

[0174] (III- A-1-a-I-A-6): Cl O O or

[0175] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-6-a): 57 ASBAttorney Docket No.: Eil.23.0001 Cl O O or(III- A-1-a-I-A-6-b): Cl O O or

[0177] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-7): 58 ASBAttorney Docket No.: Eil.23.0001 Cl O or(III- A-1-a-I-A-7-a): Cl O or

[0179] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-7-b): 59 ASBAttorney Docket No.: Eil.23.0001 or

[0180] (III- A-1-a-I-A-8): or

[0181] In some embodiments, the compounds of Formula (III) have the structure of Formula (III- A-1-a-I-A-8-a): 60 ASBAttorney Docket No.: Eil.23.0001 or(III- A-1-a-I-A-8-b): or

[0183] In some embodiments, A is CH. In some embodiments, A is N. 61 ASBAttorney Docket No.: Eil.23.0001 , , beattached to the bounded parts in both ways using free valencies, as it is shown here:

[0186] In some .ASBAttorney Docket No.: Eil.23.0001

[0187] In some .

[0188] In some .

[0189] In some .

[0190] In .

[0191] In .

[0192] In some .

[0193] In some .

[0194] In some embodiments, R1is H. In some .

[0195] In some embodiments, R2is -NO2. In someIn some embodiments, R2is -SO2CF3.

[0196] In some embodiments, R3is H. In some embodiments, R3.

[0197] In some embodiments, each R6is independently selected-CN, -NO2, - NH2, -OR7, -COOR7, C1–C6alkyl, C3-C8cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen.

[0198] In some embodiments, R6is H. 63 ASBAttorney Docket No.: Eil.23.0001

[0199] In some embodiments, R6is C1–C6alkyl.

[0200] In some embodiments, R6is methyl.

[0201] In some embodiments, each R7is independently selected from H, and C1–C6 alkyl.

[0202] In some embodiments, R7is H.

[0203] In some embodiments, R7is C1–C6 alkyl.

[0204] In some embodiments, R7is methyl.

[0205] In some embodiments, geminal R6and R7are both H.

[0206] In some embodiments, geminal R6and R7are both C1–C6 alkyl.

[0207] In some embodiments, geminal R6and R7are both methyl.

[0208] In some embodiments, in one set of geminal substituents R6and R7, each from R6and R7is H, and in the second set of geminal R6and R7, each from R6and R7is a substituent described herein that is not H.

[0209] Non-limiting illustrative compounds of the present disclosure include the compounds from the table below: Cmpd Structure IUPAC name # ]- ]- - l- -64 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - - l- - - - l- -65 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - l- - - - l- -66 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - l- - - - l- - - - l- -67 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - - l- - - -68 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - 3- l- - - 3- l- - - 3- l- -69 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - ]- - l- - - - l- - - - - l- - - - - l- -ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - - l- - - - - l- - - -71 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name 1- - - - ]- 1- - ]-72 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - ]- - ]- ]-

[0210] In some embodiments, the compound of Formula (I) is selected from: 4-[2-[1-(4-chlorophenyl)ethyl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4- (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[2-(5-chloroindan-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4-(tetrahydropyran- 4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[2-[1-(4-chlorophenyl)propyl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4- (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 73 ASBAttorney Docket No.: Eil.23.0001 4-[2-[1-(4-chlorophenyl)-2-methyl-propyl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4- (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[2-[(4-chlorophenyl)-cyclopentyl-methyl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4- (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[2-[bis(4-chlorophenyl)methyl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4- (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0211] In some embodiments, the compound of Formula (II) is selected from: 4-[2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.4]octan-7-yl]-N-[3-nitro-4- (tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[7-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-2-yl]-N-[3-nitro- 4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[3-nitro- 4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[2-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-2-en-1-yl]-2,7-diazaspiro[3.4]octan-7- yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide; 4-[2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[4-(3- morpholinopropylamino)-3-nitro-phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide; 4-[2-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-7- yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide; 74 ASBAttorney Docket No.: Eil.23.0001 4-[2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.4]octan-7-yl]-N-[4-[[3- morpholino-1-(phenylsulfanylmethyl)propyl]amino]-3-(trifluoromethylsulfonyl)- phenyl]sulfonylbenzamide; 4-[2-[2-(4-chlorophenyl)cyclohept-2-en-1-yl]-2,7-diazaspiro[3.4]octan-7-yl]-N-[4-[[3- morpholino-1-(phenylsulfanylmethyl)propyl]amino]-3-(trifluoromethylsulfonyl)- phenyl]sulfonylbenzamide; 4-[2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[4-[[3- morpholino-1-(phenylsulfanylmethyl)propyl]-amino]-3-(trifluoromethylsulfonyl)- phenyl]sulfonylbenzamide; 4-[2-[2-(4-chlorophenyl)cyclohept-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[4-[[3- morpholino-1-(phenylsulfanylmethyl)propyl]-amino]-3-(trifluoromethylsulfonyl)- phenyl]sulfonylbenzamide; 4-[2-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-2-en-1-yl]-2,7-diazaspiro[3.4]octan-7- yl]-N-[4-[[3-morpholino-1-(phenylsulfanylmethyl)propyl]-amino]-3-(trifluoromethylsulfonyl)- phenyl]sulfonylbenzamide; 4-[2-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonan-7- yl]-N-[4-[[3-morpholino-1-(phenylsulfanylmethyl)propyl]-amino]-3-(trifluoromethylsulfonyl)- phenyl]sulfonylbenzamide; or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0212] In some embodiments, the compound of Formula (III) is selected from: 4-[2-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.4]octan-7-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[2-[[2-(4-chlorophenyl)-5,5-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.4]octan-7-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[7-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.4]octan-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 75 ASBAttorney Docket No.: Eil.23.0001 4-[7-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.5]nonan-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[2-[[2-(4-chlorophenyl)-4,4-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[7-[[2-(4-chlorophenyl)-5,5-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.5]nonan-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; 4-[2-[[2-(4-chlorophenyl)-5,5-dimethyl-cyclohexen-1-yl]methyl]-2,7- diazaspiro[3.5]nonan-7-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

[0213] In some embodiments, the compound is a pharmaceutically acceptable salt. In some embodiments, the compound is a hydrochloride salt.

[0214] It should be understood that all stereoisomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans- configuration. All tautomeric forms are also intended to be included.

[0215] Compounds of the invention, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

[0216] The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional stereoisomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. each compound herein disclosed includes all the enantiomers that conform to the 76 ASBAttorney Docket No.: Eil.23.0001 general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0217] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.

[0218] It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

[0219] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, 77 ASBAttorney Docket No.: Eil.23.0001 ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

[0220] The compounds of Formula A may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0221] The compounds of Formula I may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0222] The compounds of Formula II may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0223] The compounds of Formula III may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0224] The present invention relates to compounds which are modulators of BCL-2 proteins. In one embodiment, the compounds of the present invention are inhibitors of BCL-2 proteins. In another embodiment, the BCL-2 proteins is Isoform 1. In another embodiment, the BCL-2 proteins is Isoform 2.

[0225] In some embodiments, the compounds of Formula A are selective inhibitors of BCL-2 proteins.

[0226] In some embodiments, the compounds of Formula I are selective inhibitors of BCL-2 proteins.

[0227] In some embodiments, the compounds of Formula II are selective inhibitors of BCL-2 proteins.

