RU2801647C2 - Benzamide compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof. In formula (I): R¹ is selected from the group consisting of hydrogen, halogen, unsubstituted C₁-C₆ alkyl, and unsubstituted C₁-C₆ haloalkyl; each R² is independently unsubstituted C₁-C₆ alkyl; or, when m is 2, each R² is independently unsubstituted C₁-C₆ alkyl, or two R² groups taken together with the atom(s) to which they are attached form an unsubstituted C₃-C₆ cycloalkyl; R³ is X-R^3A; R^3A is an unsubstituted 5–10-membered heteroaryl such as ; R⁴ is NO₂; R⁵ is -X¹-(Alk¹)_n-R⁷; Alk¹ is selected from unsubstituted C₁-C₄ alkylene and C₁-C₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C₁-C₃ alkyl and unsubstituted C₁-C₃ haloalkyl; R⁷ is selected from substituted or unsubstituted C₃-C₁₀ cycloalkyl and substituted or unsubstituted 3–10-membered heterocyclyl containing 1–2 heteroatoms selected from nitrogen and oxygen; m is either 0, 1 or 2; n is selected from 0 and 1; X¹ is -NH-; and X is -O-. Also the following is provided: a pharmaceutical composition, a method of treating cancer or a tumor, a method of inhibiting the replication of a malignant formation or tumor, a method of inhibiting Bcl-2 activity, and using a compound of formula (I) or a pharmaceutical composition for the manufacture of a medicinal product.

EFFECT: proposed compounds, as well as their pharmaceutically acceptable salts and compositions are used to treat diseases or conditions mediated by Bcl-2 including conditions characterized by excessive cell proliferation, such as cancer and tumors.

35 cl, 7 dwg, 3 tbl, 77 ex

Description

INFORMATION ON RELATED APPLICATIONS

[0001] This application claims priority under US Patent Publication No. 62/615,857, filed January 10, 2018, the contents of which are incorporated herein by reference in all respects.

Technical field

[0002] The present application relates to compounds that are Bcl-2 inhibitors and methods of using them to treat conditions characterized by excessive cell proliferation, such as cancer and tumors, and viral infections, such as human immunodeficiency virus (HIV) infection.

Description

[0003] Bcl-2 plays a role in the regulation of cell death, including apoptosis, necrosis, and autophagy. Accordingly, changes in Bcl-2 expression and function contribute to the pathogenesis and progression of human cancers and tumors and may contribute to some viral infections such as HIV.

Statement of the Invention

[0004] Some embodiments relate to a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0005] Some embodiments described herein relate to a pharmaceutical composition that may include an effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0006] Some embodiments described herein relate to a method of treating a cancer or tumor as described herein, which method may comprise administering an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to a subject with the cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of cancer or tumors described herein. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for the treatment of cancer or tumors as described herein.

[0007] Some embodiments described herein relate to a method for inhibiting replication of a cancer or tumor described herein, which may include contacting the tumor or tumor with an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the preparation of a medicament for inhibiting the replication of a cancer or tumor described herein. . Other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit the replication of a cancer or tumor described herein.

[0008] Some embodiments described herein relate to a method of treating cancer described herein, which may include bringing the cancer or tumor described herein into contact with an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of cancer described herein, the use comprising bringing the cancer or tumor described herein into contact with a drug. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) to contact the cancer or tumor described herein, wherein the occurrence malignancy or tumor is due to the cancer described herein.

[0009] Some embodiments described herein relate to a method of inhibiting Bcl-2 activity, which may include administering to a subject an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and may also include contacting a Bcl-2 expressing cell with an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament to inhibit Bcl-2 activity in a subject or in the manufacture of a medicament. agents for inhibiting Bcl-2 activity, the use comprising contacting the compound with a Bcl-2 expressing cell. Other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit Bcl-2 activity in a subject; or to inhibit Bcl-2 activity by contact with a Bcl-2 expressing cell.

[0010] Some embodiments described herein relate to a method for alleviating or treating HIV infection, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically thereof acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent or a pharmaceutically acceptable salt thereof. . Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for alleviating or treating HIV infection in a subject suffering from HIV infection; or in the manufacture of a medicament for alleviating or treating HIV infection, the use comprising bringing a cell infected with HIV into contact with the medicament. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent or a pharmaceutically acceptable salt thereof. to alleviate or treat HIV infection in a subject suffering from HIV infection; or to alleviate or treat HIV infection by contact with a cell infected with HIV infection.

[0011] Some embodiments described herein relate to a method for reducing the population of HIV-infected cells, which may include administering to a subject suffering from HIV infection, an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent or a pharmaceutically acceptable salt thereof. . Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the population of HIV-infected cells in a subject suffering from HIV infection; or to reduce the population of HIV-infected cells, the use comprising bringing the HIV-infected cell into contact with a drug. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent or a pharmaceutically acceptable salt thereof. to reduce the population of HIV-infected cells in a subject suffering from HIV infection; or to reduce the population of HIV-infected cells by bringing into contact with an HIV-infected cell.

[0012] Some embodiments described herein relate to a method of reducing relapses of HIV infection in a subject, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or its a pharmaceutically acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent or a pharmaceutically acceptable salt thereof. . Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent, or a pharmaceutically acceptable thereof. salt, in the manufacture of a medicament for reducing the recurrence of HIV infection in a subject suffering from HIV infection; or to reduce relapses of HIV infection, the use comprising bringing a cell infected with HIV into contact with a drug. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent or a pharmaceutically acceptable salt thereof. to reduce relapses of HIV infection in a subject suffering from HIV infection; or to reduce the recurrence of HIV infection by bringing into contact with a cell infected with HIV.

[0013] Some embodiments described herein relate to a method of ameliorating or treating HIV infection, which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable amount thereof. acceptable salt to a subject suffering from HIV infection; and may also include contacting a cell infected with HIV with a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a Bcl protein inhibitor or a pharmaceutically acceptable salt thereof and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for alleviating or treating HIV infection; or in the manufacture of a medicament for alleviating or treating HIV infection, the use comprising bringing a cell infected with HIV into contact with the medicament. Other embodiments described herein relate to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, for alleviating or treating HIV infection in a subject suffering from HIV infection; or to alleviate or treat HIV infection by contact with a cell infected with HIV infection.

[0014] Some embodiments described herein relate to a method for reducing the population of HIV-infected cells, which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV-busting agent, or a pharmaceutically acceptable amount thereof. acceptable salt to a subject suffering from HIV infection; and may also include contacting a cell infected with HIV with a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a Bcl protein inhibitor or a pharmaceutically acceptable salt thereof and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to reduce the population of cells infected with HIV; or in the manufacture of a drug to reduce the population of HIV-infected cells, the use comprising bringing an HIV-infected cell into contact with the drug. Other embodiments described herein relate to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, to reduce the population of HIV-infected cells in a subject. suffering from HIV infection; or to reduce the population of HIV-infected cells by bringing into contact with an HIV-infected cell.

[0015] Some embodiments described herein relate to a method of reducing relapses of HIV infection in a subject, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or its a pharmaceutically acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV-latenting agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the recurrence of HIV infection in a subject suffering from HIV infection; or to reduce relapses of HIV infection, the use comprising bringing a cell infected with HIV into contact with a drug. Other embodiments described herein relate to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, to reduce relapses of HIV infection in a subject suffering from from HIV infection; or to reduce the recurrence of HIV infection by bringing into contact with a cell infected with HIV.

[0016] These and other embodiments are described in more detail below.

Brief description of graphic materials

[0017] In FIG. 1 shows an example of agents that bring HIV out of its latent state.

[0018] In FIG. 2 shows examples of Bcl protein inhibitors.

[0019] In FIG. 3 shows examples of compounds of formula (I).

[0020] In FIG. 4A, 4B and 4C show examples of compounds of formula (I).

[0021] In FIG. 5 is a graph showing HIV assay data for exemplary compounds of formula (I).

Detailed description

[0022] Bcl-2 is a critical regulator of programmed cell death (apoptosis). Bcl-2 belongs to the B-cell lymphoma 2 (BCL-2) protein family, which is referred to as pro-apoptotic proteins (such as Bak, Bax, Bim, Bid, tBid, Bad, Bik, PUMA, Bnip-1, Hrk, Bmf and Noxa) and anti-apoptotic proteins (such as Bcl-2, Bcl-X _L , Bcl-W, Mcl-1 and Bcl-2A1). For example, under normal conditions, Bcl-2 inhibits apoptosis, partially preventing the activation of Bak and Bax. Activation of the intrinsic apoptotic pathway (eg, as a result of cellular stress) inhibits Bcl-2 and thus activates Bak and Bax. Thanks to proteins, the increase in the permeability of the mitochondrial membrane is facilitated by the release of cytochrome c and Smac. Thus, the caspase signaling pathway is initiated, which ultimately results in cell death. Dysregulation of Bcl-2 leads to the sequestration of proteins that stimulate cell death, resulting in evasion of apoptosis. This process contributes to malignant neoplasms and promotes cell survival under other adverse conditions, such as during a viral infection. For example, a transcriptionally active HIV may randomly generate a caspase protein fragment. This fragment binds to the proapoptotic Bak protein and activates it. However, this fragment also binds to and is sequestered by Bcl-2, reducing its effectiveness in inducing cell death. Inhibition of Bcl-2 disrupts the sequestration of proapoptotic proteins, restores apoptotic signaling, and promotes programmed death of damaged cells. Therefore, inhibition of Bcl-2 has the potential to alleviate or treat cancers and tumors, as well as alleviate or treat certain viral infections in combination with other agents.

Definitions

[0023] Unless otherwise defined, all technical and scientific terms used herein have the common meaning understood by one of ordinary skill in the art. Unless otherwise noted, all patents, applications, published applications, and other publications referenced herein are incorporated herein by reference in their entirety. Unless otherwise noted, where there are multiple definitions for a term provided in this document, the definitions provided in this section are preferred.

[0024] If a group is indicated to be "optionally substituted", the group may be unsubstituted or substituted with one or more of the indicated substituents. Similarly, if the group is indicated to be "unsubstituted or substituted" if it is substituted, the substituent(s) may be selected(s) from one or more of the indicated compounds. If substituents are not indicated, this means that the group indicated as "optionally substituted" or "substituted" may be substituted by one or more groups which are individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), cycloalkyl (alkyl), heteroaryl (alkyl), heterocyclyl (alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino group, disubstituted amino group, monosubstituted amine (alkyl) and disubstituted amine (alkyl).

[0025] Used in this document, the terms "C _a -C _b ", in which "a" and "b" are integers, means the number of carbon atoms in the group. The specified group may contain from "a" to "b" carbon atoms, inclusive. Thus, for example, the group "C ₁ -C ₄ alkyl" refers to all alkyl groups having from 1 to 4 carbon atoms, i. CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ \u003d, CH ₃ CH ₂ CH (CH ₃ ) \u003d- and (CH ₃ ) ₃ C-. If the designations "a" and "b" are absent, the widest range described in these definitions is assumed.

[0026] If two "R" groups are described as "taken together", the R groups with the atoms to which they are attached can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle. For example, without limitation, if it is indicated that R ^a and R ^b from the group NR ^a R ^b are "taken together", this means that they are linked to each other covalently to form a ring:

[0027] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl functional group may be branched or may be straight chain. Examples of branched alkyl groups include, without limitation, isopropyl, sec-butyl, t-butyl, and the like. Examples of straight chain alkyl groups include, without limitation, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have from 1 to 30 carbon atoms (as used herein, a numerical range such as "1 to 30" refers to each integer in the given range; for example, "1 to 30 carbon atoms" means that the alkyl the group may be 1 carbon, 2 carbons, 3 carbons, etc., up to and including 30 carbons, although this definition also covers the reference to the term "alkyl" where no numerical range is specified). The alkyl group may also be a medium sized alkyl having 1 to 12 carbon atoms. The alkyl group may also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted.

[0028] As used herein, the term "alkylene" refers to a straight chain divalent fully saturated aliphatic hydrocarbon group. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptane, and octylene. The alkylene group can be represented as followed by the number of carbon atoms followed by "*". For example, represents ethylene. The alkylene group may have from 1 to 30 carbon atoms (as used herein, a numerical range such as "1 to 30" refers to each integer in the given range; for example, "1 to 30 carbon atoms" means that the alkyl the group may consist of 1 carbon, 2 carbons, 3 carbons, etc., up to and including 30 carbons, although the present definition also covers the reference to the term "alkylene", which does not specify a numerical range). The alkylene group may also be a medium sized alkyl having 1 to 12 carbon atoms. The alkylene group may also be a lower alkyl having 1 to 4 carbon atoms. The alkylene group may be substituted or unsubstituted. For example, the lower alkylene group may be substituted by replacing one or more hydrogen atoms of the lower alkylene group and/or replacing both hydrogen atoms on one carbon atom with a C _3-6 monocyclic cycloalkyl group (for example, ).

[0029] As used herein, the term “alkenyl” refers to a monovalent straight or branched chain radical of two to twenty carbon atoms that contains double carbon(s) bond(s), including, without restrictions, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. The alkenyl group may be substituted or unsubstituted.

[0030] As used herein, the term "alkynyl" refers to a linear or branched monovalent radical of two to twenty carbon atoms that contains triple carbon(s) bond(s), including, without limitations, 1-propynyl, 1-butynyl, 2-butynyl, and the like. The alkynyl group may be substituted or unsubstituted.

[0031] As used herein, the term "cycloalkyl" refers to a fully saturated (no double or triple bonds) mono- or multicyclic (bicyclic) hydrocarbon ring system. If the rings are composed of two or more rings, they may be joined together by condensation, bridge, or spiro coupling. As used herein, the term "fused" refers to two rings that share two atoms and one bond. As used herein, the term "bridged cycloalkyl" refers to compounds in which the cycloalkyl has a bond between one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings having one atom in common and the two rings are not bridged. Cycloalkyl groups may contain 3 to 30 ring(s), 3 to 20 ring(s), 3 to 10 ring(s), 3 to 8 ring(s) ) or 3 to 6 atoms in the ring(s). The cycloalkyl group may be substituted or unsubstituted. Examples of monocycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups include decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bridging cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.

[0032] As used herein, the term "cycloalkenyl" refers to a mono- or multicyclic (eg, bicyclic) hydrocarbon ring system that contains one or more double bonds in at least one ring; although if more than one bond is present, the double bonds cannot form a fully delocalized pi electron system across all rings (otherwise the group would be "aryl" as defined herein). Cycloalkenyl groups may have 3 to 10 ring(s), 3 to 8 ring(s), or 3 to 6 ring(s). If the rings are composed of two or more rings, they may be connected together by condensation, bridge or spiro coupling. The cycloalkenyl group may be substituted or unsubstituted.

[0033] As used herein, the term "aryl" refers to a carbocyclic (all carbons), monocyclic or multicyclic (e.g., bicyclic) aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi -electronic system on all rings. The number of carbon atoms in the aryl group may vary. For example, the aryl group may be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, without limitation, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0034] As used herein, the term "heteroaryl" refers to a monocyclic or multicyclic (e.g., bicyclic) aromatic ring system (a ring system with a fully delocalized pi electron system) that contains one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms ), i.e. to an element other than carbon, including, without limitation, nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) with a heteroaryl group may vary. For example, a heteroaryl group may have 4 to 14 ring(s), 5 to 10 ring(s), or 5 to 6 ring(s), such as nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atoms and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Moreover, the term "heteroaryl" includes fused ring systems in which two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, without limitation, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. The heteroaryl group may be substituted or unsubstituted.