[0228] In some embodiments, the compounds of Formula III are selective inhibitors of BCL-2 proteins.

[0229] In some embodiments, the compounds of Formula A are dual inhibitors of BCL-2 / BCL- xL proteins.

[0230] In some embodiments, the compounds of Formula I are dual inhibitors of BCL-2 / BCL-xL proteins. 78 ASBAttorney Docket No.: Eil.23.0001

[0231] In some embodiments, the compounds of Formula II are dual inhibitors of BCL-2 / BCL-xL proteins.

[0232] In some embodiments, the compounds of Formula III are dual inhibitors of BCL-2 / BCL- xL proteins.

[0233] The invention is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof. Method of Synthesizing the Compounds

[0234] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0235] The compounds of any of Formulas (A), (I), (II) or (III) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formulas (A), (I), (II), (III). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994). 79 ASBAttorney Docket No.: Eil.23.0001

[0236] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes. Preparation of Compounds

[0237] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedures A–D which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.

[0238] GENERAL PROCEDURE A OASBAttorney Docket No.: Eil.23.0001 Cl Cl Cl OH O

[0240] GENERAL PROCEDURE C 81 ASBAttorney Docket No.: Eil.23.000182 ASBAttorney Docket No.: Eil.23.0001

[0242] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount the compositions and compounds of Formula (A). 83 ASBAttorney Docket No.: Eil.23.0001

[0243] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount the compositions and compounds of Formula (I).

[0244] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount the compositions and compounds of Formula (II).

[0245] Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount the compositions and compounds of Formula (III).

[0246] In another aspect, the present invention is directed to a method of inhibiting BCL-2 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A).

[0247] In another aspect, the present invention is directed to a method of inhibiting BCL-2 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I).

[0248] In another aspect, the present invention is directed to a method of inhibiting BCL-2 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (II).

[0249] In another aspect, the present invention is directed to a method of inhibiting BCL-2 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (III).

[0250] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of BCL-2 proteins, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (A). In one embodiment, the disease may be, but not limited to, cancer and metastasis. 84 ASBAttorney Docket No.: Eil.23.0001

[0251] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of BCL-2 proteins, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). In one embodiment, the disease may be, but not limited to, cancer and metastasis.

[0252] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of BCL-2 proteins, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (II). In one embodiment, the disease may be, but not limited to, cancer and metastasis.

[0253] Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of BCL-2 proteins, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (III). In one embodiment, the disease may be, but not limited to, cancer and metastasis.

[0254] The present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (A).

[0255] The present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (I).

[0256] The present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (II).

[0257] The present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a 85 ASBAttorney Docket No.: Eil.23.0001 disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (III).

[0258] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (A).

[0259] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (I).

[0260] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (II).

[0261] In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (III).

[0262] Another aspect of the present invention relates to a compound of Formula (A) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.

[0263] Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.

[0264] Another aspect of the present invention relates to a compound of Formula (II) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.

[0265] Another aspect of the present invention relates to a compound of Formula (III) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.

[0266] In another aspect, the present invention relates to the use of a compound of Formula (A) in the treatment of a disease associated with inhibiting BCL-2 proteins.

[0267] In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting BCL-2 proteins.

[0268] In another aspect, the present invention relates to the use of a compound of Formula (II) in the treatment of a disease associated with inhibiting BCL-2 proteins.

[0269] In another aspect, the present invention relates to the use of a compound of Formula (III) in the treatment of a disease associated with inhibiting BCL-2 proteins. 86 ASBAttorney Docket No.: Eil.23.0001

[0270] Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (A).

[0271] Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

[0272] Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (II).

[0273] Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (III).

[0274] Another aspect of the invention relates to a method of treating or preventing cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (A).

[0275] Another aspect of the invention relates to a method of treating or preventing cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

[0276] Another aspect of the invention relates to a method of treating or preventing cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (II).

[0277] Another aspect of the invention relates to a method of treating or preventing cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (III).

[0278] In one embodiment, the present invention relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in treatment, prevention, inhibition or elimination of a disease or disorder associated with cancer.

[0279] In another embodiment, the present invention relates to a compound of Formula (A) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, 87 ASBAttorney Docket No.: Eil.23.0001 selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0280] In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0281] In another embodiment, the present invention relates to a compound of Formula (II) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL). 88 ASBAttorney Docket No.: Eil.23.0001

[0282] In another embodiment, the present invention relates to a compound of Formula (III) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0283] In another embodiment, the present invention relates to a compound of Formula (A) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0284] In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0285] In another embodiment, the present invention relates to a compound of Formula (II) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0286] In another embodiment, the present invention relates to a compound of Formula (III) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, 89 ASBAttorney Docket No.: Eil.23.0001 marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

[0287] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0288] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0289] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0290] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (III) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0291] In one embodiment, are provided methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer or cell proliferative disorder, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (A).

[0292] In one embodiment, are provided methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer or cell proliferative disorder, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I).

[0293] In one embodiment, are provided methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer or cell proliferative disorder, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (II).

[0294] In one embodiment, are provided methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer or cell proliferative disorder, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (III). 90 ASBAttorney Docket No.: Eil.23.0001

[0295] One therapeutic use of the compounds or compositions of the present invention which inhibit BCL-2 proteins is to provide treatment to patients or subjects suffering from a cancer or cell proliferative disorder.

[0296] The disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and / or prevent the development thereof in subjects.

[0297] Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0298] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[0299] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or 91 ASBAttorney Docket No.: Eil.23.0001 dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0300] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

[0301] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0302] The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.

[0303] Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate. 92 ASBAttorney Docket No.: Eil.23.0001

[0304] Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

[0305] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.

[0306] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.

[0307] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent. Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (III) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. In some embodiments, the pharmaceutical composition can further comprise an additional pharmaceutically active agent.

[0308] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0309] The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. 93 ASBAttorney Docket No.: Eil.23.0001

[0310] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored. EXAMPLES

[0311] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0312] Abbreviations used in the following examples and elsewhere herein are: ACN acetonytrile br. broad aq. aqueous DCM dichloromethane DIAD diisopropyl azodiformate DIBAL-H diisobutylaluminium hydride DMAP N,N-dimethylpyridin-4-amine DMSO dimethyl sulfoxide EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide ESI electrospray ionization h hour(s) Hal halogen HPLC high pressure (or performance) liquid chromatography LCMS liquid chromatography mass spectrometry m multiplet 94 ASBAttorney Docket No.: Eil.23.0001 M molar MHz megahertz min minutes NMR nuclear magnetic resonance ppm parts per million rt room temperature sat. saturated STAB sodium triacetoxyborohydride TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran EXAMPLES Synthesis of Intermediates Synthesis of 4-{2-[1-(4-chlorophenyl)ethyl]-2,7-diazaspiro[3.5]non-7-yl}-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzoic acid (P4) 95 ASBAttorney Docket No.: Eil.23.0001 Cl boc boc N O N7- carboxylate (P1). To solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (150 mg, 0.66 mmol, 1 eq), 1- (4-chlorophenyl)ethanone (105 mg, 0.66) in DCM (5 mL) STAB (200 mg, 1.0 mmol) was added. Then the reaction mixture was stirred at rt for 12 h. Then reaction mixture was treated with aq. sat. solution of sodium bicarbonate to adjust pH = 7, and extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford 130 mg (62 %) of the title compound P1 that was used for the next step without additional purification.

[0314] Preparation 2. 2-[1-(4-Chlorophenyl)ethyl]-2,7-diazaspiro[3.5]nonane hydrochloride (P2). 96 ASBAttorney Docket No.: Eil.23.0001 HCl solution 3M in dioxane (1.2 mL, 3.5 mmol) was added to a stirred solution of the compound P1 (130 mg, 0.35 mmol) in DCM (2 mL). The resulted mixture was stirred overnight at ambient temperature and evaporated under reduced pressure to afford 110 mg (98%) of the title compound P2 that was used for the next step without additional purification.

[0315] Preparation 3. tert-Butyl 5-(2-(tert-butoxycarbonyl)-5-{2-[1-(4-chlorophenyl)ethyl]- 2,7-diazaspiro[3.5]non-7-yl}phenoxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (P3). A mixture of tert-butyl 5-[5-bromo-2-(tert-butoxycarbonyl)phenoxy]-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate P27 (178 mg, 0.37 mmol), P2 (110 mg, 0.37 mmol), palladium diacetate (5.6 mg, 0.025 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (68 mg, 0.1 mmol), and cesium carbonate (590 mg, 1.8 mmol) in toluene (2 mL) was heated under Argon at 100°C for 16 h, cooled to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), obtained solution was filtered through Celite pad, and filtrate was washed with water, and then with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (5 → 50 %) and DCM to afford 195 mg (80 %) of the title compound P3.

[0316] Preparation 4. 4-{2-[1-(4-Chlorophenyl)ethyl]-2,7-diazaspiro[3.5]non-7-yl}-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (P4). TFA (0.2 mL, 2.8 mmol) was added to a stirred solution of compound P3 (195 mg, 0.29 mmol) in DCM (1 mL), the mixture was stirred at rt for 12 h, then volatiles were removed under reduced pressure, the residue was diluted with ether and the precipitate was filtered off to afford 150 mg (99 %) of the title compound P4 as trifluoro acetic salt that was used for the next step without further purification. Synthesis of 4-{2-[1-(4-chlorophenyl)ethyl]-2,7-diazaspiro[3.5]non-7-yl}-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzoic acid (P8) 97 ASBAttorney Docket No.: Eil.23.00012,7- diazaspiro[3.5]nonane-7-carboxylate (P5). To solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.88 mmol, 1 eq), (4- chlorophenyl)(cyclopentyl)methanone (184 mg, 0.88), TEA (0.2 mL, 1.3 mmol) in toluene (5 mL) Ti(iOPr)4 (0.4 mg, 1.3 mmol) was added. Then the reaction mixture was reflux for 12 h. Then reaction mixture was evaporated, the residue was added methanol and NaBH4 (67 mg, 1.8 mmol). The mixture was stirred 5 h, then treated with aq. sat. solution of sodium bicarbonate to adjust pH = 7, and extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford 100 mg (27 %) of the title compound that was used for the next step without additional purification. 98 ASBAttorney Docket No.: Eil.23.0001

[0318] Preparation 6. 2-[(4-Chlorophenyl)(cyclopentyl)methyl]-2,7-diazaspiro[3.5]nonane hydrochloride (P6). HCl solution 3M in dioxane (0.8 mL, 2.4 mmol) was added to a stirred solution of the compound P5 (100 mg, 0.24 mmol) in DCM (2 mL). The resulted mixture was stirred overnight at ambient temperature and evaporated under reduced pressure to afford 100 mg (99%) of the title compound P6 that was used for the next step without additional purification.

[0319] Preparation 7. tert-Butyl 5-(2-(tert-butoxycarbonyl)-5-{2-[(4- chlorophenyl)(cyclopentyl)methyl]-2,7-diazaspiro[3.5]non-7-yl}phenoxy)-1H-pyrrolo[2,3- b]pyridine-1-carboxylate (P7). A mixture of tert-butyl 5-[5-bromo-2-(tert-butoxycarbonyl)phenoxy]-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate P27 (153 mg, 0.31 mmol), compound P6 (100 mg, 0.31 mmol), palladium diacetate (10 mg, 0.047 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (68 mg, 0.1 mmol), and cesium carbonate (510 mg, 1.6 mmol) in toluene (2 mL) was heated under Argon at 100°C for 16 h, cooled to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), obtained solution was filtered through Celite pad, and filtrate was washed with water, and then with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (5 → 50 %) and DCM to afford 100 mg (44 %) of the title compound P7.

[0320] Preparation 8. 4-{2-[1-(4-Chlorophenyl)ethyl]-2,7-diazaspiro[3.5]non-7-yl}-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (P8). TFA (0.1 mL, 1.4 mmol) was added to a stirred solution of compound P7 (100 mg, 0.14 mmol) in DCM (1 mL), the mixture was stirred at rt for 12 h, then volatiles were removed under reduced pressure, the residue was diluted with ether and the precipitate was filtered off to afford 80 mg (99 %) of the title compound as trifluoroacetic salt that was used for the next step without further purification. Synthesis of 4-{2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]non-7-yl}-2- (1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (P12) 99 ASBAttorney Docket No.: Eil.23.0001

[0321] Preparation 9. tert-Butyl 2-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7- diazaspiro[3.5]nonane-7-carboxylate (P9). To solution of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (100 mg, 0.44 mmol, 1 eq), 1- (6-bromocyclohex-1-en-1-yl)-4-chlorobenzene (130 mg, 0.44), K2CO3 (90 mg, 0.66 mmol) in ACN (5 mL) was refluxed for 12 h. Then reaction mixture was evaporated in vacuo. The residue was subjected to silica flash chromatography eluting with a mixture of MeOH (0→ 10 %) and DCM to afford 190 mg (44 %) of the title compound P9.

[0322] Preparation 10. 2-[2-(4-Chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]nonane hydrochloride (P10). 3M HCl solution in dioxane (0.8 mL, 2.4 mmol) was added to a stirred solution of the compound P9 (100 mg, 0.24 mmol) in DCM (2 mL). The resulted mixture was stirred overnight at ambient 100 ASBAttorney Docket No.: Eil.23.0001 temperature and evaporated under reduced pressure to afford 100 mg (99%) of the title compound P10 that was used for the next step without additional purification.

[0323] Preparation 11. tert-Butyl 5-(2-(tert-butoxycarbonyl)-5-{2-[2-(4-chlorophenyl)cyclohex- 2-en-1-yl]-2,7-diazaspiro[3.5]non-7-yl}phenoxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (P11). A mixture of tert-butyl 5-[5-bromo-2-(tert-butoxycarbonyl)phenoxy]-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate P27 (153 mg, 0.31 mmol), compound P10 (100 mg, 0.31 mmol), palladium diacetate (10 mg, 0.047 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (68 mg, 0.1 mmol), and cesium carbonate (510 mg, 1.6 mmol) in toluene (2 mL) was heated under Argon at 100°C for 16 h, cooled to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in DCM (30 mL), obtained solution was filtered through Celite pad, and filtrate was washed with water, and then with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was subjected to silica flash chromatography eluting with a mixture of EtOAc (5 → 50 %) and DCM to afford 100 mg (44 %) of the title compound P11.