[0035] As used herein, the terms “heterocyclyl” or “heteroalicyclyl” refer to three-, four-, five-, six-, seven-, eight-, nine-, ten- and up to 18-membered monocyclic, bicyclic and tricyclic ring systems in which carbon atoms together with 1-5 heteroatoms constitute said ring system. The heterocycle may optionally contain one or more unsaturated bonds, which however are arranged in such a way that the fully delocalized pi-electron system does not extend to all rings. The heteroatom(s) is(are) an element(s) other than carbon, including, without limitation, oxygen, sulfur and nitrogen. The heterocycle may further contain one or more carbonyl or thiocarbonyl functional groups such that oxo systems and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates are included in the formation. If the rings are composed of two or more rings, they may be joined together by condensation, bridge, or spiro coupling. As used herein, the term "fused" refers to two rings that share two atoms and one bond. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to compounds in which the heterocyclyl or heteroalicyclyl contains a bond between one or more atoms connecting non-adjacent atoms. As used herein, the term "spiro" refers to two rings having one atom in common and the two rings are not bridged. Heterocyclyl and heteroalicyclyl groups may contain 3 to 30 ring(s), 3 to 20 ring(s), 3 to 10 ring(s), 3 to 8 ring ( -ax) or 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. In addition, any nitrogens in the heterocycle can be quaternized. Heterocyclyl or heteroalicyclic groups may be substituted or unsubstituted. Examples of such heterocyclyl or heteroalicyclyl groups include, without limitation, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3 -oxatian, 1,4-oxathiine, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxatian, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide , succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane , piperidine N-oxide, piperidine, pipeperin, pyrroline, azepan, pyrrolidon, pyrrolidion, 4-piperidone, pyrazolin, pyrazolydine, 2-oxopyrrolidine, tetrahydropiran, 4h-piraera, tetrahydrotiopyrane, thiamorpholin, sulphoxide thiamorpholine, tiamorpholin sulfine and their gas-confented anus logs (for example, benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of spiro-heterocyclyl groups include 2-azaspiro[3.3]-heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro-[3.3]heptane, 2-oxaspiro [3.4]octane and 2-azaspiro[3.4]octane.

[0036] As used herein, the terms "aralkyl" and "aryl(alkyl)" refer to an aryl group attached as a substituent via a lower alkylene group. The lower alkylene and aryl group of the aralkyl may be substituted or unsubstituted. Examples include, without limitation, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0037] As used herein, the terms "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group attached as a substituent via a lower alkylene group. The lower alkylene and heteroaryl group of the heteroalkyl may be substituted or unsubstituted. Examples include, without limitation, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, and their benzofused analogs.

[0038] "Heteroalicyclyl(alkyl)" and "heterocyclyl(alkyl)" refer to a heterocyclic or heteroalicyclic group attached as a substituent via a lower alkylene group. The lower alkylene group and heterocyclyl (heteroalicyclyl) alkyl may be substituted or unsubstituted. Examples include, without limitation, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0039] As used herein, the term "hydroxy" refers to a -OH group.

[0040] As used herein, the term "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) as defined herein. The non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, t-butoxy, phenoxy, and benzoxy. Alkoxy may be substituted or unsubstituted.

[0041] As used herein, the term "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) substituted via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acrylic. The acyl may be substituted or unsubstituted.

[0042] A "cyano" group refers to a -CN group.

[0043] As used herein, the term "halogen atom" or "halogen" means any of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0044] A "thiocarbonyl" group refers to a -C(=S)R group in which R may be the same as defined with respect to O-carboxy. The thiocarbonyl may be substituted or unsubstituted.

[0045] "O-carbamyl" group refers to the group "-OC(=O)N(R _A R _B )", in which R _A and R _B can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-carbamyl may be substituted or unsubstituted.

[0046] "N-carbamyl" group refers to the group "ROC(=O)N(R _A )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-carbamyl may be substituted or unsubstituted.

[0047] "O-thiocarbamyl" group refers to the group "-OC(=S)-N(R _A R _B )", where R _A and R _B can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). O-thiocarbamyl may be substituted or unsubstituted.

[0048] "N-thiocarbamyl" group refers to the group "ROC(=S)N(R _A )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-thiocarbamyl may be substituted or unsubstituted.

[0049] "C-amido" group refers to the group "-C(=O)N(R _A R _B )", in which R _A and R _B can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). C-amido may be substituted or unsubstituted.

[0050] "N-amido" group refers to the group "RC(=O)N(R _A )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-amido may be substituted or unsubstituted.

[0051] "S-sulfonamido" group refers to the group "-SO ₂ N(R _A R _B )", in which R _A and R _B can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The S-sulfonamido may be substituted or unsubstituted.

[0052] "N-sulfonamido" group refers to the group "RSO ₂ N(R _A )-", in which R and R _A can independently represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl , cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-sulfonamido may be substituted or unsubstituted.

[0053] "O-carboxy" group refers to the group "RC(=O)O-" in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl) , aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy may be substituted or unsubstituted.

[0054] The terms "ether" and "C-carboxy" refer to the group "-C(=O)OR" in which R may be the same as defined with respect to O-carboxy. The ether and C-carboxy may be substituted or unsubstituted.

[0055] The "nitro" group refers to the "-NO ₂ " group.

[0056] A "sulphenyl" group refers to a "-SR" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl). The sulfenyl may be substituted or unsubstituted.

[0057] A "sulfinyl" group refers to a "-S(=O)-R" group in which R may be the same as defined with respect to sulfenyl. The sulfinyl may be substituted or unsubstituted.

[0058] "Sulfonyl" group refers to the group "SO ₂ R", in which R may be the same as defined in relation to sulfenyl. The sulfonyl may be substituted or unsubstituted.

[0059] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen (eg, monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). Such groups include, without limitation, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. The haloalkyl may be substituted or unsubstituted.

[0060] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced by a halogen (eg, monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, without limitation, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. The haloalkoxy may be substituted or unsubstituted.

[0061] As used herein, the terms "amino""unsubstitutedamino" refers to
group -NH ₂ .

[0062] "Mono-substituted amino" group means the group "-NHR _A ", in which R _A can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl (alkyl) or heterocyclyl(alkyl) as defined herein. The R _A group may be substituted or unsubstituted. The monosubstituted amino group may include, for example, a monoalkylamino group, a mono-C ₁ -C ₆ alkylamino group, a mono-arylamino group, a mono-C ₆ -C ₁₀ arylamino group, and the like. Examples of monosubstituted amino groups include, without limitation, -NH(methyl), -NH(phenyl), and the like.

[0063] "Disubstituted amino" group means the group "-NR _A R _B ", in which R _A and R _B can independently represent alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. R _A and R _B may independently be substituted or unsubstituted. The disubstituted amino group may include, for example, a dialkylamino group, a di-C ₁ -C ₆ alkylamino group, a di-arylamino group, a di-C ₆ -C ₁₀ arylamino group, and the like. Examples of disubstituted amino groups include, without limitation, -NH(methyl) ₂ , -N(phenyl)(methyl), -N(ethyl)(methyl), and the like.

[0064] As used herein, a "mono-substituted amino(alkylo)" group refers to a mono-substituted amine, as described herein, connected as a substituent via a lower alkylene group. The monosubstituted amino(alkylo) group may be substituted or unsubstituted. A monosubstituted amine(alkyl) group may include, for example, a monoalkylamine(alkyl) group, a mono-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl) group, a mono-arylamine (alkyl) group, a mono-C ₆ -C ₁₀ an arylamine(C ₁ -C ₆ alkyl) group; and the like. Examples of monosubstituted amino(alkylo) groups include, without limitation, -CH ₂ NH (methyl), -CH ₂ NH (phenyl), -CH ₂ CH ₂ NH (methyl), -CH ₂ CH ₂ NH (phenyl) and t .P.

[0065] As used herein, a "disubstituted amino(alkylo)" group refers to a disubstituted amine, as described herein, connected as a substituent via a lower alkylene group. The disubstituted amino(alkylo) group may be substituted or unsubstituted. The disubstituted amine(alkyl) group may include, for example, dialkylamine(alkyl) group, di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl) group, di-arylamine(alkyl) group, di-C ₆ -C ₁₀ an arylamine(C _1- C ₆ alkyl) group; and the like. Examples of disubstituted amino(alkylo) groups include, without limitation, −CH ₂ N(methyl) ₂ , −CH ₂ N(phenyl)(methyl), −NCH ₂ (ethyl)(methyl), −CH ₂ CH ₂ N( methyl) ₂ , −CH ₂ CH ₂ N(phenyl)(methyl), −NCH ₂ CH ₂ (ethyl)(methyl), etc.

[0066] Where the number of substituents is not specified (eg, haloalkyl), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl" may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0067] As used herein, the term "radical" means a compound with one unpaired electron to allow compounds containing the radical to be covalently bonded to other compounds. Thus, in this context, "radical" is not necessarily a free radical. Instead, "radical" means a specific part of a larger molecule. The term "radical" can be used interchangeably with the term "group".

[0068] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation in the body into which it is administered and does not inhibit the biological action and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting the compound with inorganic acids such as hydrohalic acids (eg, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, such as formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, trifluoroacetic , benzoic, salicylic, 2-oxo-pentanedioic or naphthalenesulfonic acid. Pharmaceutical salts can also be prepared by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium or magnesium salt, a carbonate salt, a bicarbonate salt, an organic base salt such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C ₁ -C ₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and amino acid salts such as arginine and lysine. With respect to compounds of formula (I), those skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-containing group (eg, NH ₂ ), the nitrogen-containing group may be associated with a positive charge (eg, NH ₂ may become NH ₃ ⁺ ), and a positive charge can be balanced by a negatively charged counterion (such as Cl ^- ).

[0069] Cells infected with latent HIV carry a transcriptionally inactive virus that can still replicate to produce active HIV. The term "HIV de-latenting agent" refers to an agent (including small molecule compounds and proteins) that stimulates HIV transcription to convert cells infected with latent HIV into cells expressing replicating HIV. Anti-HIV latency agents include, but are not limited to, protein kinase C agonists (e.g., prostratin, bryostatin-1, and ingenol), PD-1 inhibitors (such as nivolumab, pembrolizumab, BGB-A317, pidilizumab, AMP-224, AMP-514, PDR001, REGN2810, and MEDI0680), PD-L1 inhibitors (such as atezolizumab, durvalumab, avelumab, and BMS-936559), HDAC inhibitors (such as vorinostat, panobinostat, romidepsin, and valproic acid), phorbol esters (such as phorbol 12-myristate-13-acetate and (S)-tert-butyl-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2 ,4]triazolo[4,3-a][1,4]diazepen-6-yl)acetate) and bromodomain inhibitors (such as JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610, RVX2135, FT-1101, BAY1238097, INCB054329, TEN-010, GSK2820151, ZEN003694, BAY-299, BMS-986158, ABBV-075 and GS-5829).

[0070] The term "Bcl protein inhibitor" refers to an agent (including small molecule compounds and proteins) that inhibits the binding of anti-apoptotic Bcl protein (such as Bcl-2, Bcl-X _L , Bcl-W, Mcl-1 and Bcl-2A1) to proapoptotic Bcl protein (such as Bak, Bax, Bim, Bid, tBid, Bad, Bik, PUMA, Bnip-1, Hrk, Bmf and Noxa). Bcl protein inhibitors include, without limitation, venetoclax, navitoclax, obatoclax, S55746, APG-2575, ABT-737, AMG176, AZD5991, and APG-1252. Additional Bcl protein inhibitors include, but are not limited to, the compounds described in Published Cooperation Treaty Application Nos. WO2017/132474, WO 2014/113413, and WO 2013/110890, US Published Application No. 2015/0051189, and China Patent Application No. CN 106565607, each of which is incorporated herein by reference for the limited purpose of describing additional Bcl protein inhibitors. As will be understood by those skilled in the art, there are many ways to evaluate binding protein interactions, including, but not limited to, co-immunoprecipitation, fluorescence resonance energy transfer (FRET), surface plasmon resonance (SPR), and fluorescent polarization/anisotropy.

[0071] It should be understood that in any compound described herein having one or more chiral centers, each center may independently have an R-configuration, or an S-configuration, or a mixture thereof, unless the absolute stoichiometry is explicitly stated. Therefore, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, may be a racemic mixture, may be diastereomeric pure, diastereomeric enriched, or may be a stereoisomeric mixture. In addition, it should be understood that in any compound described herein having one or more double bonds, creating geometric isomers that can be denoted as E or Z, each double bond can independently be E or Z, or a mixture thereof. Likewise, it is to be understood that any compound described is also intended to include all tautomeric forms.

[0072] It should be understood that when there are unfilled valences in the compounds described herein, these valences should be filled with hydrogen atoms or its isotopes, for example, hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0073] It should be understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as, for example, a longer in vivo half-life or a lower dose requirement. Each chemical element present in the structure of a compound can include any isotope of the specified element. For example, a hydrogen atom may be explicitly described in the structure of a compound, or its presence in the structure of a compound may be implied. At any location on the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Therefore, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0074] It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystalline ways of packing the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed during a crystallization process with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein may exist in unsolvated and solvated forms. In general, the solvated forms are, for the purposes of the present compounds and methods, considered equivalent to the unsolvated forms.

[0075] If a range of values is proposed, it should be understood that the embodiments include upper and lower limits, as well as any intermediate value between the upper and lower limits.

[0076] The terms and phrases used in this application, as well as their variations, in particular in the attached claims, unless expressly stated otherwise, should be considered non-limiting, and not having a restrictive nature. As examples of the above, the term "including" should be considered "including, without limitation", "including, but not limited to", or the like; as used herein, the term "comprising" is synonymous with the terms "including", "comprising", or "characterized" and is inclusive or non-limiting, and does not exclude additional unspecified elements or method steps; the term "having" should be interpreted as "having at least"; the term "includes" should be interpreted as "includes, without limitation"; the term "example" is used to provide examples of the implementation of the description element, but not an exhaustive or limiting list; and the use of terms such as "preferred", "preferred", "desired" or "desirable" or similar words should not be understood as suggesting that certain features are critical, essential or even important to structure or function, but they are intended to highlight alternative or additional features that may or may not be used in a particular embodiment. In addition, the term "comprising" should be interpreted as synonymous with the phrases "having at least" or "comprising at least". In the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the indicated features or components, but may include additional features or components.

[0077] With respect to the application of essentially any plural and/or singular variations for terms herein, those skilled in the art may change plural to singular and/or singular to plural as required by context and/or scope. In this document, various combinations of singular/plural may be explicitly indicated for clarity. The use of the singular does not exclude plurality. The mere fact that certain indicators are indicated in mutually different dependent claims does not mean that these indicators cannot be combined if necessary. Any reference designations in the claims should not be considered as limiting the scope.

Connections

[0078] Some embodiments described herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

(I)

where: R ¹ can be selected from hydrogen, halogen, substituted or unsubstituted C _{1 -C 6} alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine; each R ² may be independently selected from halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; R ³ may be selected from hydrogen, halogen, XR ^3A , R ^3A may be substituted or unsubstituted 5-10 membered heteroaryl; R ⁴ may be selected from NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano and unsubstituted C ₁ -C ₆ haloalkyl; R ⁵ may be selected from -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ; Alk ¹ and Alk ² may be independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl; R ⁶ may be selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; R ⁷ may be selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted disubstituted amino, substituted or unsubstituted N-carbamyl, substituted or unsubstituted C-amido, and substituted or unsubstituted N-amido; R ⁸ may be selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono-C ₁ -C ₆ alkylamine (C ₁ -C ₆ alkyl); R ⁹ may be selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl; m can be equal to 0, 1, 2 and 3; n and p can be independently chosen from 0 and 1; X, X ¹ , X ² and X ³ may be independently selected from -O-, -S- and -NH-; and wherein, when m is 2 or 3, the two R ² groups, taken together with the atom(s) to which they are attached, may form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3 -6-membered heterocyclyl.