[0324] Preparation 12. 4-{2-[2-(4-Chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]non-7- yl}-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (P12). TFA (0.1 mL, 1.4 mmol) was added to a stirred solution of compound P11 (100 mg, 0.14 mmol) in DCM (1 mL), the mixture was stirred at rt for 12 h, then volatiles were removed under reduced pressure, the residue was diluted with ether and the precipitate was filtered off to afford 80 mg (99 %) of the title compound P12 as trifluoroacetic salt that was used for the next step without further purification. Synthesis of (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)benzenesulfonamide (P18) 101 ASBAttorney Docket No.: Eil.23.0001 3

[0325] Preparation 13. (R)-Benzyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (P13). N-Methylmorpholine (4.41 ml, 40.1 mmol) and ethyl chloroformate (4.43 ml, 34.2 mmol) were added into a stirred solution of N-Boc D-aspartic acid 4-benzyl ester (10.0 g, 30.9 mmol) in THF (250 ml) at -25°C. The resulting mixture was stirred at -25°C for 30 min and allowed to warm to -15°C. A solution of NaBH4(2.94 g, 77.7 mmol) in water (100 ml) was then added to the mixture in one portion resulting in evolution of gas. The mixture was stirred for 30 min at -15°C and 102 ASBAttorney Docket No.: Eil.23.0001 quenched with 1N HCl (aq.). The solution was extracted with ethyl acetate three times, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product P13 (12.5g; 98%) was used directly in the next step.1H NMR (400 MHz, CDCl3), δ: 7.48–7.29 (m, 5H), 5.17 (br s, 1H), 5.12 (s, 2H), 4.05–3.93 (m, 1H), 3.69 (t, J = 5.2 Hz, 2H), 2.67 (d, J = 6.1 Hz, 2H), 2.38 (br s, 1H), 1.42 (s, 9H). LCMS (ESI)+m / z: 310.3 [MH]+.

[0326] Preparation 14. (R)-Benzyl 3-(tert-butoxycarbonylamino)-4-(phenylthio)butanoate (P14). Thiophenol (3.7 g, 0.033 mol) and PPh3 (9.66 g, 0.036 mol) was dissolved in 100 mL THF and the reaction mixture was cooled to -10°C. DIAD (6.83 g, 0.033 mol) was added to reaction mixture at -10°C dropwise, stirred 30 min and added compound P13 (9.5 g, 0.03 mol) in 20 mL THF. The reaction mixture was stirred at rt overnight. Evaporation of the solvents under reduced pressure gave an oily residue which was purified by column chromatography (DCM) to give compound P14 (6.0 g, yield 49.5%). LCMS (ESI)+m / z: 402.5 [MH]+.

[0327] Preparation 15. (R)-Benzyl 4-oxo-1-(phenylthio)butan-2-ylcarbamate (P15). Diisobutylaluminium hydride (DIBAL-H; 1.2 M in toluene, 21.3 ml, 31.7 mmol) was added dropwise to a solution of compound P14 (6.0 g, 13.7 mmol) in toluene (80 ml) at -78°C and stirred for 3 h. The reaction mixture was then quenched with NH4Cl (aq.), warmed to rt, and diluted with ethyl acetate. The resulting mixture was filtered, and the filtrate was poured into water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and were evaporated to dryness under reduced pressure. The crude product was purified by silica gel flash column chromatography using ethyl acetate and hexanes as eluent to afford the title compound P15 (2.2 g, yield 48.5%).1H NMR (400 MHz, DMSO-d6), δ: 9.59 (s, 1H), 7.52-7.12 (m, 10H), 5.1 (s, 2H), 4.1-4.05 (m, 1H), 3.17-3.11 (m, 2H), 2.83-2.76 (m, 1H), 2.65-2.56 (m, 1H). LCMS (ESI)+m / z: 330.4 [MH]+.

[0328] Preparation 16. (R)-Benzyl 4-morpholino-1-(phenylthio)butan-2-ylcarbamate (P16). To a mixture of compound P15 (2.2 g, 5.6 mmol), morpholine (0.68 g, 7.9 mmol) and TEA (3.9 ml, 28.4 mmol) in DCM (75 ml) was added NaBH(OAc)3 (2.4 g, 11.35 mmol). The resulting solution was stirred at rt overnight before being poured into water and extracted with DCM. The 103 ASBAttorney Docket No.: Eil.23.0001 combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified by silica gel flash column chromatography using ethyl acetate and hexanes as eluent to afford the title compound (1.9 g, yield 84%).1H NMR (400 MHz, DMSO-d6), δ: 7.45–7.12 (m, 10H), 5.1(s, 2H), 4.10-4.07 (m, 1H), 3.73- 3.64 (br m,1H), 3.45-3.40 (m, 4H), 3.24–3.23 (m, 4H), 3.17-3.16 (m, 1H), 3.06-3.04 (d, J = 6.8Hz, 2H), 1.83-1.79 (br m,1H), 1.65-1.61 (br. m, 1H). LCMS (ESI)+m / z: 401 [MH]+.

[0329] Preparation 17. (R)-4-morpholino-1-(phenylthio)butan-2-amine (P17). Compound P16 (1.9 g, 4.7 mmol) was dissolved in DCM (10 ml), then added the 30% solution of HBr in AcOH (7ml). The resulting solution was stirred at rt 5 h and evaporated to dryness under reduced pressure. The crude product P17 was used in next step without purification (1.9 g, yield 86%). LCMS (ESI)+m / z: 267 [MH]+.

[0330] Preparation 18. (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)benzenesulfonamide (P18). A mixture of compounds P17 (1.9 g, 4.4 mmol) and 4-fluoro-3- (trifluoromethylsulfonyl)benzenesulfonamide (1.48 g, 4.84 mmol) and TEA (3.4ml, 24 mmol) in ACN (50 ml) was stirred under reflux for 4 h. Solvents were evaporated under reduced pressure and the crude product was purified by silica gel flash column chromatography using ethyl acetate and hexanes as eluent to afford the title compound P18 (1.92 g, yield 79%) as a white solid.1H NMR (400 MHz, DMSO-d6), δ: 7.98 (s, 1H), 7.42–7.37 (m, 6H), 7.22 (t, J = 7.2Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.9 (d, J = 8.8Hz, 1H), 6.51 (br. s, 1H), 4.11 (br s, 1H), 3.4 (m, 2H), 3.25-3.19 (m, 6H), 2.4-2.25 (m, 2H), 2.24-2.11 (m, 2H), 2.19–2.05 (m, 1H). LCMS (ESI)+m / z: 554.6 [MH]+. Synthesis of 4-(2-(2-(4-chlorophenyl)cyclohex-2-enyl)-2,6-diazaspiro[3.4]octan-6-yl)benzoic acid (P21) 104 ASBAttorney Docket No.: Eil.23.0001To a solution of 2-(4-chlorophenyl)-2-cyclohexen-1-ol (0.5 g, 2.4 mmol) and CBr4(1.03 g, 3.1 mmol) in DCM (50 mL) was added PPh3 (0.94 g, 3.6 mmol) at 0°C and the solution was stirred at rt for 2.5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane / ethyl acetate, 20 / 1) to give 3-bromo-2-(4-chlorophenyl)cyclohexene P19 (0.65 g, yield 98%).1H NMR (400 MHz, DMSO-d6), δ: 7.48 (d, J = 8.8Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2H), 6.27 (m, 1H), 5.63 (br. s, 1H), 2.41-2.25 (m, 3 H), 2.16-2.07 (m, 1H), 1.92-1.81 (m, 1H), 1.78-1.74 (m, 1H), 7.15−7.30 (m, 1H).