[0079] In some embodiments, R ¹ may be halogen, such as fluorine, chlorine, bromine, or iodine. In some embodiments, R ¹ may be fluorine. In some embodiments, R ¹ may be chlorine. In some embodiments, R ¹ may be hydrogen.

[0080] In some embodiments, R ¹ may be substituted or unsubstituted C ₁ -C ₆ alkyl. For example, in some embodiments, R ¹ may be a substituted C ₁ -C ₆ alkyl. In other embodiments, R ¹ may be unsubstituted C ₁ -C ₆ alkyl. Examples of suitable C ₁ -C ₆ alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl (branched and straight chain), and hexyl (branched and straight chain). chain). In some embodiments, R ¹ may be unsubstituted methyl or unsubstituted ethyl.

[0081] In some embodiments _, R ¹ may be a _substituted or unsubstituted C _{1 -C 6} haloalkyl, _e.g. or unsubstituted tri-halogen C ₁ -C ₆ alkyl, substituted or unsubstituted tetra-halogen C ₁ -C ₆ alkyl or substituted or unsubstituted penta-halogen C ₁ -C ₆ alkyl. In some embodiments, R ¹ may be unsubstituted -CHF ₂ , -CF ₃ , -CH ₂ CF _{3 ,} or -CF ₂ CH ₃ .

[0082] In some embodiments, R ¹ may be a substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl. For example, in some embodiments, R ¹ may be a substituted monocyclic C ₃ -C ₆ cycloalkyl. In other embodiments, R ¹ may be an unsubstituted monocyclic C ₃ -C ₆ cycloalkyl. Examples of suitable monocyclic or bicyclic C ₃ -C ₆ cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, [1.1.1]bicyclopentyl, and cyclohexyl.

[0083] In some embodiments, R ¹ may be substituted or unsubstituted C ₁ -C ₆ alkoxy. For example, in some embodiments, R ¹ may be a substituted C ₁ -C ₆ alkoxy. In other embodiments, R ¹ may be an unsubstituted C ₁ -C ₆ alkoxy. Examples of suitable C ₁ -C ₆ alkoxy groups include, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentoxy (branched and straight chain), and hexoxy (branched and straight chain). ). In some embodiments, R ¹ may be unsubstituted methoxy or unsubstituted ethoxy.

[0084] In some embodiments, R ¹ may be an unsubstituted mono-C ₁ -C ₆ alkylamine, e.g., methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, t-butylamine, pentylamine (branched and straight chain ) and hexylamine (branched and straight chain). In some embodiments, R ¹ may be methylamine or ethylamine.

[0085] In some embodiments, R ¹ may be an unsubstituted di-C ₁ -C ₆ alkylamine. In some embodiments, all C ₁ -C ₆ alkyl groups in di-C ₁ -C ₆ alkylamine are the same. In other embodiments, all C ₁ -C ₆ alkyl groups in di-C ₁ -C ₆ alkylamine are different. Examples of suitable di-C ₁ -C ₆ alkylamine groups include, without limitation, di-methylamine, di-ethylamine, (methyl)(ethyl)amine, (methyl)(isopropyl)amine and (ethyl)(isopropyl)amine.

[0086] In some embodiments, m may be 0. If m is 0, it will be understood by those skilled in the art that the ring to which R ² is attached is unsubstituted. In some embodiments, m may be equal to 1. In some embodiments, m may be equal to 2. In some embodiments, m may be equal to 3.

[0087] In some embodiments, one R ² may be unsubstituted C ₁ -C ₆ alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl (branched and straight chain ) and hexyl (branched and straight chain)), and any other R ² , if any, may be independently selected from halogen (eg, fluorine or chlorine), substituted or unsubstituted C ₁ -C ₆ alkyl (eg, those described herein document), substituted or unsubstituted C ₁ -C ₆ haloalkyl (eg, described herein) and substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl (eg, described herein). In some embodiments, each R ² may be independently selected from unsubstituted C ₁ -C ₆ alkyl, such as those described herein.

[0088] In some embodiments, m may be 2; and each R ² may be attached to the same atom. In some embodiments, m may be 2; and each R ² can be attached to an adjacent atom. In some embodiments, m may be 2; and each R ² may be unsubstituted methyl. In some embodiments, m may be 2; and each R ² may be unsubstituted methyl attached to the same atom.

[0089] In some embodiments, two R ² groups, taken together with the atom(s) to which they are attached, may form a substituted or unsubstituted monocyclic C ₃ -C ₆ cycloalkyl. For example, in some embodiments, two R ² groups, taken together with the atom(s) to which they are attached, can form a substituted monocyclic C ₃ -C ₆ cycloalkyl, such as described herein. In other embodiments, the two R ² groups, taken together with the atom(s) to which they are attached, may form an unsubstituted monocyclic C ₃ -C ₆ cycloalkyl, such as described herein. In some embodiments, two R ² groups, taken together with the atom(s) to which they are attached, may form an unsubstituted cyclopropyl.

[0090] In some embodiments, two R ² groups taken together with the atom(s) to which they are attached can form a substituted or unsubstituted monocyclic 3-6 membered heterocyclyl. For example, in some embodiments, two R ² groups taken together with the atom(s) to which they are attached can form a substituted monocyclic 3-6 membered heterocyclyl. In other embodiments, the two R ² groups, taken together with the atom(s) to which they are attached, may form an unsubstituted monocyclic 3-6 membered monocyclic heterocyclyl. In some embodiments, a substituted monocyclic 3-6 membered heterocyclyl may be substituted on one or more nitrogen atoms. Examples of suitable substituted or unsubstituted monocyclic 3-6 membered heterocyclyl groups include, without limitation, azidirine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, and dioxane.

[0091] In some embodiments, R ³ may be In some embodiments, R ³ may be

[0092] In some embodiments, R ³ may be XR ^3A . In some embodiments, X may be -O-. In some embodiments, X may be -S-. In some embodiments, X may be -NH-. In some embodiments, R ^3A may be In some embodiments, R ^3A may be

[0093] In some embodiments, R ^3A may be a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments, R ^3A may be a substituted 5-10 membered monocyclic heteroaryl. In other embodiments, R ^3A may be a substituted 5-10 membered bicyclic heteroaryl. In some embodiments, R ^3A may be an unsubstituted 5-10 membered monocyclic heteroaryl. In other embodiments, R ^3A may be an unsubstituted 5-10 membered bicyclic heteroaryl. Examples of suitable substituted or unsubstituted monocyclic or bicyclic 5- to 10-membered heteroaryl groups include, without limitation, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, pyrrolo -pyrroles, pyrrolo-furans, pyrrolo-thiophenes, indole, isoindole, indolizine, indazole, benzimidazole, azaindoles, azaindazoles, purine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, 1.8 -naphthyridine, pyrido-pyrimidines and pteridine.

[0094] In some embodiments, R ³ may be hydrogen. In some embodiments, R ³ may be halogen. In some embodiments, R ³ may be fluorine or chlorine.

[0095] In some embodiments, R ⁴ may be NO ₂ . In some embodiments, R ⁴ may be cyano. In some embodiments, R ⁴ may be halogen.

[0096] In some embodiments, R ⁴ may be an unsubstituted C ₁ -C ₆ haloalkyl, such as described herein. In some embodiments, R ⁴ may be -CF ₃ .

[0097] In some embodiments, R ⁴ may be S(O)R ⁶ . In some embodiments, R ⁴ may be SO ₂ R ⁶ . In some embodiments, R ⁴ may be SO ₂ CF ₃ .

[0098] In some embodiments, R ⁶ may be substituted or unsubstituted C ₁ -C ₆ alkyl. For example, in some embodiments, R ⁶ may be a substituted C ₁ -C ₆ alkyl, such as described herein. In other embodiments, R ⁶ may be unsubstituted C ₁ -C ₆ alkyl, such as those described herein.

[0099] In some embodiments, R ⁶ may be a substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl. For example, in some embodiments, R ⁶ may be a substituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl. In other embodiments, R ⁶ may be an unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl. Examples of suitable monocyclic or bicyclic C ₃ -C ₆ cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, [1.1.1]bicyclopentyl, and cyclohexyl.

[0100] In some embodiments, R ⁶ may be a substituted or unsubstituted C ₁ -C ₆ haloalkyl, such as described herein. In some embodiments, R ⁶ may be -CF ₃ .

[0101] In some embodiments, R ⁵ may be -X ^1- (Alk ¹ ) _n -R ⁷ . In some embodiments, X ¹ may be -O-. In some embodiments, X ¹ may be -S-. In some embodiments, X ¹ may be -NH-.

[0102] In some embodiments, Alk ¹ may be unsubstituted -(CH ₂ ) _1-4 -*, for which "*" denotes the point of attachment to R ⁷ . In some embodiments, Alk ¹ may be , , , or .

[0103] In some embodiments, Alk ¹ may be a substituted , for which "*" denotes the point of attachment to R ⁷ . For example, in some embodiments, Alk ¹ may be substituted methylene, substituted ethylene, substituted propylene, or substituted butylene. In some embodiments, Alk ¹ may be monosubstituted, disubstituted, or trisubstituted. In some embodiments, Alk ¹ may be monosubstituted with halogen (such as fluorine or chlorine) or unsubstituted C ₁ -C ₃ alkyl, such as those described herein. In other embodiments, Alk ¹ may be monosubstituted with an unsubstituted C ₁ -C ₃ haloalkyl, such as those described herein. In some embodiments, Alk ¹ may be monosubstituted with fluorine or unsubstituted methyl. In some embodiments, Alk ¹ may be disubstituted with one fluorine and one unsubstituted C ₁ -C ₃ alkyl, such as those described herein. In other embodiments, Alk ¹ may be disubstituted with one unsubstituted C ₁ -C ₃ haloalkyl, eg, as described herein, and one unsubstituted C ₁ -C ₃ alkyl, eg, as described herein. In some embodiments, Alk ¹ may be disubstituted with one fluorine and one unsubstituted methyl. In some embodiments, Alk ¹ may be disubstituted with two independently selected unsubstituted C ₁ -C ₃ alkyl groups, such as those described herein. In some embodiments, Alk ¹ may be disubstituted with unsubstituted methyl.

[0104] In some embodiments, Alk ¹ may be selected from: , , , , , , , , , , , , , , , And .

[0105] In some embodiments, n may be 0. If n is 0, those skilled in the art will understand that X ¹ is directly related to R ⁷ . In some embodiments, n may be equal to 1.

[0106] In some embodiments, R ⁷ may be a substituted or unsubstituted mono-substituted amino group. For example, R ⁷ may be an amino group mono-substituted with substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl, substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl, substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl (unsubstituted C ₁ -C ₆ alkyl), substituted or unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl (unsubstituted C ₁ -C ₆ alkyl), substituted or unsubstituted monocyclic or bicyclic 5-10- membered heteroaryl(unsubstituted C ₁ -C ₆ alkyl) or substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl(unsubstituted C ₁ -C ₆ alkyl). Examples of suitable mono-substituted amino groups include, without limitation, −NH(methyl), −NH(isopropyl), −NH(cyclopropyl), −NH(phenyl), −NH(benzyl), and −NH(pyridin-3-yl ).

[0107] In some embodiments, R ⁷ may be a disubstituted amino group with or without substituents. For example, R ⁷ may be an amino group substituted with two substituents independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl, substituted or unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl, substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl, substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₆ cycloalkyl (unsubstituted C ₁ -C ₆ alkyl), substituted or unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl (unsubstituted C ₁ -C ₆ alkyl), substituted or unsubstituted monocyclic or bicyclic 5- 10-membered heteroaryl (unsubstituted C ₁ -C ₆ alkyl) or substituted or unsubstituted monocyclic or bicyclic 3-10-membered heterocyclyl (unsubstituted C ₁ -C ₆ alkyl). In some embodiments, the two substituents may be the same. In other embodiments, the two substituents may be different. Examples of suitable disubstituted amino groups include, without limitation, -N(methyl) ₂ , -N(ethyl) ₂ , -N(isopropyl) ₂ , -N(benzyl) ₂ , -N(ethyl)(methyl), -N( isopropyl)(methyl), −N(ethyl)(isopropyl), −N(phenyl)(methyl), and −N(benzyl)(methyl).

[0108] In some embodiments, R ⁷ may be selected from substituted or unsubstituted N-carbamyl, substituted or unsubstituted C-amido, and substituted or unsubstituted N-amido.

[0109] In some embodiments, R ⁷ may be a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl. In some embodiments, R ⁷ may be a substituted or unsubstituted monocyclic C ₃ -C ₁₀ cycloalkyl. In other embodiments, R ⁷ may be a substituted or unsubstituted bicyclic C ₃ -C ₁₀ cycloalkyl, such as bridged, fused, or spiro C ₃ -C ₁₀ cycloalkyl. Suitable substituted or unsubstituted monocyclic or bicyclic C ₃ -C ₁₀ cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, spiro[3.3]heptyl, spiro[2.3]hexyl, spiro[ 3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[2.4]heptyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[2.5]octyl, spiro[3.5]nonyl, bicyclo[1.1. 1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthelenyl, octahydro-1H-indenyl, octahydropentalenyl, bicyclo[4.2.0]octyl, bicyclo[2.1.0]pentyl and bicyclo[3.2. 0]heptyl.

[0110] In some embodiments, R ⁷ may be a substituted or unsubstituted C ₆ -C ₁₀ spirocycloalkyl. In some embodiments, R ⁷ may be a substituted C ₆ -C ₁₀ spirocycloalkyl. In other embodiments, R ⁷ may be unsubstituted C ₆ -C ₁₀ spirocycloalkyl. In some embodiments, R ⁷ may be substituted or unsubstituted -cyclopropyl-cyclobutyl spiroalkyl, -cyclopropyl-cyclopentyl spiroalkyl, -cyclopropyl-cyclohexyl spiroalkyl, -cyclopropyl-cycloheptyl spiroalkyl, -cyclopropyl-cyclooctyl spiroalkyl, -cyclobutyl-cyclopropyl spiroalkyl, -cyclobutyl -cyclobutyl spiroalkyl, -cyclobutyl-cyclopentyl spiroalkyl, -cyclobutyl-cyclohexyl spiroalkyl, -cyclobutyl-cycloheptyl spiroalkyl, -cyclopentyl-cyclopropyl spiroalkyl, -cyclopentyl-cyclobutyl spiroalkyl, -cyclopentyl-cyclopentyl spiroalkyl, cyclopentyl-cyclohexyl spiroalkyl, -cyclohexyl-cyclopropyl spiroalkyl , -cyclohexyl-cyclobutyl spiroalkyl, -cyclohexyl-cyclopentyl spiroalkyl, -cycloheptyl-cyclopropyl spiroalkyl, -cycloheptyl-cyclobutyl spiroalkyl or -cyclooctyl-cyclopropyl spiroalkyl.

[0111] In some embodiments, R ⁷ may be a substituted or unsubstituted 3-10 membered heterocyclyl. In some embodiments, R ⁷ may be a substituted 3-10 membered heterocyclyl. In other embodiments, R ⁷ may be an unsubstituted 3-10 membered heterocyclyl. In some embodiments, R ⁷ may be a substituted or unsubstituted monocyclic 3-10 membered heterocyclyl. In other embodiments, R ⁷ may be a substituted or unsubstituted bicyclic 5-10 membered heterocyclyl, such as a fused, bridged or spiro 5-10 membered heterocyclyl. Suitable substituted or unsubstituted 3-10 membered heterocyclyl groups include, without limitation, azidirine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, dioxane, 2-azaspiro[3.3 ]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[3.4]octane, 6 -oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane and 2-oxa-8-azaspiro[4.5]decane. In some embodiments, the implementation of the substituted or unsubstituted monocyclic or bicyclic 3-10-membered heterocyclyl can be connected to the rest of the molecule through a nitrogen atom. In other embodiments, a substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl may be linked to the rest of the molecule via a carbon atom. In some embodiments, a substituted monocyclic or bicyclic 3-10 membered heterocyclyl may be substituted on one or more nitrogen atoms.

[0112] In some embodiments, R ⁷ may be a substituted or unsubstituted 6-10 membered spiro-heterocyclyl. In some embodiments, R ⁷ may be a substituted 6-10 membered spiro-heterocyclyl. In other embodiments, R ⁷ may be an unsubstituted 6-10 membered spiro-heterocyclyl. In some embodiments, R ⁷ may be substituted or unsubstituted azaspirohexane, azaspiroheptane, azaspirooctane, oxaspirohexane, oxaspiroheptane, oxaspirooctane, diazaspirohexane, diazaspiroheptane, diazaspirooctane, dioxaspirohexane, dioxaspiroheptane, dioxaspirooctane, oxaspirohexane, oxa -azaspiroheptane or oxa-azaspirooctane. Suitable substituted or unsubstituted 3-10 membered heterocyclyl groups include, without limitation, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro [3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5 ]nonane and 2-oxa-8-azaspiro[4.5]decane. In some embodiments, the implementation of the substituted or unsubstituted 6-10-membered spiro-heterocyclyl can be connected to the rest of the molecule through a nitrogen atom. In other embodiments, the implementation of the substituted or unsubstituted 6-10-membered spiro-heterocyclyl can be connected to the rest of the molecule through a carbon atom. In some embodiments, a substituted 6- to 10-membered spiroheterocyclyl may be substituted on one or more nitrogen atoms.

[0113] In some embodiments, R ⁷ may be a hydroxy or amino functional group.

[0114] In some embodiments, R ⁷ may be unsubstituted. In other embodiments, R ⁷ may be substituted. In some embodiments, R ⁷ may be substituted with 1 or 2 substituents independently selected from unsubstituted C ₁ -C ₆ alkyl (eg, described herein), unsubstituted C ₁ -C ₆ alkoxy (eg, described herein), fluoro , chlorine, hydroxy and -SO ₂ -(unsubstituted C ₁ -C ₆ alkyl). For example, the C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, monosubstituted amino, disubstituted amino, N-carbamyl, C-amido, and N-amido groups in R ⁷ may be substituted with 1 or 2 substituents independently selected from any of the above substituents.

[0115] In some embodiments, R ⁷ may be , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0116] In some embodiments, R ⁷ may be , , , , , , , , , , , , , , , , , , , , or .

[0117] In some embodiments, R ⁷ may be . For example, in some embodiments, R ⁷ may be or . In some embodiments, R ⁷ may be . For example, in some embodiments, R ⁷ may be or . In some embodiments, R ⁷ may be . In some embodiments, R ⁷ may be . For example, in some embodiments, R ⁷ may be or . In some embodiments, R ⁷ may be . For example, in some embodiments, R ⁷ may be or , For example , , or .

[0118] In some embodiments, R ⁵ may be -X ² -(CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ . In some embodiments, X ² may be -O-. In some embodiments, X ² may be -S-. In some embodiments, X ² may be -NH-. In some embodiments, X ³ may be -O-. In some embodiments, X ³ may be -S-. In some embodiments, X ³ may be -NH-. In some embodiments, X ² may be -NH- and X ³ may be -S-. In some embodiments, X ² may be -O- and X ³ may be -S-. In some embodiments, X ² may be -NH- and X ³ may be -O-. In some embodiments, X ² may be -O- and X ³ may be -O-.

[0119] In some embodiments, Alk ² may be unsubstituted -(CH ₂ ) _1-4 -*, for which "*" indicates the point of attachment to X ³ . In some embodiments, Alk ² may be unsubstituted methylene, unsubstituted ethylene, unsubstituted propylene, or unsubstituted butylene. In some embodiments, Alk ² may be , or .

[0120] In some embodiments, Alk ² may be a substituted , for which "*" denotes the point of attachment to X ³ . In some embodiments, Alk ² may be substituted methylene, substituted ethylene, substituted propylene, or substituted butylene. In some embodiments, Alk ² may be monosubstituted, disubstituted, or trisubstituted. In some embodiments, Alk ² may be mono-substituted fluoro or unsubstituted C ₁ -C ₃ alkyl, such as those described herein. In some embodiments, Alk ² may be monosubstituted with fluorine or unsubstituted methyl. In some embodiments, Alk ² may be disubstituted with one fluorine and one unsubstituted C ₁ -C ₃ alkyl, such as those described herein. In some embodiments, Alk ² may be disubstituted with one fluorine and one unsubstituted methyl. In some embodiments, Alk ² may be disubstituted with two independently selected unsubstituted C ₁ -C ₃ alkyls, such as those described herein. In some embodiments, Alk ² may be disubstituted with unsubstituted methyl.

[0121] In some embodiments, Alk ² may be selected from:

[0122] In some embodiments, p may be equal to 0. If p is equal to 0, it will be clear to those skilled in the art that the group (CHR ⁸ ) is directly linked to X ³ . In some embodiments, p may be equal to 1.

[0123] In some embodiments, C ₁ -C ₆ alkyl in substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) in R ⁸ may be substituted or unsubstituted C ₁ -C ₆ alkyl, such as those described in this document. In some embodiments, the 3-10 membered heterocyclyl in substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) in R ⁸ may be monocyclic. In some embodiments, a 3-10 membered heterocyclyl in a substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) may be bicyclic. In other embodiments, a 3-10 membered heterocyclyl in a substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) may be coupled to a C ₁ -C ₆ alkyl of a substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) via a carbon atom. In some embodiments, the 3-10 membered heterocyclyl in the substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) may be unsubstituted. In other embodiments, the 3-10 membered heterocyclyl in the substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) may be substituted. In some embodiments, the 3-10 membered heterocyclyl in the substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) may be substituted on one or more nitrogen atoms. Examples of suitable substituted or unsubstituted monocyclic or bicyclic 3-10 membered heterocyclyl groups in R ⁸ include, without limitation, azidirine, oxirane, azetidine, oxetane, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine, piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, dioxane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6- oxaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, and 2-oxa-8-azaspiro[4.5]decane. In some embodiments, the C ₁ -C ₆ alkyl in R ⁸ may be unsubstituted methyl or unsubstituted ethyl, and the substituted or unsubstituted 3-10 membered heterocyclyl in R ⁸ may be piperidine, tetrahydropyran, piperazine, morpholine, thiomorpholine, dioxane, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[ 3.4]octane, 6-oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, or 2-oxa-8-azaspiro[4.5]decane.

[0124] In some embodiments, R ⁸ may be a substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl). In some embodiments, the C ₁ -C ₆ alkyl in the substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) in R ⁸ may be substituted or unsubstituted C ₁ -C ₆ alkyl, such as those described herein. document. In some embodiments, the C ₁ -C ₆ alkyl in the substituted or unsubstituted 6- to 10-membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be unsubstituted. In some embodiments, a 6-10 membered spiro-heterocyclyl in a substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be connected to a C ₁ -C ₆ alkyl in R ⁸ via a nitrogen atom. In other embodiments, a 6-10 membered spiro-heterocyclyl in a substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be coupled to a C ₁ -C ₆ alkyl of a substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) via a carbon atom. In some embodiments, the substituted or unsubstituted 6-10 membered spiro-heterocyclyl in the substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be unsubstituted. In other embodiments, the 6-10 membered spiro-heterocyclyl substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be substituted. In some embodiments, the 6-10 membered spiro-heterocyclyl substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be substituted on one or more nitrogen atoms. In some embodiments, the substituted or unsubstituted 6-10 membered spiro-heterocyclyl substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be azaspirohexane, azaspiroheptane, azaspirooctane, oxaspirohexane, oxaspiroheptane, oxaspirooctane, diazaspirohexane , diazaspiroheptane, diazaspirooctane, dioxaspirohexane, dioxaspiroheptane, dioxaspirooctane, oxazaspirohexane, oxazaspiroheptane, or oxazaspirooctane. Examples of suitable substituted or unsubstituted 6-10 membered spiro-heterocyclyl in R ⁸ include, without limitation, 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[3.4]octane, 6-oxa-2-azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane and 2-oxa-8-azaspiro[4.5]decane. In some embodiments, the C ₁ -C ₆ alkyl of the substituted or unsubstituted 6-10 membered spiro-heterocyclyl(C ₁ -C ₆ alkyl) may be unsubstituted methyl or unsubstituted ethyl, and the 6-10 membered spiro-heterocyclyl in R ⁸ may be azaspirohexane, azaspiroheptane, azaspirooctane, oxaspirohexane, oxaspiroheptane, oxaspirooctane, diazaspirohexane, diazaspiroheptane, diazaspirooctane, dioxaspirohexane, dioxaspiroheptane, dioxaspirooctane, oxa-azaspirohexane, oxa-azaspiroheptane or oxa-azaspir ooctane, e.g. 2-azaspiro[3.3]heptane, 2 -oxaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 6-oxaspiro[3.4]octane, 6-oxa-2 -azaspiro[3.4]octane, 7-oxa-2-azaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, or 2-oxa-8-azaspiro[4.5]decane.

[0125] In some embodiments, R ⁸ may be a substituted or unsubstituted di-C ₁ -C ₆ alkylamine (C ₁ -C ₆ alkyl), for example, di-C ₁ -C ₆ alkylamine (ethyl), di-C ₁ -C ₆ alkylamine (propyl), di-C ₁ -C ₆ alkylamine (butyl), di-C ₁ -C ₆ alkylamine (pentyl) or di-C ₁ -C ₆ alkylamine (hexyl). In some embodiments, all C ₁ -C ₆ alkyl groups in di-C ₁ -C ₆ alkylamine may be the same. In other embodiments, all C ₁ -C ₆ alkyl groups in the di-C ₁ -C ₆ alkylamine may be different. Suitable substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl) include, without limitation -N(methyl) ₂ , -N(ethyl) ₂ , -N(n-propyl) ₂ , - N(isopropyl) ₂ , −N(tert-butyl) ₂ , −N(ethyl)(methyl), −N(isopropyl)(methyl), −N(tert-butyl)(methyl) and −N(isopropyl)( ethyl); each of which is connected to a substituted or unsubstituted C ₁ -C ₆ alkyl group.

[0126] In some embodiments, R ⁸ may be substituted or unsubstituted di-methylamine(C ₁ -C ₆ alkyl), e.g.

[0127] In some embodiments, R ⁸ may be a substituted or unsubstituted mono-C ₁ -C ₆ alkylamine (C ₁ -C ₆ alkyl), such as a substituted or unsubstituted mono-C ₁ -C ₆ alkylamine (ethyl), mono- C ₁ -C ₆ alkylamine (propyl), mono-C ₁ -C ₆ alkylamine (butyl), mono-C ₁ -C ₆ alkylamine (pentyl) or mono-C ₁ -C ₆ alkylamine (hexyl). In some embodiments, the C ₁ -C ₆ alkyl in the unsubstituted mono-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl) group may be unsubstituted C ₁ -C ₆ alkyl, such as described herein.

[0128] In some embodiments, R ⁸ may be unsubstituted. In other embodiments, R ⁸ may be substituted. In some embodiments, R ⁸ may be substituted with 1 or 2 substituents independently selected from unsubstituted C ₁ -C ₆ alkyl (for example, as described herein), unsubstituted C ₁ -C ₆ alkoxy (for example, as described herein), unsubstituted di-C ₁ -C ₆ alkylamine (eg as described herein), unsubstituted acyl(C ₁ -C ₆ alkyl) (eg acetyl or benzoyl), unsubstituted C-carboxy (eg −CO ₂ H, −CO ₂ -C ₁ -C ₆ alkyl, -CO ₂ -C ₃ -C ₆ cycloalkyl or -CO ₂ -C ₆ -C ₁₀ aryl), fluorine, chlorine and hydroxy. For example, groups of 3-10-membered heterocyclyl (C ₁ -C ₆ alkyl), di-C ₁ -C ₆ alkylamine (C ₁ -C ₆ alkyl) and mono-C ₁ -C ₆ alkylamine (C ₁ -C ₆ alkyl ) in R ⁸ may be substituted with 1 or 2 substituents independently selected from any of the above substituents.

[0129] In some embodiments, R ⁸ may be:

[0130] In some embodiments, R ⁸ may be . , , , , or ,

[0131] In some embodiments, R ⁹ may be a substituted or unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl. In some embodiments, R ⁹ may be a substituted monocyclic or bicyclic C ₆ -C ₁₀ aryl. In other embodiments, R ⁹ may be an unsubstituted monocyclic or bicyclic C ₆ -C ₁₀ aryl. In some embodiments, R ⁹ may be a substituted phenyl or a substituted naphthyl. In some embodiments, R ⁹ may be unsubstituted phenyl or unsubstituted naphthyl.

[0132] In some embodiments, R ⁹ may be a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments, R ⁹ may be a substituted 5-10 membered heteroaryl. In other embodiments, R ⁹ may be an unsubstituted 5-10 membered heteroaryl. In some embodiments, R ⁹ may be a monocyclic substituted or unsubstituted 5-10 membered heteroaryl. In other embodiments, R ⁹ may be a bicyclic substituted or unsubstituted 5-10 membered heteroaryl. Suitable substituted or unsubstituted monocyclic or bicyclic 5 to 10 membered heteroaryls include, but are not limited to, pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine, pyrrolo-pyrroles , pyrrolo-furans, pyrrolo-thiophenes, indole, isoindole, indolizine, indazole, benzimidazole, azaindoles, purine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, 1,8-naphthyridine, pyrido pyrimidines and pteridines.

[0133] In some embodiments, R ³ is hydrogen or halogen. For example, in an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0134] R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine;

[0135] each R ² is independently selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; or

[0136] when m is 2 or 3, each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl, or two R ² groups, taken together with the atom(s) to which they are connected, form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl;

[0137] R ³ is hydrogen or halogen;

[0138] R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano and unsubstituted C ₁ -C ₆ haloalkyl;

[0139] R ⁵ is selected from the group consisting of -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ;

[0140] Alk ¹ and Alk ² are independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl;

[0141] R ⁶ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

[0142] R ⁷ is selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted a disubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido, and a substituted or unsubstituted N-amido;

[0143] R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono- C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl);

[0144] R ⁹ is selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted C ₆ -C ₁₀ aryl;

[0145] m is 0, 1, 2, or 3;

[0146] n and p are independently selected from 0 and 1; And

[0147] X ¹ , X ² and X ³ are independently selected from the group consisting of -O-, -S- and -NH-.

[0148] In some embodiments, R ³ is selected from the group consisting of XR ^3A , For example, in an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0149] R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine;

[0150] each R ² is independently selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; or

[0151] when m is 2 or 3, each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl, or two R ² groups, taken together with the atom(s) to which they are connected, form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl;

[0152] R ³ is selected from the group consisting of XR ^3A ,

[0153] R ^3A is a substituted or unsubstituted 5-10 membered heteroaryl;

[0154] R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano, and unsubstituted C ₁ -C ₆ haloalkyl;

[0155] R ⁵ is selected from the group consisting of -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ;

[0156] Alk ¹ and Alk ² are independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl;

[0157] R ⁶ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

[0158] R ⁷ is selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted a disubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido, and a substituted or unsubstituted N-amido;

[0159] R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono- C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl);

[0160] R ⁹ is selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted C ₆ -C ₁₀ aryl;

[0161] m is 0, 1, 2, or 3;

[0162] n and p are independently selected from 0 and 1;

[0163] X, X ¹ , X ² and X ³ are independently selected from the group consisting of -O-, -S- and -NH-.