[0332] Preparation 20. tert-Butyl 4-(2-(2-(4-chlorophenyl)cyclohex-2-enyl)-2,6- diazaspiro[3.4]octan-6-yl)benzoate (P20). Compound P19 (0.65 g, 2.4 mmol) was dissolved in ACN (6.0 mL). To this solution were added K2CO3(0.66g, 4.8 mmol) and tert-butyl 4-(2,6-diazaspiro[3.4]octan-6-yl)benzoate (0.76 g, 3.6 mmol), and the solution was stirred at rt for 15 h. Water was added at 0°C and the aq. layer was 105 ASBAttorney Docket No.: Eil.23.0001 extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate, 6 / 1) to give a compound P20 (0.4 g, 41%).1H NMR (400 MHz, CDCl3), δ: 7.70-7.64 (m, 2 H), 7.51 (d, J = 8.8Hz, 1 H), 7.35 (s, 4H), 6.93 (d, J = 10,8Hz, 1H), 6.87 (d, J = 9.2Hz, 1H), 5.83 (m, 1 H), 3.36 (m, 1 H), 3.15-3.05 (m, 4 H), 2.86-2.78 (m, 4 H), 2.14 (m, 2H), 1.79-1.75 (m, 4 H), 1.5-1.41 (m, 2 H), 1.35 (s, 9 H). LCMS (ESI)+m / z: 480 [MH]+.

[0333] Preparation 21. 4-(2-(2-(4-Chlorophenyl)cyclohex-2-enyl)-2,6-diazaspiro[3.4]octan-6- yl)benzoic acid (P21). To a solution of compound P20 (0.4 g, 0.99 mmol) in DCM (10 ml) was added 3M solution of HCl in dioxane (10 ml) and the reaction mixture was stirred for 24 h at rt. Upon completion, the mixture was evaporated under vacuum and the compound P21 was used in next step without purification (0.36 g, 99%). LCMS (ESI)+m / z: 376 [MH]+. Synthesis of 4-(2-(2-(4-chlorophenyl)cyclohex-2-enyl)-2,7-diazaspiro[3.5]nonan-7-yl)benzoic acid (P24) 106 ASBAttorney Docket No.: Eil.23.0001

[0334] To a solution of 2-(4-chlorophenyl)-2-cyclohexen-1-ol (0.5 g, 2.4 mmol) and CBr4 (1.03 g, 3.1 mmol) in DCM (50 mL) was added PPh3(0.94 g, 3.6 mmol) at 0°C and the solution was stirred at rt for 2.5 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel (hexane / ethyl acetate, 20 / 1) to give 3-bromo-2-(4-chlorophenyl)cyclohexene P22 (0.65 g, yield 98%).1H NMR (400 MHz, DMSO-d6), δ: 7.48 (d, J = 8.8Hz, 2 H), 7.39 (d, J = 8.6Hz, 2H), 6.27 (m, 1 H), 5.63 (br s, 1 H), 2.41-2.25 (m, 3 H), 2.16-2.07 (m, 1 H), 1.92-1.81 (m, 1 H), 1.78-1.74(m, 1 H), 7.15−7.30 (m, 1H).

[0335] Preparation 23. tert-Butyl 4-(2-(2-(4-chlorophenyl)cyclohex-2-enyl)-2,7- diazaspiro[3.5]nonan-7-yl)benzoate (P23). 107 ASBAttorney Docket No.: Eil.23.0001 Compound P22 (0.18 g, 0.66 mmol) was dissolved in ACN (3.0 mL). To this solution were added K2CO3 (0.27 g, 1.99 mmol) and tert-butyl 4-(2,7-diazaspiro[3.5]nonan-7-yl)benzoate (0.2 g, 0.66 mmol), and the solution was stirred at rt for 15 h. Water was added at 0°C and the aq. layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (hexane / ethyl acetate, 6 / 1) to give a compound P23 (0.23 g, 70%).1H NMR (400 MHz, CDCl3), δ: 7.70-7.64 (m, 2H), 7.51 (d, J = 8.8Hz, 1H), 7.35 (s, 4H), 6.93 (d, J = 10.8Hz, 1H), 6.87 (d, J = 9.2Hz, 1H), 6.16 (m, 0.5H), 5.88 (m, 0.5H), 3.70 (m, 1H), 3.20 (m,2H), 2.70 (m, 2H), 2.20 (m, 4H), 1.75-1.55 (m, 10H), 1.50 (d, J = 5.2Hz, 9H). LCMS (ESI)+m / z: 493 [MH]+.

[0336] Preparation 24. 4-(2-(2-(4-Chlorophenyl)cyclohex-2-enyl)-2,7-diazaspiro[3.5]nonan-7- yl)benzoic acid (P24). To a solution of compound P23 (0.14 g, 0.28 mmol) in DCM (7 ml) was added 3M solution of HCl in dioxane (2 ml) and the reaction mixture was stirred for 24 hours at room temperature. Upon completion, the mixture was evaporated under vacuum and the compound P24 was used in next step without purification (0.12 g, 99%). LCMS (ESI)+m / z: 437 [MH]+. Synthesis of tert-butyl 5-[5-bromo-2-(tert-butoxycarbonyl)phenoxy]-1H-pyrrolo[2,3-b]pyridine- 1-carboxylate (P27) 108 ASBAttorney Docket No.: Eil.23.0001tert- . To a mixture of 4-bromo-2-fluorobenzoic acid (8,8 g, 0.04 mol), tert-BuOH (8,7 g, 0.12 mol), DMAP (0.24 g, 2 mmol) and pyridine (3.1 g, 0.04 mol) in DCM (200 ml) a solution of Boc2O (17 g, 0.08 mol) in DCM (50ml) was added dropwise at rt. Reaction mixture was stirred overnight, diluted with water and the organic layer was separated. The aq. one was extracted with DCM (2 x 70 mL). Combined organic layers were washed with H2SO4 (5%), brine, dried over Na2SO4, and concentrated on rotary evaporator under reduced pressure. The residue was subjected to silica flash chromatography eluting with DCM – hexane 1:1 to afford 9.9 g (80%) of ester P25.

[0338] Preparation 26. tert-Butyl 4-bromo-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate (P26). Ester P25 (3.7 g, 0.0134 mol), 1H-pyrrolo[2,3-b]pyridin-5-ol (2 g, 0.015 mol) and K2CO3(4.17 g, 0.03 mol) was stirred in DMF (50 ml) at 60°C for 2 days. The reaction mixture was diluted with water (100 ml) and cooled to room temperature. Formed precipitate was filtered off, washed with water, and dried on air to get 4.5 g (86%) of product P26 which was used for the next step without purification. 109 ASBAttorney Docket No.: Eil.23.0001

[0339] Preparation 27. tert-Butyl 5-[5-bromo-2-(tert-butoxycarbonyl)phenoxy]-1H-pyrrolo[2,3- b]pyridine-1-carboxylate (P27). Product P26 (4.5 g, 0.0116 mol) was stirred in DCM (100 ml) with Boc2O (2.65 g. 0.012 mol) and DMAP (67 mg, 0.55 mmol) overnight at ambient temperature. The reaction mixture was concentrated on rotary evaporator under reduced pressure to dryness. Compound P27 was used in the next steps without further purification.

[0340] In the Table 2 presented LSMS data for non-limiting examples of the invention.

[0341] Table 2. Compound [MH]+[MH]+# IUPAC name calculated found110 ASBAttorney Docket No.: Eil.23.0001 4-[7-[2-(4-chlorophenyl)cyclohex-2-en-1-yl]-2,7- diazaspiro[3.5]nonan-2-yl]-N-[3-nitro-4-111 ASBAttorney Docket No.: Eil.23.0001 4-[7-[[2-(4-chlorophenyl)-4,4-dimethyl- cyclohexen-1-yl]methyl]-2,7-diazaspiro[3.5]nonan-ASBAttorney Docket No.: Eil.23.0001 4-[2-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-2- en-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-N-[4-[[3--4- [(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide (Compound 1). 4-ylmethyl)amino]benzenesulfonamide (95 mg, 0.3 mmol), EDCI (83 mg, 0.43 mmol), DMAP (48 mg, 0.43 mmol) and Et3N (0.04 mL, 0.29 mmol) in DCM (10 mL) was stirred at ambient temperature for 16 h and partitioned between water (2 mL) and DCM. Organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica flash-chromatography eluting with a mixture of methanol (1 to 5%) in DCM to afford compound P5 (97 mg, 42 %).1H NMR (400 MHz, DMSO-d6), δ: 11.61 (s, 1H), 8.56 – 8.41 (m, 2H), 8.04 – 7.92 (m, 1H), 7.73 (d, J = 9.1 Hz, 1H), 7.58 – 7.31 (m, 7H), 7.00 (d, J = 9.2 Hz, 1H), 6.76 – 6.65 (m, 1H), 6.40 – 6.31 (m, 1H), 6.29 – 6.20 (m, 1H), 3.91 – 3.58 (m, 3H), 3.30 (s, 8H), 3.14 – 2.99 (m, 5H), 1.94 – 1.82 (m, 1H), 1.74 – 1.54 (m, 6H), 1.35 – 1.04 (m, 5H). 113 ASBAttorney Docket No.: Eil.23.0001

[0343] Example 2. Compounds 2, 3, 8, 11, 12, 13, 17, 19 were prepared according to procedures described in Preparations P1-P4, and in Example 1 using corresponding starting matherials. Descriptions of the H-NMR spectra of some of these compounds are presented in the table below. Compound1H NMR (400 MHz, DMSO-d6), δ # 9 , – 7 ), z, s, ), , z, 8 , 0 , 9 s, 8 J m, 1 2 ), 2114 ASBAttorney Docket No.: Eil.23.0001 Compound1# H NMR (400 MHz, DMSO-d6), δ 68, -N- ({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide (Compound 6). Cl Cl A pyran-4-ylmethyl)amino]benzenesulfonamide (48 mg, 0.15 mmol), EDCI (40 mg, 0.2 mmol), DMAP (22 mg, 0.2 mmol) and Et3N (0.04 mL, 0.3 mmol) in DCM (10 mL) was stirred at ambient temperature for 16 h and partitioned between water (2 mL) and DCM. Organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica flash- chromatography eluting with a mixture of methanol (1 to 5%) in DCM to afford compound 6 (35 mg, 30%).1H NMR (400 MHz, DMSO-d6), δ: 11.61 (s, 1H), 11.14 (s, 1H), 8.56 – 8.45 (m, 2H), 115 ASBAttorney Docket No.: Eil.23.0001 7.99 (d, J = 2.6 Hz, 1H), 7.73 (d, J = 9.1 Hz, 1H), 7.57 – 7.20 (m, 7H), 7.00 (d, J = 9.1 Hz, 1H), 6.75 – 6.64 (m, 1H), 6.40 – 6.18 (m, 2H), 3.91 – 3.76 (m, 2H), 3.42 – 3.16 (m, 8H), 3.16 – 2.87 (m, 5H), 2.12 – 1.95 (m, 1H), 1.94 – 1.72 (m, 2H), 1.71 – 1.54 (m, 6H), 1.51 – 1.40 (m, 2H), 1.40 – 1.04 (m, 6H), 1.04 – 0.90 (m, 1H).

[0345] Example 4. 4-{2-[1-(4-chlorophenyl)-2-methylpropyl]-2,7-diazaspiro[3.5]non-7-yl}-N- ({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide (Compound 4). This compound was prepared according to procedures described in P5-P8 and in Example 3 using corresponding starting matherials.

[0346] Example 5. 4-{2-[2-(4-Chlorophenyl)cyclohex-2-en-1-yl]-2,7-diazaspiro[3.5]non-7-yl}- N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide (Compound 10). A mixture of acid P12 (80 mg, 0.14 mmol) 3-nitro-4-[(tetrahydro-2H-pyran-4- ylmethyl)amino]benzenesulfonamide (48 mg, 0.15 mmol), EDCI (40 mg, 0.2 mmol), DMAP (22 mg, 0.2 mmol) and Et3N (0.04 mL, 0.3 mmol) in DCM (10 mL) was stirred at ambient temperature for 16 h and partitioned between water (2 mL) and DCM. Organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica flash- chromatography eluting with a mixture of methanol (1 to 5%) in DCM to afford compound 10 (12 mg, 10%).1H NMR (400 MHz, DMSO-d6), δ: 11.60 (s, 1H), 10.12 (s, 1H), 8.66 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.74 – 7.64 (m, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 2.9 Hz, 1H), 7.44 – 7.32 (m, 5H), 6.92 (d, J = 9.4 Hz, 1H), 6.67 (dd, J = 9.1, 2.3 Hz, 1H), 6.33 (dd, J = 3.4, 1.9 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 6.09 (s, 1H), 3.68 – 3.52 (m, 4H), 3.49 – 3.35 (m, 4H), 3.13 – 2.86 (m, 4H), 2.47 – 2.29 (m, 7H), 2.26 – 2.09 (m, 2H), 2.00 – 1.48 (m, 12H).

[0347] Example 6. Compounds 5, 9, 14 were prepared according to procedures described in Preparations P9-P12, and in Example 5 using corresponding starting matherials. Descriptions of the H-NMR spectra of some of these compounds are presented in the table below. Compound1H NMR (400 MHz DMSO-d6) δ =ASBAttorney Docket No.: Eil.23.0001 Compound1# H NMR (400 MHz, DMSO-d6), δ 2 , 1 9 ,p . p y y y , p . y -N- (4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)phenylsulfonyl)benzamide (Compound 20).2- ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide P18 (240 mg, 0.43 mmol), EDCI (250 mg, 1.3 mmol) and 4-dimethylaminopyridine (159 mg, 1.3 mmol) in DCM (15 ml) was stirred at rt overnight. After the reaction completion, solvent was evaporated under reduced pressure, and 117 ASBAttorney Docket No.: Eil.23.0001 the crude product was purified by HPLC to afford the title compound 20 (25 mg, 7%).1H NMR (400 MHz, DMSO-d6), δ: 8.09 (d, J = 2.2 Hz, 1H), 7.92 (dd, J = 9.3, 2.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.43 (s, 4H), 7.38 – 7.12 (m, 6H), 7.05 – 6.73 (m, 2H), 6.38 (d, J = 8.5 Hz, 2H), 6.18 (s, 1H), 4.19 – 3.92 (m, 2H), 3.58 – 3.44 (m, 7H), 2.37 – 2.15 (m, 12H), 2.10 – 1.84 (m, 5H), 1.83 – 1.49 (m, 5H). LCMS (ESI)+m / z: 959 [M+H]+.