[0164] In some embodiments, R ³ is selected from the group consisting of XR ^3A , and X ¹ and X ² are -NH-. For example, in an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0165] R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine;

[0166] each R ² is independently selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; or

[0167] when m is 2 or 3, each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl, or two R ² groups, taken together with the atom(s) to which they are connected, form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl;

[0168] R ³ is selected from the group consisting of XR ^3A ,

[0169] R ^3A is a substituted or unsubstituted 5-10 membered heteroaryl;

[0170] R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano, and unsubstituted C ₁ -C ₆ haloalkyl;

[0171] R ⁵ is selected from the group consisting of -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ;

[0172] Alk ¹ and Alk ² are independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl;

[0173] R ⁶ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

[0174] R ⁷ is selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted a disubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido, and a substituted or unsubstituted N-amido;

[0175] R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono- C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl);

[0176] R ⁹ is selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted C ₆ -C ₁₀ aryl;

[0177] m is 0, 1, 2, or 3;

[0178] n and p are independently selected from 0 and 1;

[0179] X ¹ and X ² are -NH-; And

[0180] X and X ³ are independently selected from the group consisting of -O-, -S- and -NH-.

[0181] In some embodiments, R ¹ is the same as described above, provided that it is not -CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is selected from the group consisting of XR ^3A , and X ¹ and X ² are -NH-. For example, in an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0182] R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine, with the proviso that R ¹ is not -CH ₂ F, -CHF ₂ or -CF ₃ ;

[0183] each R ² is independently selected from the group consisting of halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; or

[0184] when m is 2 or 3, each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl, or two R ² groups, taken together with the atom(s) to which they are connected, form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl;

[0185] R ³ is selected from the group consisting of XR ^3A ,

[0186] R ^3A is a substituted or unsubstituted 5-10 membered heteroaryl;

[0187] R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano and unsubstituted C ₁ -C ₆ haloalkyl;

[0188] R ⁵ is selected from the group consisting of -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ;

[0189] Alk ¹ and Alk ² are independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl;

[0190] R ⁶ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

[0191] R ⁷ is selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted a disubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido, and a substituted or unsubstituted N-amido;

[0192] R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono- C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl);

[0193] R ⁹ is selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted C ₆ -C ₁₀ aryl;

[0194] m is 0, 1, 2, or 3;

[0195] n and p are independently selected from 0 and 1;

[0196] X ¹ and X ² are -NH-; And

[0197] X and X ³ are independently selected from the group consisting of -O-, -S- and -NH-.

[0198] In some embodiments, R ¹ is
-CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is selected from the group consisting of XR ^3A , and X ¹ and X ² are -NH-. For example, in an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0199] R ¹ is -CH ₂ F, -CHF ₂ or -CF ₃ ;

[0200] each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; or

[0201] when m is 2 or 3, each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl, or two R ² groups, taken together with the atom(s) to which they are connected, form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl;

[0202] R ³ is selected from the group consisting of XR ^3A ,

[0203] R ^3A is a substituted or unsubstituted 5-10 membered heteroaryl;

[0204] R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano and unsubstituted C ₁ -C ₆ haloalkyl;

[0205] R ⁵ is selected from the group consisting of -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ;

[0206] Alk ¹ and Alk ² are independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl;

[0207] R ⁶ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

[0208] R ⁷ is selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted a disubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido, and a substituted or unsubstituted N-amido;

[0209] R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono- C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl);

[0210] R ⁹ is selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted C ₆ -C ₁₀ aryl;

[0211] m is 0, 1, 2, or 3;

[0212] n and p are independently selected from 0 and 1;

[0213] X ¹ and X ² are -NH-; And

[0214] X and X ³ are independently selected from the group consisting of -O-, -S- and -NH-.

[0215] In some embodiments, R ³ is selected from the group consisting of XR ^3A , and X ¹ and X ² are -O-. For example, in an embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein:

[0216] R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine;

[0217] each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl; or

[0218] when m is 2 or 3, each R ² is independently selected from the group consisting of halo, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl, or two R ² groups, taken together with the atom(s) to which they are connected, form a substituted or unsubstituted C ₃ -C ₆ cycloalkyl or a substituted or unsubstituted 3-6 membered heterocyclyl;

[0219] R ³ is selected from the group consisting of XR ^3A ,

[0220] R ^3A is a substituted or unsubstituted 5-10 membered heteroaryl;

[0221] R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ , SO ₂ R ⁶ , halogen, cyano, and unsubstituted C ₁ -C ₆ haloalkyl;

[0222] R ⁵ is selected from the group consisting of -X ¹ -(Alk ¹ ) _n -R ⁷ and -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ;

[0223] Alk ¹ and Alk ² are independently selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl;

[0224] R ⁶ is selected from the group consisting of substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₃ -C ₆ cycloalkyl;

[0225] R ⁷ is selected from substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclyl, hydroxy, amino, substituted or unsubstituted monosubstituted amino, substituted or unsubstituted a disubstituted amino group, a substituted or unsubstituted N-carbamyl, a substituted or unsubstituted C-amido, and a substituted or unsubstituted N-amido;

[0226] R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl), substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl), and substituted or unsubstituted mono- C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl);

[0227] R ⁹ is selected from substituted or unsubstituted 5-10 membered heteroaryl and substituted or unsubstituted C ₆ -C ₁₀ aryl;

[0228] m is 0, 1, 2, or 3;

[0229] n and p are independently selected from 0 and 1;

[0230] X ¹ and X ² are -O-; And

[0231] X and X ³ are independently selected from the group consisting of -O-, -S- and
-NH-.

[0232] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be selected from a compound of formula (Ia), formula (Ib), formula (Ic), and formula (Id):

or pharmaceutically acceptable salts of any of the above compounds.

[0233] In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ³ may be hydrogen, In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁴ may be nitro or -SO ₂ CF ₃ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ¹ may be fluorine, chlorine, -CH ₃ , -CH ₂ CH ₃ , -CHF ₂ , -CF ₃ , - CH ₂ CF ₃ , -CF ₂ CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH3) ₂ or -N(CH ₂ CH ₃ ) ₂ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁵ may be -OR ⁷ or -NH-R ⁷ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁵ may be -O-Alk ¹ -R ⁷ or -NH-Alk ¹ -R ⁷ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), Alk ¹ may be unsubstituted methylene, unsubstituted ethylene, or ethylene mono-substituted with —CH ₃ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁷ may be unsubstituted cyclohexanyl or cyclohexanyl substituted with one or two substituents independently selected from hydroxy, amino, fluoro, and unsubstituted C ₁ -C ₃ alkyl (eg as described herein). In some embodiments of this paragraph, R ⁷ may be a substituted or unsubstituted monocyclic 5 or 6 membered heterocyclyl, such as pyrrolidine, piperidine, morpholine, piperazine, or tetrahydropyran; each of the above substituted groups may be substituted with 1 or 2 substituents independently selected from hydroxy, amino, fluoro, unsubstituted C ₁ -C ₃ alkyl (for example, described herein), unsubstituted C ₁ -C ₃ alkoxy (for example, described herein) or -SO ₂ CH ₃ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁷ may be connected to Alk ¹ via a nitrogen atom. In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁷ may be connected to Alk ¹ via a carbon atom. In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁷ may be substituted on one or more nitrogen atoms. In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id) R ⁵ may be -NH-(CHR ⁸ )-Alk ² -SR ⁹ , -O-(CHR ⁸ )-Alk ² -SR ⁹ , -NH-(CHR ⁸ )-Alk ² -OR ⁹ or -O-(CHR ⁸ )-Alk ² -OR ⁹ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), Alk ² may be unsubstituted methylene, unsubstituted ethylene, methylene monosubstituted with -CH ₃ , or methylene disubstituted with -CH ₃ . In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁸ may be an unsubstituted di-C ₁ -C ₃ alkylamine(methyl) or an unsubstituted di-C ₁ -C ₃ alkylamine( ethyl). In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁸ may be substituted or unsubstituted 5-7 membered heterocyclyl(C ₁ -C ₆ alkyl); wherein C ₁ -C ₆ alkyl may be unsubstituted methyl, unsubstituted ethyl or unsubstituted n-propyl; A 5-7 membered heterocyclyl may (a) be monocyclic or spiro, (b) contain 1 oxygen atom, 1 nitrogen atom, or 1 oxygen atom and one nitrogen atom, (c) be unsubstituted or substituted with 1 or 2 substituents independently selected from unsubstituted C ₁ -C ₃ alkyl (eg as described herein), -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , unsubstituted acetyl, -CO ₂ H, fluoro or hydroxy. In some embodiments of formulas (Ia), (Ib), (Ic) and/or (Id), R ⁹ may be unsubstituted phenyl.

[0234] Examples of a compound of formula (I) include:

or a pharmaceutically acceptable salt of any of the above compounds.

[0235] FIG. 3 shows the chemical names and structures of, for example, compounds of formula (I) above in which R ³ is hydrogen or halogen, as well as other examples of such compounds. In an embodiment, the compound of formula (I) is a compound selected from those shown in FIG. 3, or a pharmaceutically acceptable salt of any of the compounds shown in FIG. 3. In FIG. 4A, 4B and 4C are the chemical names and structures of, for example, compounds of formula (I) above in which R ³ is XR ^3A , as well as other examples of such compounds, including those in which R ¹ represents any of the above variants of R ¹ with the exception that R ¹ is not -CH ₂ F, -CHF ₂ or -CF ₃ but X ¹ and X ² are -NH- (FIG. 4A); those in which R ¹ is any of the above variants of R ¹ and X ¹ and X ² are -O- (FIG. 4B); and those in which R ¹ is -CH ₂ F, -CHF ₂ or -CF ₃ and X ¹ and X ² are -NH- (FIG. 4C). In an embodiment, the compound of formula (I) is a compound selected from those shown in FIG. 3, 4A, 4B and/or 4C, or a pharmaceutically acceptable salt of any of the compounds shown in FIG. 3, 4A, 4B and/or 4C. In an embodiment, the compound of formula (I) is a compound selected from those shown in FIG. 3, or a pharmaceutically acceptable salt of any of the compounds shown in FIG. 3. In an embodiment, the compound of formula (I) is a compound selected from those shown in FIG. 4A, or a pharmaceutically acceptable salt of any of the compounds shown in FIG. 4A. In an embodiment, the compound of formula (I) is a compound selected from those shown in FIG. 4B, or a pharmaceutically acceptable salt of any of the compounds shown in FIG. 4b. In an embodiment, the compound of formula (I) is a compound selected from those shown in FIG. 4C, or a pharmaceutically acceptable salt of any of the compounds shown in FIG. 4C.

[0236] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have increased metabolic and/or plasma stability. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be more resistant to hydrolysis and/or more resistant to enzymatic transformations. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have improved characteristics. The non-limiting list of properties of examples includes, without limitation, increased biological half-life, increased bioavailability, increased efficacy, prolonged in vivo response, extended dosing intervals, reduced dosage, reduced cytotoxicity, reduced morbidity and mortality as clinical outcomes, reduction or prevention opportunistic infections, improved patient compliance, and improved drug compatibility. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have stronger anticancer activity (eg, a lower EC ₅₀ in a cell replication assay) than the current reference drug (such as venetoclax). In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may have stronger antiviral activity (eg, a lower EC ₅₀ in an HIV replicon assay) than the current reference drug (such as dolitegravir).

Synthesis

[0237] the Compounds of formula (I) or their pharmaceutically acceptable salts can be obtained in various ways known in the art, in accordance with the ideas set forth herein. For example, in an embodiment, compounds of formula (I) are prepared according to General Scheme 1 as shown herein.

[0238] In general, coupling reactions between compounds in general formulas A and B to form compounds of formula (I), as shown in General Scheme 1, can be carried out in a manner similar to the reactions described herein in the examples, by appropriately adjusting the reagents and conditions described in the examples. Any preliminary reaction steps necessary to obtain the starting compounds of formulas A and B, or other precursor products, can be easily performed by experts in this field of technology. As shown in General Scheme 1, R ¹ , R ² , R ³ R ⁴ , R ⁵ and m may be as described herein.

General scheme 1

Pharmaceutical compositions

[0239] Some embodiments described herein relate to a pharmaceutical composition that may include an effective amount of one or more of the compounds described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0240] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds and/or salts described herein with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound to the body. Pharmaceutical compositions can also be prepared by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutical compositions can be substantially optimized for the specific route of administration intended for them.

[0241] The term "physiologically acceptable" means a carrier, diluent, or excipient that does not interfere with the biological activity or properties of the compound and does not cause significant harm or injury to the animal to which the composition is intended to be administered.

[0242] As used herein, the term "carrier" refers to a compound that facilitates incorporation of the compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a widely used carrier that facilitates the uptake of many organic compounds by a subject's cells or tissues.

[0243] As used herein, the term "diluent" refers to an ingredient in a pharmaceutical composition that does not have significant pharmacological activity, but may be pharmacologically necessary or desirable. For example, a diluent may be used to increase the volume of a potent drug that is too small to manufacture and/or administer. In addition, it may be a liquid for dissolving the drug for administration by injection, ingestion or inhalation. The commonly used form of the diluent in the art is in the form of a buffered aqueous solution, such as, but not limited to, phosphate-buffered saline, which mimics the pH and isotonicity of human blood.

[0244] As used herein, the term "excipient" refers essentially to an inert substance that is added to a pharmaceutical composition to provide, without limitation, volume, consistency, stability, binding ability, lubricity, disintegration ability, etc. compositions. For example, excipients are stabilizers such as antioxidants and metal chelating agents. In an embodiment, the pharmaceutical composition contains an antioxidant and/or a metal chelating agent. "Diluent" is a type of excipient.

[0245] The pharmaceutical compositions described herein can be administered to a human patient per se or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients, or combinations thereof. The proper formulation depends on the route of administration chosen. One skilled in the art will be familiar with the formulation and administration of the compounds described herein.

[0246] The pharmaceutical compositions described herein can be made in a manner that is known per se, such as by conventional mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, incorporating, or tableting processes. In addition, the active ingredients are contained in an amount effective to achieve their intended purpose. Many of the compounds used in the pharmaceutical combinations described herein may be provided as salts with pharmaceutically compatible counterions.

[0247] There are many routes of administration of a compound, salt, and/or composition in the art, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral administration, including intramuscular, subcutaneous, intravenous, intramedullary injections. , intrathecal, direct intra-tricular, intraperitoneal, intranasal and intraocular injections. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered orally.

[0248] It is also possible to administer the compound, salt and/or composition in a local rather than systemic manner, for example by injection or implantation of the compound directly into the affected area, often as a depot or sustained release formulation. Moreover, the compound can be administered in a targeted drug delivery system, such as a liposome coated with a tissue-specific antibody. The organ will be targeted by liposomes and will selectively absorb them. For example, intranasal or pulmonary delivery may be desirable for the treatment of a respiratory disease or condition.

[0249] The compositions may optionally be present in a packaging or dispensing device, which may contain one or more dosage forms containing the active ingredient. The package may, for example, contain a metal foil or a plastic film, such as a blister pack. The packaging or dispensing device may be accompanied by instructions for administration. The packaging device or dispenser may also be accompanied by a notice appended to the container in the form prescribed by the governmental authority that regulates the manufacture, use or sale of pharmaceuticals, the notice containing the authority's authorization to use the form of the drug for human or veterinary use. For example, such a notice could be a US Food and Drug Administration approved label for prescription drugs or an approved package leaflet. Compositions that may include a compound and/or salt described herein constituting a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container and labeled for the treatment of the indicated condition.

Application and methods of treatment

[0250] Some embodiments described herein relate to a method of treating a cancer or tumor described herein, which method may comprise administering an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to a subject with the cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of cancer or tumors described herein. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for the treatment of cancer or tumors as described herein.

[0251] Some embodiments described herein relate to a method for inhibiting replication of a cancer or tumor described herein, which may include contacting the cancer or tumor with an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the preparation of a medicament for inhibiting the replication of a cancer or tumor described herein. . In some embodiments, the implementation of the application may include the introduction of education or tumor in contact with the drug. Other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit the replication of a cancer or tumor described herein.

[0252] Some embodiments described herein relate to a method of treating cancer described herein, which may include bringing the cancer or tumor described herein into contact with an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the preparation of a medicament for the treatment of cancer described herein. In some embodiments, the implementation of the application may include the introduction of a malignant formation or tumor, described herein, in contact with the drug. Other embodiments described herein relate to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) to contact the cancer or tumor described herein, wherein the occurrence malignancy or tumor is due to the cancer described herein.

[0253] Examples of suitable malignancies, cancers, and tumors include, but are not limited to, bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemias, follicular lymphomas, lymphoid malignancies of T-cell or B-cell origin, melanomas, myelogenous leukemias, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemias, myelomas ( including multiple myelomas), prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastomas, osteosarcomas, Ewing's tumor, and Wilm's tumor.

[0254] As described herein, a cancer, cancer, or tumor may become resistant to one or more antiproliferative agents. In some embodiments, a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), can be used to treat and/or alleviate a malignancy, cancer or tumor that has become resistant to one or more antiproliferative agents (such as one or more Bcl-2 inhibitors). Examples of antiproliferative agents to which a subject may develop resistance include, without limitation, Bcl-2 inhibitors (such as venetoclax, navitoclax, obatoclax, S55746, APG-1252, APG-2575, and ABT-737). In some embodiments, the cancer, cancer, or tumor that has become resistant to one or more antiproliferative agents may be the cancer, cancer, or tumor described herein.

[0255] Some embodiments described herein relate to a method for inhibiting Bcl-2 activity, which may include administering to a subject an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and may also include contacting a Bcl-2 expressing cell with an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament to inhibit Bcl-2 activity in a subject or in the manufacture of a medicament. agents for inhibiting Bcl-2 activity, the use comprising contacting the compound with a Bcl-2 expressing cell. Other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit Bcl-2 activity in a subject; or to inhibit Bcl-2 activity by contact with a Bcl-2 expressing cell.

[0256] Some embodiments described herein relate to a method for alleviating or treating HIV infection, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically thereof acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent or a pharmaceutically acceptable salt thereof. . Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for alleviating or treating HIV infection in a subject suffering from HIV infection; or in the manufacture of a medicament for alleviating or treating HIV infection, the use comprising bringing a cell infected with HIV into contact with the medicament. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent or a pharmaceutically acceptable salt thereof. to alleviate or treat HIV infection in a subject suffering from HIV infection; or to alleviate or treat HIV infection by contact with a cell infected with HIV infection. In some embodiments, the implementation of the cells may be inside the subject. In some embodiments, the cells may be CD4+ T cells. In some embodiments, CD4+ T cells may reside within a subject.

[0257] Some embodiments described herein relate to a method for reducing the population of HIV-infected cells, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent or a pharmaceutically acceptable salt thereof. . Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the population of HIV-infected cells in a subject suffering from HIV infection; or to reduce the population of HIV-infected cells, the use comprising bringing the HIV-infected cell into contact with a drug. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent or a pharmaceutically acceptable salt thereof. to reduce the population of HIV-infected cells in a subject suffering from HIV infection; or to reduce the population of HIV-infected cells by bringing into contact with an HIV-infected cell. In some embodiments, the implementation of the cells may be inside the subject. In some embodiments, the cells may be CD4+ T cells. In some embodiments, CD4+ T cells may reside within a subject.

[0258] Some embodiments described herein relate to a method for reducing relapses of HIV infection in a subject, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-latenting agent or a pharmaceutically acceptable salt thereof. . Other embodiments described herein relate to the use of an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent, or a pharmaceutically acceptable thereof. salt, in the manufacture of a medicament for reducing the recurrence of HIV infection in a subject suffering from HIV infection; or to reduce relapses of HIV infection, the use comprising bringing a cell infected with HIV into contact with a drug. Other embodiments described herein refer to an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV-busting agent or a pharmaceutically acceptable salt thereof. to reduce relapses of HIV infection in a subject suffering from HIV infection; or to reduce the recurrence of HIV infection by bringing into contact with a cell infected with HIV. In some embodiments, the implementation of the cells may be inside the subject. In some embodiments, the cells may be CD4+ T cells. In some embodiments, CD4+ T cells may reside within a subject.

[0259] Some embodiments described herein relate to a method of ameliorating or treating HIV infection, which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable amount thereof. acceptable salt to a subject suffering from HIV infection; and may also include contacting a cell infected with HIV with a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for alleviating or treating HIV infection; or in the manufacture of a medicament for alleviating or treating HIV infection, the use comprising bringing a cell infected with HIV into contact with the medicament. Other embodiments described herein relate to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, for alleviating or treating HIV infection in a subject suffering from HIV infection; or to alleviate or treat HIV infection by contact with a cell infected with HIV infection. In some embodiments, the implementation of the cells may be inside the subject. In some embodiments, the cells may be CD4+ T cells. In some embodiments, CD4+ T cells may reside within a subject.

[0260] Some embodiments described herein relate to a method for reducing the population of HIV-infected cells, which may include administering an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV-latenting agent, or a pharmaceutically acceptable amount thereof. acceptable salt to a subject suffering from HIV infection; and may also include contacting a cell infected with HIV with a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a Bcl protein inhibitor or a pharmaceutically acceptable salt thereof and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to reduce the population of cells infected with HIV; or in the manufacture of a drug to reduce the population of HIV-infected cells, the use comprising bringing an HIV-infected cell into contact with the drug. Other embodiments described herein relate to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, to reduce the population of HIV-infected cells in a subject. suffering from HIV infection; or to reduce the population of HIV-infected cells by bringing into contact with an HIV-infected cell. In some embodiments, the implementation of the cells may be inside the subject. In some embodiments, the cells may be CD4+ T cells. In some embodiments, CD4+ T cells may reside within a subject.

[0261] Some embodiments described herein relate to a method of reducing relapses of HIV infection in a subject, which may include administering to a subject suffering from HIV infection an effective amount of a compound described herein (e.g., a compound of formula (I) or its a pharmaceutically acceptable salt) or a pharmaceutical composition that includes a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof; and may also include contacting an HIV-infected cell with an effective amount of a Bcl protein inhibitor or a pharmaceutically acceptable salt thereof and an effective amount of an HIV de-latenting agent or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to the use of an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the recurrence of HIV infection in a subject suffering from HIV infection; or to reduce relapses of HIV infection, the use comprising bringing a cell infected with HIV into contact with a drug. Other embodiments described herein relate to an effective amount of a Bcl protein inhibitor, or a pharmaceutically acceptable salt thereof, and an effective amount of an HIV de-latenting agent, or a pharmaceutically acceptable salt thereof, to reduce relapses of HIV infection in a subject suffering from from HIV infection; or to reduce the recurrence of HIV infection by bringing into contact with a cell infected with HIV. In some embodiments, the implementation of the cells may be inside the subject. In some embodiments, the cells may be CD4+ T cells. In some embodiments, CD4+ T cells may reside within a subject.

[0262] In some embodiments, the HIV de-latenting agent can be a protein kinase C agonist, a PD-1 inhibitor, a PD-L1 inhibitor, an HDAC inhibitor, a phorbol ester, or a bromodomain inhibitor. In some embodiments, the HIV de-latenting agent may be a protein kinase C agonist, which includes, but is not limited to, prostratin, bryostatin-1, and ingenol. In some embodiments, the HIV de-latenting agent may be a PD-1 inhibitor, which includes, but is not limited to, nivolumab, pembrolizumab, BGB-A317, pidilizumab, AMP-224, AMP-514, PDR001, REGN2810, and MEDI0680 . In some embodiments, the HIV de-latenting agent may be a PD-L1 inhibitor, which includes, but is not limited to, atezolizumab, durvalumab, avelumab, and BMS-936559. In some embodiments, the HIV de-latent agent may be an HDAC inhibitor, which includes, but is not limited to, vorinostat, panobinostat, romidepsin, and valproic acid. In some embodiments, the HIV de-latenting agent may be a phorbol ester, which includes, but is not limited to, phorbol 12-myristate-13-acetate and (S)-tert-butyl-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate. In some embodiments, the HIV de-latent agent may be a bromodomain inhibitor, which includes, but is not limited to, JQ1, I-BET762, OTX015, I-BET151, CPI203, PFI-1, MS436, CPI-0610, RVX2135, FT-1101, BAY1238097, INCB054329, TEN-010, GSK2820151, ZEN003694, BAY-299, BMS-986158, ABBV-075 and GS-5829. In some embodiments, a combination of two or more anti-HIV agents may be used.

[0263] In some embodiments, the Bcl protein inhibitor of formula (I) can be a Bcl-2 selective inhibitor, a Bcl- _XL selective inhibitor, a Bcl-W selective inhibitor, a Mcl-1 selective inhibitor, or a Bcl-2A1 selective inhibitor. In some embodiments, the Bcl protein inhibitor of formula (I) can inhibit more than one Bcl protein. In some embodiments, the Bcl protein inhibitor may be an inhibitor of Bcl-2 activity and one of Bcl-X _L , Bcl-W, Mcl-1, and Bcl-2A1. In some embodiments, the Bcl protein inhibitor may be an inhibitor of Bcl-X _L activity and one of Bcl-W, Mcl-1, and Bcl-2A1. In some embodiments, the Bcl protein inhibitor of formula (I) can inhibit both Bcl-2 and Bcl-X _L . In some embodiments, the Bcl protein inhibitor may be venetoclax, navitoclax, obatoclax, ABT-737, S55746, AT-101, APG-1252, APG-2575, AMG176, or AZD5991, or a combination of any of the above.

[0264] In some embodiments, methods of alleviating or treating HIV infection may also include the use of one or more agents selected from a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor (PI), a fusion inhibitor/ entry, an integrase strand transfer inhibitor (INSTI), an HIV vaccine, another HIV antiretroviral therapeutic compound, and combinations thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a subject suffering from HIV infection is not using an agent selected from a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a protease inhibitor (PI), a fusion/entry inhibitor, an integrase strand transfer inhibitor ( INSTI), an HIV vaccine, another HIV antiretroviral therapeutic compound, and combinations thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0265] Examples of suitable NNRTIs include, without limitation, delavirdine (Rescriptor®), efavirenz (Sustiva®), etravirine (Intelence®), nevirapine (Viramune®), rilpivirine (Edurant®), doravirine, and pharmaceutically acceptable salts of any of the above. and/or combinations thereof. Examples of suitable NRTIs include, without limitation, abacavir (Ziagen®), adefovir (Hepsera®), amdoxovir, apricitabine, censavudine, didanosine (Videx®), elvucitabine, emtricitabine (Emtriva®), entecavir (Baraclude®), lamivudine (Epivir ®), racivir, stampidine, stavudine (Zerit®), tenofovir disoproxil (including Viread®), tenofovir alafenamide, zalcitabine (Hivid®), zidovudine (Retrovir®) and pharmaceutically acceptable salts of any of the above and/or combinations thereof. Examples of vaccines include, without limitation, Heplislav®, ABX-203, INO-1800, and pharmaceutically acceptable salts of any of the above and/or combinations thereof. Examples of suitable protease inhibitors include, without limitation, atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir/ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir ( Norvir®) and saquinavir (Invirase®). Examples of suitable fusion/entry inhibitors include, without limitation, enfuvirtide (Fuzeon®), maraviroc (Selzentry®), vikriviroc, apliviroc, ibalizumab, fostemsavir, and PRO-140. Examples of suitable INSTIs include, without limitation, raltegravir (Isentress®), dolitegravir (Tivicay®) and elvitegravir (Viteka®).

[0266] Two types of HIV have been characterized: HIV-1 and HIV-2. HIV-1 is a more virulent and more infectious strain and has a global prevalence. HIV-2 is considered less virulent and geographically restricted. In some embodiments, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, may be effective in treating HIV-1. In some embodiments, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, may be effective in treating HIV-2. In some embodiments, a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) may be effective in treating both HIV genotypes (HIV-1 and HIV-2).

[0267] Various indicators are known to those skilled in the art to determine the effectiveness of a method of treating HIV infection. Examples of acceptable measures include, but are not limited to, reduction in viral load, reduction in plasma viral load, reduction in viral replication, reduction in time to seroconversion (no virus detected in patient serum), increase in CD4+ T-lymphocytes, reduction in HIV-infected cell population, reduction clinical outcome morbidity or mortality and/or a reduction in the incidence of opportunistic infections. Similarly, successful therapy with an effective amount of a compound or pharmaceutical composition as described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and an effective amount of an HIV de-latenting agent or pharmaceutically acceptable salt thereof may reduce the incidence of opportunistic infections in HIV-infected subjects.

[0268] In some embodiments, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective in reducing the HIV-bearing CD4+ T-lymphocyte population to undetectable levels.

[0269] In some embodiments, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective in increasing the number of CD4+ T lymphocytes from less than about 200 cells/ml to more than about 1200 cells/ml. In some embodiments, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is an amount that is effective in increasing the number of CD4+ T lymphocytes from less than about 200 cells/ml to more than about 500 cells/ml.

[0270] Over time, infectious agents may develop resistance to one or more therapeutic agents. As used herein, the term "resistance" refers to a viral line that exhibits a delayed, reduced and/or nil response to the therapeutic agent(s). In some cases, the virus sometimes mutates or produces variants that are resistant or partially resistant to certain drugs. For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may decrease to a lesser extent compared to the magnitude of the reduction in viral load in a subject infected with a non-resistant strain. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be offered to a subject infected with a strain of HIV that is resistant to one or more different anti-HIV drugs (eg, an agent used in a conventional standard of care). Examples of HIV agents include, but are not limited to, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), fusion/entry inhibitors, integrase strand transfer inhibitors (INSTIs), HIV vaccines, and their combinations, or pharmaceutically acceptable salts of any of the above compounds.

[0271] Several known inhibitors of Bcl-2 may cause one or more undesirable side effects in a treated patient. Examples of undesirable side effects include, without limitation, thrombocytopenia, neutropia, anemia, diarrhea, vomiting, and upper respiratory tract infection. In some embodiments, a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) can reduce the number and/or severity of one or more side effects associated with known Bcl-2 inhibitors. In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof may cause a severe side effect (such as one described herein) 25% less than the severity of the same side effect in a patient receiving known Bcl-2 inhibitors. (such as venetoclax, navitoclax, obatoclax, ABT-737, S55746, AT-101, APG-1252 and APG-2575). In some embodiments, due to the compound of formula (I) or a pharmaceutically acceptable salt thereof, the number of side effects is 25% less than the number of side effects in a subject receiving known Bcl-2 inhibitors (for example, venetoclax, navitoclax, obatoclax, ABT-737, S55746, AT -101, APG-1252 and APG-2575). In some embodiments, due to the compound of formula (I) or a pharmaceutically acceptable salt thereof, the severity of a side effect (such as one described herein) is about 10% to about 30% less than the severity of the same side effect in a patient receiving known Bcl-2 inhibitors (eg, venetoclax, navitoclax, obatoclax, ABT-737, S55746, AT-101, APG-1252 and APG-2575). In some embodiments, due to the compound of formula (I) or a pharmaceutically acceptable salt thereof, the number of side effects is from about 10% to about 30% less than the number of side effects in a subject receiving known Bcl-2 inhibitors (for example, venetoclax, navitoclax, obatoclax, ABT-737, S55746, APG-1252 and APG-2575).