[0349] Example 8. 4-(2-(2-(4-Chlorophenyl)-4,4-dimethylcyclohex-2-enyl)-2,6- diazaspiro[3.4]octan-6-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)phenylsulfonyl)benzamide (Compound 24). Compound 24 was prepared according to procedures described in Preparations P13-P21 and in Example 7 using corresponding starting matherials.1H NMR (400 MHz, DMSO-d6), δ: 8.12 – 8.05 (m, 2H), 7.98 – 7.87 (m, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.41 (s, 5H), 7.37 – 7.13 (m, 5H), 6.89 (d, J = 9.3 Hz, 1H), 6.76 (d, J = 8.6 Hz, 1H), 6.36 (d, J = 8.5 Hz, 2H), 5.79 (s, 1H), 4.03 (s, 1H), 3.58 – 3.43 (m, 6H), 3.25 – 3.15 (m, 6H), 2.42 – 2.02 (m, 9H), 2.02 – 1.49 (m, 6H), 1.39 (s, 1H), 1.13 (s, 3H), 0.98 (s, 3H).

[0350] Example 9. 4-(2-((Z)-2-(4-Chlorophenyl)cyclohept-2-enyl)-2,6-diazaspiro[3.4]octan-6- yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)phenylsulfonyl)benzamide (Compound 21). Compound 24 was prepared according to procedures described in Preparations P13-P21 and in Example 7 using corresponding starting matherials.

[0351] Example 10. 4-(2-(2-(4-chlorophenyl)cyclohex-2-enyl)-2,7-diazaspiro[3.5]nonan-7-yl)- N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)phenylsulfonyl)benzamide (Compound 22). 118 ASBAttorney Docket No.: Eil.23.0001 3A mixture of acid P24 (100 mg, 0.23 mmol) and (R)-4-(4-morpholino-1-(phenylthio)butan-2- ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide P18 (105 mg, 0.19 mmol), EDCI (109 mg, 0.57 mmol) and 4-dimethylaminopyridine (69 mg, 0.57 mmol) in DCM (15 ml) was stirred at rt overnight. After the reaction completion, solvent was evaporated under reduced pressure, and the crude product was purified by HPLC to afford the title compound 22 (5 mg, 4%).1H NMR (400 MHz, DMSO-d6), δ: 8.18 (s, 1H), 8.06 – 7.93 (m, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.54 – 7.40 (m, 4H), 7.36 – 7.09 (m, 7H), 7.03 – 6.83 (m, 3H), 6.23 (s, 1H), 4.78 – 4.63 (m, 1H), 4.04 – 3.86 119 ASBAttorney Docket No.: Eil.23.0001 (m, 4H), 3.58 – 3.44 (m, 9H), 2.39 – 2.19 (m, 8H), 1.95 – 1.49 (m, 10H). LCMS (ESI)+m / z: 973 [MH]+.

[0352] Example 11. Compounds 23, 25 were prepared according to procedures described in Preparations P13-P18, P22-P24 and in Example 10 using corresponding starting matherials. Descriptions of the H-NMR spectra of some of these compounds are presented in the table below. Compound1H NMR (400 MHz, DMSO-d6), δ # , 3 = , –

[0353] Example 12. Primary PPI inhibition assays.

[0354] BCL-2 TR-FRET Assay (BPS Bioscience, #50222) The following assay concentrations and times were used: 3 ng BCL-2, 5 µl of 1:100 anti-His Tb-labeled donor, 5 µl of 1:100 Dye- labeled acceptor, 5 µl of 1:40 BCL-2 Peptide Ligand, and 2ul of test compound, with 60 min incubation time. The results of the assay were read using a Clariostar (BMG Labtech) plate reader with the following parameters: TR FRET, 340ex / 620 and 665em; 60 µsec Delay; and 500 µsec integration.

[0355] BCL-XL TR-FRET Assay (BPS Bioscience, #50223) The following assay concentrations and times were used: 10.5 ng BCL-XL, 5 µl of 1:100 anti-His Tb-labeled donor, 5 µl of 1:100 Dye-labeled acceptor, 5 µl of 1:80 BCL-XL Peptide Ligand, and 2 µl of test compound, with 60 min incubation time. The results of the assay were read using a Clariostar (BMG Labtech) plate reader with the following parameters: TR FRET, 340ex / 620 and 665em; 60 µsec Delay; and 500 µsec integration.

[0356] MCL-1 TR-FRET Assay (BPS Bioscience, #79506) The following assay concentrations and times were used: 10 ng MCL-1, 5 µl of 1:200 anti-His Tb-labeled donor, 5 µl of 1:200 Dye- labeled acceptor, 5 µl of 1:10 MCL-1 Peptide Ligand, and 2 µl of test compound, with 60 min 120 ASBAttorney Docket No.: Eil.23.0001 incubation time. The results of the assay were read using a Clariostar (BMG Labtech) plate reader with the following parameters: TR FRET, 340ex / 620 and 665em; 60 µsec Delay; and 500 µsec integration.

[0357] Table B assigns a code for potency for BCL-2 TR-FRET Assay: A, B, C, or D. According to the code, A represents an IC50 value ≤50 nM; B represents IC50 > 50 nM and ≤ 100 nM; C represents IC50 >100 nM and ≤ 500 nM D represents IC50 > 500 nM.

[0358] Table B assigns a code for potency for BCL-XL TR-FRET Assay: A, B, or C. According to the code, A represents IC50 value ≤ 2,000 nM; B represents IC50 values >2,000 nM and ≤4,000 nM; C represents IC50 values >4,000 nM. Table B: Primary PPI inhibition Cmpd. Cmpd. Cmpd. BCL2 BCLxL BCL2 BCLxL BCL2 BCLxL

[0359] Example 13. Cell Viability Assays (Cell lines HEK293, RS4-11, MOLT-4).

[0360] Culture medium for HEK293 – DMEM (PanEco, Cat# С420) was used. RPMI-1640 (PanEco, Cat# С363) was used for the rest of the cell lines.

[0361] Compounds were prepared as 200x stocks with serial dilution in 100% DMSO with a final concentration of 1x.

[0362] Compound solutions were dispersed in 40 μL aliquots in 384-well plates at a concentration of 2000 cells per well for HEK293 and at a concentration of 4000 cells per well for the rest of the cell lines using a robotic station Biomek (Beckman). Before adding compounds, the cells were incubated at 37 °C (HEK293 were incubated for a day before adding compounds). 121 ASBAttorney Docket No.: Eil.23.0001

[0363] A dilution plate was prepared by pouring 78 μL of the appropriate culture medium using a robotic station Biomek (Beckman). Sequentially, using a robotic station, 2 μL of substances were taken and added to 78 μL of culture medium (dilution of compounds 40x). 10 μL aliquots were taken and added to the plates of the cells (dilution of compounds 5x). The plates were incubated for 3 days at a temperature 37 °С. After 3 days, 10 μL of CellTiter-Glo (Promega) was added to the cells and the luminescence was measured.

[0364] Table C assigns a code for potency for RS4-11 Assay: A, B, or C. According to the code, A represents an CC50 value ≤0.1 µM; B represents CC50>0.1 µM and ≤1.0 µM; C represents CC50>1.0 µM.