[0272] One or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat, facilitate and/or inhibit the replication of cancer, malignancy or tumor, and inhibition of Bcl-2 activity is advantageous, is provided in any of the options implementation described in the above under the heading "Compounds". For example, in various embodiments, the methods and uses described above in the "use and methods of treatment" section of this specification are carried out as described (essentially involving cancer, malignancy, and/or tumor) using a compound of formula (I), in wherein R ³ is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0273] In other embodiments, the methods and uses described in the "use and methods of treatment" section above are carried out as described (essentially involving cancer, malignancy, and/or tumor) using a compound of formula (I) wherein R ³ is XR ^3A ,

[0274] In other embodiments, the methods and uses described above in the "use and methods of treatment" section of this description are carried out in the manner described (essentially involving cancer, malignancy and / or tumor) using a compound of formula (I), in which R ³ is XR ^3A , and wherein X ¹ and X ² are -NH-.

[0275] In other embodiments, the methods and uses described above in the "use and methods of treatment" section of this description are carried out as described (essentially involving cancer, malignancy and / or tumor) using a compound of formula (I), in which R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ - C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine, with the proviso that R ¹ is not -CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is XR ^3A , and X ¹ and X ² are -NH-.

[0276] In other embodiments, the methods and uses described above in the "use and methods of treatment" section of this description are carried out in the manner described (essentially involving cancer, malignancy and / or tumor) using a compound of formula (I), in which R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ - C ₆ alkoxy, unsubstituted mono-C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine; R ³ is XR ^3A , and X ¹ and X ² are -O-.

[0277] In other embodiments, the methods and uses described in the "use and methods of treatment" section above are performed as described (essentially involving cancer, malignancy, and/or tumor) using a compound of formula (I) wherein R ¹ is -CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is XR ^3A , and X ¹ and X ² are -NH-.

[0278] One or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, which can be used to treat and / or alleviate HIV infection and / or reduce the likelihood of recurrence of HIV infection and / or reduce the population of HIV-infected cells, moreover, inhibition of activity Bcl-2 advantageously provided in any of the embodiments described in above under the heading "Compounds". For example, in various embodiments, the methods and uses described above in the Uses and Methods of Treatment section of this specification are carried out as described (essentially involving HIV) using a compound of formula (I) wherein R ³ is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0279] In other embodiments, the methods and uses described above in the "use and methods of treatment" section are carried out as described (essentially involving HIV) using a compound of formula (I) wherein R ³ is XR ^3A ,

[0280] In other embodiments, the methods and uses described above in the Uses and Methods of Treatment section of this specification are performed as described (essentially involving HIV) using a compound of formula (I) wherein R ³ is XR ^3A , and wherein X ¹ and X ² are -NH-.

[0281] In other embodiments, the methods and uses described above in the "use and methods of treatment" section of this description are carried out as described (essentially involving HIV) using a compound of formula (I), in which R ¹ is selected from the group , consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ haloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, unsubstituted mono- C ₁ -C ₆ alkylamine and unsubstituted di-C ₁ -C ₆ alkylamine, provided R ¹ is not -CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is XR ^3A , and X ¹ and X ² are -NH-.

[0282] In other embodiments, the methods and uses described above in the "use and methods of treatment" section are carried out as described (essentially involving HIV) using a compound of formula (I) wherein R ³ is XR ^3A , and wherein X ¹ and X ² are -O-.

[0283] In other embodiments, the methods and uses described in the Uses and Methods of Treatment section above are performed as described (essentially involving HIV) using a compound of formula (I) wherein R ¹ is -CH ₂ F, -CHF ₂ or -CF ₃ ; R ³ is XR ^3A , and X ¹ and X ² are -NH-.

[0284] As used herein, the term "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates such as fish, molluscs, reptiles, and in particular mammals. "Mammals" include, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees and great apes, and in particular humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and/or infant, such as a child or infant with a fever. In other embodiments, the subject may be an adult.

[0285] As used herein, the terms "treat", "treating", "treatment", "therapeutic" and "therapy" do not necessarily mean the complete cure or elimination of a disease or condition. Any relief of any undesirable signs and symptoms of a disease or condition to any extent may be considered a treatment and/or therapy. Moreover, the treatment may include actions that may make the general health or appearance of the subject worse.

[0286] The terms "therapeutically effective amount" and "effective amount" are used to refer to the amount of active compound or pharmaceutical agent that induces the specified biological or medical response. For example, a therapeutically effective amount of a compound, salt, or composition may be the amount necessary to prevent, alleviate, or alleviate the symptoms of a disease or condition, or prolong the life of the patient being treated. Such a response may occur in a tissue, system, animal, or human and includes amelioration of signs or symptoms of the disease or condition being treated. The determination of an effective amount is well known to those skilled in the art in light of the disclosures herein. The therapeutically effective amount of the compounds described herein, which is required as a dose, will depend on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal in question. The dose can be optimized to achieve the desired effect, but this procedure will depend on factors such as body weight, diet, concomitant medications and other factors that will be obvious to specialists in this field.

[0287] For example, an effective amount of a compound is an amount that: (a) reduces, alleviates, or eliminates one or more symptoms caused by cancer, (b) reduces the size of a tumor, (c) destroys the tumor, and/or (d) long-term stabilize the disease (stop tumor growth). In the treatment of lung cancer (eg, non-small cell lung cancer), a therapeutically effective amount is an amount that alleviates or eliminates cough, shortness of breath and/or pain. As another example, an effective amount or a therapeutically effective amount of a Bcl-2 inhibitor is an amount that reduces Bcl-2 activity and/or increases apoptosis. The decrease in Bcl-2 activity is known to those skilled in the art and can be determined by assaying Bcl-2 binding and determining the corresponding levels of cells undergoing apoptosis.

[0288] The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof required for use in treatment varies not only depending on the particular compound or salt chosen, but also depending on the route of administration, the nature and/or symptoms of the disease to be treated or condition, age and condition of the patient and is ultimately chosen at the discretion of the attending physician or medical professional. When administering a pharmaceutically acceptable salt, doses can be calculated based on the free base. Those skilled in the art will appreciate that in certain situations it may be necessary to administer the compounds described herein in amounts that exceed or even significantly exceed the dosage ranges described herein in order to effectively and aggressively treat certain diseases or conditions.

[0289] However, in general, a suitable dose will often be in the range of about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dosage may be in the range of about 0.10 mg/kg to about 7.5 mg/kg body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg body weight of a patient in day, from about 0.2 mg/kg to 4.0 mg/kg of the patient's body weight per day, or any amount in between. The compound can be administered as a unit dosage form; for example, containing from 1 to 500 mg, from 10 to 100 mg or from 5 to 50 mg or any amount in between of the active ingredient per unit dosage form.

[0290] The desired dose may conveniently be presented as a single dose or divided doses administered at appropriate intervals, such as two, three, four or more dose portions per day. The dose portion itself can be further divided, for example, into several discrete administrations at freely definable intervals.

[0291] It will be apparent to one of skill in the art that the in vivo dose to be administered and the particular route of administration will vary depending on age, weight, severity of injury, species of mammal being treated, particular compounds used, and particular application, in according to which these compounds are used. Determination of effective dose levels, i.e. dosage levels necessary to achieve the desired result can be performed by a person skilled in the art using standard methods, such as human clinical trials, in vivo and in vitro studies. For example, usable dosages of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by comparing their in vitro and in vivo activities in animal models. Such a comparison can be made by comparison with an established drug such as cisplatin and/or gemcitabine).

[0292] The amount and interval of dose can be adjusted individually to obtain plasma levels of the active functional fragment that are sufficient to maintain modulating effects or minimum effective concentration (MEC). The IEC will vary for each compound, but can be estimated from in vivo and/or in vitro data. The doses required to achieve the MEC will depend on individual characteristics and the route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dose intervals can also be determined using the IEC value. The compositions should be administered using a regimen that maintains plasma levels above the MEK for 10-90% of the time, preferably 30-90%, and most preferably 50-90%. With topical administration or selective absorption, the effective local drug concentration may not be related to plasma concentration.

[0293] It should be noted that the attending physician will understand how and when to complete, interrupt or adjust the introduction due to toxicity or organ failure. The treating physician will also understand how to reverse treatment (to higher levels) for an inappropriate clinical response (prevention of toxicity). The amplitude of the dose of administration to control the disorder of interest will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of the disease or condition may, for example, be partially assessed by standard predictive assessment methods. Additionally, the dose and possibly the frequency of dosing will also vary depending on the age, body weight and response of the individual patient. In veterinary medicine, a program comparable to that described above can be used.

[0294] The efficacy and toxicity of the compounds, salts and compositions described herein can be assessed using known methods. For example, the toxicology of a particular compound, or a subset of compounds having certain chemical moieties, can be ascertained by determining in vitro toxicity to a cell line, such as a mammalian cell line, and preferably a human cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically in humans. In an alternative embodiment, the toxicity of individual compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several established methods, such as in vitro methods, animal models, or human clinical studies. In selecting a model for determining efficacy, one of skill in the art will be guided by recent advances in the art to select an appropriate model, dose, route of administration, and/or regimen.

Examples

[0295] The following examples describe additional embodiments in more detail, and the examples are not intended to limit the scope of the claims.

Intermediate 1

3-Chloro- N -methoxy- N -methylbicyclo[1.1.1]pentane-1-carboxamide

[0296] To a stirred solution of 3-chlorobicyclo[1.1.1]pentane-1-carboxylate (10.0 g, 62.3 mmol) and N , O -dimethylhydroxylamine hydrochloride (12.15 g, 124.5 mmol) in anhydrous THF (200 ml) at -78°C was added i -PrMgCl (2 M in THF, 124.5 ml, 249 mmol). The temperature was then brought to -50° C. and stirred for 2 hours. The reaction mixture was quenched with sat. aq. NH ₄ Cl and extracted with EtOAc (3×150 ml). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give intermediate 1 (7.30 g, 62%) as an oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.67 (s, 3H), 3.18 (s, 3H), 2.47 (s, 6H).

Intermediate 2

tert- Butyl 2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate

[0297] A solution of t- butyl 2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-4-fluorobenzoate (3.5 g, 10.67 mmol) in DMSO (35 mL) was treated with piperazine (2.33 ml, 32.0 mmol) at rt and stirred at 100° C. for 4 h. The reaction mixture was cooled to rt and water (50 ml) was added. The mixture was extracted with EtOAc (3×50 ml) and the organic layers were concentrated and triturated with n -pentane to give intermediate 2 (3.0 g, 71%) as a white solid. LC/MS (ESI) m/z 395.5 [M+H] ⁺ .

Intermediate 3

4-(2-Oxaspiro[3,3]heptan-6-ylmethylamino)-3-nitrobenzenesulfonamide

[0298] A solution of 4-chloro-3-nitrobenzenesulfonamide (200 mg, 0.85 mmol) in CH ₃ CN (8 ml) was treated with (2-oxaspiro[3,3]heptan-6-yl)methanamine (129 mg, 1 .01 mmol) and DIPEA (0.5 ml 2.95 mmol). The mixture was heated to 90° C. and stirred for 16 hours. The reaction mixture was cooled to rt, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/hexanes) to give Intermediate 3 (120 mg, 43%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47-8.43 (m, 2H), 7.83-7.80 (m, 1H), 7.30 (br. s, 2H), 7.22 (d, J = 9.6 Hz, 1H), 4.56 (s, 2H), 4.49 (s, 2H), 3.42-3.38 (m, 2H), 2.45 -2.39(m, 1H), 2.33-2.27(m, 2H), 1.99-1.94(m, 2H).

Intermediate 4

4-(2-(2-Oxa-8-azaspiro[4,5]decan-8- yl )ethylamino)-3-nitrobenzenesulfonamide

[0299] Step 1. A solution of 2-oxa-8-azaspiro[4.5]decane hydrochloride (500 mg, 2.81 mmol) in CH ₃ CN (20 ml) was treated with tert- butyl-2-bromoethyl carbamate (700 mg, 3.12 mmol) and K ₂ CO ₃ (1.55 g, 11.24 mmol) and heated at 80°C for 16 h. The reaction mixture was concentrated, diluted with water (20 ml) and extracted with EtOAc (3× 20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give tert -butyl 2-(2-oxa-8-azaspiro[4,5]decan-8-yl)ethyl carbamate ( intermediate 4-1 ) (500 mg, 62%) as an oil. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.62 (br. s, 1H), 3.70 (t, J = 6.9 Hz, 2H), 3.40 (s, 2H), 3 .04-2.98 (m, 2H), 2.40-2.25 (m, 4H), 1.64 (t, J = 7.5 Hz, 2H), 1.56-1.40 (m , 4H), 1.37 (s, 9H), 1.24 (s, 2H).

[0300] Step 2 To a stirred solution of intermediate 4-1 (500 mg, 1.76 mmol) in DCM (20 ml) was added HCl (4 M in dioxane, 10 ml) at 0°C. The reaction mixture was heated to rt, stirred for 2 h, concentrated and triturated with Et ₂ O to give 2-(2-oxa-8-azaspiro[4,5]decan-8-yl)ethanamine dihydrochloride ( Intermediate 4-2 ) (300 mg, 66%) as an off-white solid, which was used in the next step without further purification. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.84 (br. s, 1H), 8.38 (br. s, 3H), 3.85-3.70 (m, 2H), 3, 59-3.40 (m, 8H), 3.12-2.90 (m, 2H), 2.05-1.60 (m, 6H).

[0301] Step 3. A solution of intermediate 4-2 (300 mg, 1.17 mmol) in CH ₃ CN (15 ml) was treated with 4-chloro-3-nitrobenzenesulfonamide (276 mg, 1.17 mmol) followed by the addition of DIPEA (0.82 ml, 4.68 mmol) and then heated to 80°C. After 16 hours the reaction mixture was cooled to rt and concentrated . The crude product was purified by column chromatography (SiO ₂ , MeOH(0.1% triethylamine)/DCM) to give Intermediate 4 (300 mg, 66%) as a yellow solid. LC/MS (ESI) m/z 385.3 [M+H] ⁺ .

Intermediate 5

2-(7-Oxa-2-azaspiro[3,5]nonan-2- yl )ethanamine dihydrochloride

[0302] Step 1. tert- Butyl 2-(7-oxa-2-azaspiro[3,5]nonan-2- yl )ethyl carbamate ( intermediate 5-1 ) was prepared according to the procedure described in step 1 for intermediate compound 4 using 7-oxa-2-azaspiro[3,5]nonane hemisoxalic acid instead of 2-oxa-8-azaspiro[4,5]decane hydrochloride. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.94 (br. s, 1H), 3.74 (br. s, 4H), 3.51-3.42 (m, 4H), 3. 10 (br. s, 4H), 1.76 (br. s, 4H), 1.39 (s, 9H).

[0303] Step 2. 2-(7-Oxa-2-azaspiro[3,5]nonan-2-yl)ethanamine dihydrochloride ( Intermediate 5-2 ) was prepared according to the procedure described in Step 2 for p intermediate . 4 using Intermediate 5-1 instead of Intermediate 4-1 . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.42 (br. s, 1H), 8.3 (br. s, 3H), 4.05-3.99 (m, 2H), 3, 92-3.86 (m, 2H), 3.57-3.54 (m, 4H), 3.49-3.40 (m, 4H), 3.10-3.05 (m, 2H), 1.88 (br. s, 2H), 1.72 (br. s, 2H).