[0365] Table C assigns a code for potency for MOLT-4 Assay: A, B, or C. According to the code, A represents an CC50 value ≤2 µM; B represents CC50>2 µM and ≤10 µM; C represents CC50>10 µM.

[0366] Table C assigns a code for potency for HEK293 Assay: A, B, or C. According to the code, A represents an CC50value ≤10 µM; B represents CC50>10 µM and ≤20 µM; C represents CC50>20 µM. Table C. Cellular models efficacy and cytotoxicity. Cmpd. No. RS4-11 MOLT-4 HEK293ASBAttorney Docket No.: Eil.23.0001 Cmpd. No. RS4-11 MOLT-4 HEK293 20 C A C

[0367] Example 14..

[0368] Assay Principle: The Caspase-Glo 3 / 7 Assay is homogeneous, luminescent assay that measures caspase-3 and -7 activities. The assay provides a luminogenic caspase-3 / 7 substrate, which contains the tetrapeptide sequence DEVD, in a reagent optimized for caspase activity.

[0369] Assay Procedure: Incubate RS4-11 cells with varying concentrations of test compounds for 3.5 h in a humidified incubator at 37 °C and 5 % CO2 and 30 min at r.t. Add 15 µl Caspase- Glo reagent to each well and incubate the plate for 30 min at r.t. Read on ClarioStar Plus instrument.

[0370] Materials: Promega Caspase-Glo (Promega , #8212); Frozen RS4-11 cells; 384-well white plate (Corning, #3570).

[0371] Instrumentation: ClarioStar Plus; Biomek FX for liquid handling (Beckman Coulter).

[0372] Table D assigns a code for potency for Cas-3 / 7 Assay: A, B, or C. According to the code, A represents an EC50 value ≤ 1.0 µM; B represents EC50 > 1.0 µM and ≤ 2.0 µM; C represents EC50> 2.0 µM. Table D. Caspase-3 / 7 activation. Cmpd. No. Cas-3 / 7123 ASBAttorney Docket No.: Eil.23.0001 Equivalents

[0373] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 124 ASB

Claims

Attorney Docket No.: Eil.23.0001 What is claimed is:

1. A compound of Formula (A): , andor tautomers thereof, wherein: A is selected from CH and N;ASBAttorney Docket No.: Eil.23.0001 , ,alkyl, cycloalkyl, or aryl is optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6 alkyl; R5is selected from H, halogen, -OH, -NH2, -CN, C1–C6 alkyl, and C1–C6 alkoxy; or R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered cycloalkyl or a 5-8 membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, C1-C6alkyl, C1-C6alkoxy; each R6is independently selected from H, halogen, -CN, -NO2, -NH2, -OR7, -COOR7, C1– C6 alkyl, C3-C8 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen; each R7is independently selected from H, and C1–C6alkyl; k is an integer selected from 0, 1, and 2; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 1, 2, and 3; o is an integer selected from 0, 1, 2, and 3; 126 ASBAttorney Docket No.: Eil.23.0001 p is an integer selected from 1, 2, and 3; r is an integer selected from 0, 1, and 2.

2. The compound of claim 1, wherein Formula (A) is Formula (I): , tautomersthereof, wherein: A is selected from CH and N; R1is selected ; R2is selectedR3is selected ; R4is selectedC3-C7 cycloalkyl, C6-C10 aryl, wherein alkyl, cycloalkyl, or aryl is optinally substituted with one or more substitutients selected from -OH, -CN, halogen, C1–C6alkyl; R5is selected from H, halogen, -OH, -NH2, -CN, C1–C6 alkyl, and C1–C6 alkoxy; or R4and R5together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered cycloalkyl or a 5-8 membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, C1-C6 alkyl, C1-C6 alkoxy; k is an integer selected from 0, 1, and 2; 127 ASBAttorney Docket No.: Eil.23.0001 m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 1, 2, and 3; o is an integer selected from 0, 1, 2, and 3; p is an integer selected from 1, 2, and 3.

3. The compound of claim 1, wherein Formula (A) is Formula (II): ,thereof, wherein: A is selected from CH and N; R1is selected ; R2is selectedR3is selected ; R6is selected-NH2, -OR7, -COOR7, C1–C6alkyl, C3-C8cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen; each R7is independently selected from H, and C1–C6 alkyl; k is an integer selected from 0, 1, and 2; m is an integer selected from 0, 1, 2, and 3; n is an integer selected from 1, 2, and 3; o is an integer selected from 0, 1, 2, and 3; 128 ASBAttorney Docket No.: Eil.23.0001 p is an integer selected from 1, 2, and 3; and r is an integer selected from 0, 1, and 2.

4. The compound of claim 1, wherein Formula (A) is Formula (III): , tautomersthereof, wherein: A is selected from CH and N; , ,ASBAttorney Docket No.: Eil.23.0001 each R6is independently selected from H, halogen, -CN, -NO2, -NH2, -OR7, -COOR7, C1– C6 alkyl, C3-C8 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen; each R7is independently selected from H, and C1–C6alkyl; k is an integer selected from 0, 1, and 2.

5. The compound of claim 2, wherein Formula (I) is Formula (I-A): , or a6. The compound of claim 5, wherein Formula (I-A) is Formula (I-A-1): Cl 1), or a130 ASBAttorney Docket No.: Eil.23.0001 7. The compound of claim 3, wherein Formula (II) is Formula (II-A): Cl O , or a8. The compound of claim 7, wherein Formula (II-A) is Formula (I-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

9. The compound of claim 3, wherein Formula (II) is Formula (II-B): 131 ASBAttorney Docket No.: Eil.23.0001 B), or a10. The compound of claim 9, wherein Formula (II-B) is Formula (II-B-1): 1), or11. The compound of claim 4, wherein Formula (III) is Formula (III-A): 132 ASBAttorney Docket No.: Eil.23.0001 O Cl , or a12. The compound of claim 11, wherein Formula (III-A) is Formula (III-A-1): Cl 1), or a13. A compound selected from: 133 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name ]- ]- - l- - - - - l- -134 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - l- - - - l- -135 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - l- - - - l- - - - l- -ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - l- - - - - l- - - -137 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - 3- l- - - 3- l- - - 3- l- -138 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - ]- - l- - - - l- - - - - l- - - - - l- -ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - - l- - - - - l- - - -140 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name 1- - - - ]- 1- - ]-141 ASBAttorney Docket No.: Eil.23.0001 Cmpd # Structure IUPAC name - - - ]- - - ]- ]-14. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or tautomer thereof of any one of claims 1–13, and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, further comprising an additional pharmaceutically active agent.

16. A method of inhibiting a BCL-2 protein, comprising of administering to a subject in need of a treatment for cancer a compound or composition of any one of claims 1–15. 142 ASBAttorney Docket No.: Eil.23.0001 17. A method of treating a disease or disorder associated with the inhibition of a BCL-2 protein, comprising of administering to a subject in need of a treatment for cancer a compound of any one of claims 1–13 or a composition of any one of claims 14, 15.

18. A method of treating cancer, comprising of administering to a subject in need of a treatment for cancer a compound of any one of claims 1–13 or a composition of any one of claims 14, 15.

19. The method of claim 18, wherein the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, prostate cancer, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL)..

20. The method of claim 19, wherein the cancer is selected from marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

21. The method of any one of claims 16–20, wherein the subject is a mammal.

22. The method of claim 21, wherein the subject is a human. 143 ASB

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