[0304] Step 3. A solution of intermediate 5-2 (250 mg, 1.03 mmol) in CH ₃ CN (13 mL) was treated with 4-fluoro-3-nitrobenzenesulfonamide (226.8 mg, 1.03 mmol) and then triethylamine (0.58 ml, 4.12 mmol) at rt. After 16 hours, the reaction mixture was concentrated to give the crude product, which was purified by column chromatography (SiO ₂ , MeOH (containing 7N NH ₃ )/DCM) to give Intermediate 5 (200 mg, 52%) as a yellow solid. LC/MS (ESI) m/z 371.3 [M+H] ⁺ .

Intermediate 6

4-(7-Oxaspiro[3,5]nonan-2- yl -methylamino)-3-nitrobenzenesulfonamide

[0305] A solution of 7-oxaspiro[3,5]nonan-2- yl -methanamine (100 mg, 0.64 mmol) in THF (2 ml) was treated with 4-fluoro-3-nitrobenzenesulfonamide (157.6 mg, 0. 72 mmol) and Et ₃ N (0.18 ml, 1.29 mmol) and the mixture was stirred at rt. After 16 h the reaction mixture was concentrated and the residue was purified by column chromatography (SiO ₂ , MeOH/DCM) to give intermediate 6 (126 mg, 55%) as a yellow solid. LC/MS (ESI) m/z 356.1 [M+H] ⁺ .

Intermediate 7

4-((4-Oxaspiro[2,4]heptan-6-yl)oxy)-3-nitrobenzenesulfonamide

[0306] Step 1. To a stirred solution of 1-(3-hydroxy-2-(tetrahydro- 2H -pyran-2-yloxy)propyl)cyclopropanol (prepared according to CN106565706) and triphenylphosphine (9.10 g, 34 7 mmol) in THF (50 ml) diethyl azodicarboxylate (DEAD) (5.44 ml, 34.7 mmol) was added dropwise at rt. After 16 h the reaction mixture was quenched with H ₂ O (50 ml) and was extracted with EtOAc (3×50 ml). The combined organic layers were washed with water (50 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (SiO2, EtOAc/pet. ether) to give 6-(tetrahydro- 2H- pyran-2-yloxy)-4-oxaspiro[2,4]heptane ( Intermediate 7-1 ) (3 .2 g, 69% yield) as a clear yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.65-4.63 (m, 1H), 4.59-4.56 (m, 1H), 4.02-3.85 (m, 3H), 3.53-3.48(m, 1H), 2.25-1.95(m, 2H), 1.89-1.76(m, 1H), 1.72-1.68(m, 1H ), 1.62-1.49 (m, 4H), 0.92-0.89 (m, 1H), 0.81-0.75 (m, 1H), 0.65-0.53 (m , 1H), 0.48-0.39 (m, 1H).

[0307] Step 2 To a stirred solution of intermediate 7-1 (3.2 g, 16.1 mmol) in MeOH (32 ml) was added pyridinium p-toluenesulfonate (811 mg, 3.23 mmol) and stirred at 40° C for 5 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give 4-oxaspiro[2,4]heptan-6-ol ( intermediate 7-2 ) (1, 0 g, 54% yield) as a colorless oil. GC/MS m/z 114.1 [M] ⁺ .

[0308] Step 3 To a stirred solution of intermediate 7-2 was added sodium hydride (63% dispersion in oil, 1.05 g, 26.3 mmol) at 0°C. After 30 minutes, a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.92 g, 8.76 mmol) in THF (5 ml) was added dropwise at 0°C. The reaction mixture was heated to rt and stirred for 6 h. The reaction mixture was cooled to 0° C. and quenched with sat. aq. NH ₄ Cl and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was triturated with Et ₂ O and n -pentane to give intermediate 7 (700 mg, 25% yield) as a white solid. LC/MS (ESI) m/z 313.0 [MH] ^- .

Intermediate 8

4-(2-(2-Oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy)-3-nitrobenzenesulfonamide

[0309] Intermediate 8 was prepared according to the procedure described in Step 3 for Intermediate 7 using 2- (2-oxa-6-azaspiro[3,3]heptan-6-yl)ethanol instead of Intermediate 7-2 . LC/MS (ESI) m/z 344.2 [M+H] ⁺ .

Intermediate 9

4-(2-Oxaspiro[3,3]heptan-6-ylmethoxy)-3-nitrobenzenesulfonamide

[0310] Intermediate 9 was prepared according to the procedure described in Step 3 for the synthesis of Intermediate 7 using 2-oxaspiro[3,3]heptan-6-ylmethanol instead of Intermediate 7-2 . LC/MS (ESI) m/z 327.4 [MH] ^- .

Intermediate 10

N -Methoxy- N ,3-dimethylbicyclo[1.1.1]pentane-1-carboxamide

[0311] To a stirred solution of 3-methylbicyclo[1.1.1]pentane-1-carboxylic acid (3 g, 23.8 mmol) in DCM (100 mL) was added N , O -dimethylhydroxylamine hydrochloride (3.48 g, 35. 7 mmol) and Et ₃ N (11.6 ml, 83.2 mmol) at rt. The mixture was then cooled to 0°C and T ₃ P (50 wt.% in EtOAc, 6.43 g, 40.4 mmol) was added dropwise and the reaction mixture was heated to rt. After 16 h the reaction mixture was quenched with water (100 ml) and extracted with DCM (3×100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO2, EtOAc/pet. ether) to give intermediate 10 as an oil (2.5 g, 62% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.65 (s, 3H), 3.17 (s, 3H), 1.98 (s, 6H), 1.18 (s, 3H).

Intermediate 11

3-Fluoro -N -methoxy- N -methylbicyclo[1.1.1]pentane-1-carboxamide

[0312] Intermediate 11 was prepared according to the procedure described for the synthesis of intermediate 10 using 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid in place of 3-methylbicyclo[1.1.1]pentane-1-carboxylic acid . LC/MS (ESI) m/z 174.3 [M+H] ⁺ .

Intermediate 12

3-Isopropyl-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide

[0313] Intermediate 12 was prepared according to the procedure described for the synthesis of Intermediate 10 using 3-isopropylbicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-methylbicyclo[1.1.1]pentane-1-carboxylic acid . LC/MS (ESI) m/z 198.4 [M+H] ⁺ .

Intermediate 13

3-(1,1-Difluoroethyl) -N -methoxy- N -methylbicyclo[1.1.1]pentane-1-carboxamide

[0314] Step 1. To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (10 g, 58.8 mmol), N , O -dimethylhydroxylamine hydrochloride (6.88 g, 42. 4 mmol) and triethylamine (12.3 ml, 176.4 mmol) in DCM (200 ml) at 0°C was added T ₃ P (50% solution in EtOAc, 18.8 g, 58.8 mmol). The resulting reaction mixture was heated to rt and stirred for 16 h. The reaction mixture was quenched with water (250 ml) and extracted with DCM (3×250 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give methyl 3-(methoxy(methyl)carbamoyl)bicyclo[1.1.1]pentane-1-carboxylate ( intermediate 13-1 ) (9, 5 g, 76% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.69 (s, 3H), 3.68 (s, 3H), 3.19 (s, 3H), 2.38 (s, 6H).

[0315] Step 2 To a stirred solution of intermediate 13-1 (5 g, 23.5 mmol) in THF (100 ml) at -78°C was added MeMgBr (3 M in Et ₂ O, 31.3 ml, 93 .8 mmol). After stirring for 2 hours at -78° C., the reaction mixture was quenched with sat. aq. NH ₄ Cl (100 ml) and extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give methyl 3-acetylbicyclo[1.1.1]pentane-1-carboxylate ( intermediate 13-2 ) (2 g, 51% yield) as white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.70 (s, 3H), 2.29 (s, 6H), 2.14 (s, 3H).

[0316] Stage 3. SolutionIntermediate 13-2 (2.3 g, 13.6 mmol) in DCM (50 ml) at -78° C. was treated dropwise with DAST (6.62 g, 41.0 mmol). After the addition, the temperature was raised to rt. After 16 h, the reaction mixture was cooled to -78°C and carefully quenched with sat. aq. NaHCO₃ (100 ml). The mixture was extracted with DCM (3×100 ml) and the combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was purified by chromatography (SiO₂, EtOAc / Petr. ether) to form methyl 3-(1,1-difluoroethyl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 13-3) (1.8 g, 69% yield) as a clear oil.¹H NMR (400 MHz, CDCl₃) δ 3.70 (s, 3H), 2.12 (s, 6H), 1.55 (t,J=18.0 Hz, 3H).

[0317] Step 4 To a stirred solution of intermediate 13-3 (1.8 g, 9.46 mmol) and N , O -dimethylhydroxylamine hydrochloride (0.923 g, 9.46 mmol) in anhydrous THF (40 ml) at - 78°C was added i -PrMgCl (2 M in THF, 18.9 ml, 37.8 mmol). The reaction mixture was heated to -50° C. and stirred for 2 hours. The reaction mixture was quenched with sat. aq. NH ₄ Cl (50 ml) and extracted with EtOAc (3×75 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give intermediate 13 (1.7 g, 82% yield) as a clear oil. LC/MS (ESI) m/z 220.4 [M+H] ⁺ .

Intermediate 14

4-[[(1-Methyl-4-piperidinyl)methyl]amino]-3-nitrobenzenesulfonamide

[0318] To a solution of (1-methylpiperidin-4-yl)methanamine (1 g, 7.80 mmol) in THF (75 ml), was added 4-fluoro-3-nitrobenzenesulfonamide (1.71 g, 7.80 mmol) , and then triethylamine (3.15 g, 31.2 mmol) and the reaction mixture was stirred at rt. After 16 h the reaction mixture was concentrated, diluted with water (50 ml) and extracted with 10% MeOH in DCM (3×50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (C18, 0.1% HCO ₂ H(aq)/MeCN) to give 650 mg of 4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide as the formate salt. The compound was dissolved in 10% MeOH in DCM (50 ml) and washed with sat. aq. _NaHC03 . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 14 as a yellow solid (510 mg, 20% yield). LC/MS (ESI) m/z 329.2 [M+H] ⁺ .

Intermediate 15

4-(((4-Fluoro-1-methylpiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0319] Step 1 To a stirred solution of tert- butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate (2.00 g, 8.61 mmol) in THF (30 ml) was added 4-fluoro-3- nitrobenzenesulfonamide (2.08 g, 9.47 mmol) followed by triethylamine (4.8 ml, 34.45 mmol). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was then concentrated and the resulting residue was diluted with 10% MeOH-DCM (50 ml) and washed with ice water (5×50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by trituration with Et ₂ O to give tert- butyl 4-fluoro-4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)piperidine-1-carboxylate ( Intermediate 15-1 ) (1.6 d, 43% yield). LC/MS (ESI) m/z 333.10 [MC ₅ H ₉ O ₂ +H] ⁺ .

[0320] Step 2 To a stirred solution of intermediate 15-1 (1.6 g, 3.70 mmol) in 1,4-dioxane (10 ml) at 0°C was added HCl (4 M HCl in 1,4- dioxane, 20 ml). The reaction mixture was heated to rt and stirred for 6 h. The reaction mixture was concentrated and triturated with Et ₂ O to give 4-(((4-fluoropiperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide hydrochloride ( intermediate 15- 2) (1.3 g, 96%) as a yellow solid. LC/MS (ESI) m/z 333.1 [C ₁₂ H ₁₇ FN ₄ O ₄ S+H] ⁺ .

[0321] Stage 3 To the mixed solutionIntermediate 15-2 (430 mg, 1.35 mmol) in MeOH (15 ml) was added paraformaldehyde (81 mg, 2.71 mmol) at 0°C. After 15 min NaCNBH was added₃ (128 mg, 2.03 mmol) and heated the reaction mixture to rt. After 18 hours the reaction mixture was quenched with sat. aq. NaHCO₃ (15 ml) and the reaction mixture was extracted with DCM (3×100 ml). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was triturated with Et₂O and then with 1:1 EtOAc/hexane to giveintermediate connection 15 (340 mg, 25% yield) as a yellow solid. LC/MS (ESI)m/z 347.1 [M+H]⁺.

Intermediate 16

4-(((1r,4r)-4-(Dimethylamino)cyclohexyl)amino)-3-nitrobenzenesulfonamide

[0322] To a stirred solution of trans- N ¹ , N ¹ -dimethylcyclohexane-1,4-diamine dihydrochloride (350 mg, 1.39 mmol) in THF (10 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (322 mg, 1 .39 mmol) followed by triethylamine (844 mg, 8.34 mmol). After stirring for 16 h at rt, the reaction mixture was concentrated and triturated with EtOAc and Et ₂ O to give the crude product. The product was further purified by HPLC (75 : 25 - 1 : 99 10 mM NH ₄ OAc(aq) : CH ₃ CN) to give intermediate 16 as a yellow solid. LC/MS (ESI) m/z 343.1 [M+H] ⁺ .

Intermediate 17

4-((4-Methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

[0323] To a stirred solution of (4-methylmorpholin-2-yl)methanamine (400 mg, 3.07 mmol) in THF (25 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (609 mg, 2.76 mmol) and then triethylamine (1.24 g, 12.28 mmol). After stirring at rt for 16 h, the reaction mixture was concentrated and the resulting crude material was diluted with 10% MeOH-DCM (50 ml) and washed with ice water (3×50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was triturated with Et ₂ O/pentane to give intermediate 17 (600 mg, 65% yield) as a yellow solid. LC/MS (ESI) m/z 331.2 [M+H] ⁺ .

Intermediate 17A

(R)-4-(((4-Methylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0324] Racemic 4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide (400 mg) was separated by chiral supercritical fluid chromatography (Chiralpak AD-H (250 x 30 mm), 5 µm, 30% MeOH ) to give 4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide (160 mg) as the first eluting peak (RT = 3.06 min) with 99.6% enantiomeric excess. LC/MS (ESI) m/z 331.2 [M+H] ⁺ . The absolute stereochemistry of intermediate 17A was set arbitrarily.

Intermediate 17B

(S)-4-(((4-Methylmorpholin-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0325] Racemic 4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide (400 mg) was separated by chiral supercritical fluid chromatography (Chiralpak AD-H (250 x 30 mm), 5 µm, 30% MeOH ) to give 4-((4-methylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide (150 mg) as a second eluting peak (RT = 3.64 min) with 99.8% enantiomeric excess. LC/MS (ESI) m/z 331.2 [M+H] ⁺ . The absolute stereochemistry of intermediate 17B was set arbitrarily.

Intermediate 18

4-((((1 r ,4 r )-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide

[0326] Intermediate 18 was prepared according to the procedure described in WO2014/165044A1. LC/MS (ESI) m/z 344.1 [M+H] ⁺ .

Intermediate 19

2-(Diethoxymethyl)-5,5-dimethylcyclohexan-1-one

[0327] To a solution of triethyl orthoformate (1.32 L, 7.923 mol) in DCM (8.0 L) at -30°C was added BF₃⋅OEt₂ (1.244 L, 9.9 mmol) for 30 min. The reaction mixture was heated to 0°C and stirred for 30 min. The reaction mixture was then cooled to -78°C and 3,3-dimethylcyclohexanone (500 g, 3.96 mol) and N,N-diisopropylethylamine (2.08 L, 11.9 mol) were added dropwise and the reaction mixture was stirred for 2 h at the same temperature. The reaction mixture was then carefully poured into a mixture of sat. aq. NaHCO₃ (25 l) and DCM (10 l). The resulting mixture was stirred for 15 min at rt and the organic layer was separated. The aqueous layer was extracted with DCM (2 x 10 L) and the combined organic layers washed with 10% NaCl (aq) (5 L), dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, EtOAc / Petr. ether) to receiveintermediate connection 19 (750 g, 83% yield) as a pale yellow oil.¹H NMR (400 MHz, CDCl₃) δ 4.83 (d,J=6.0 Hz, 1H), 3.73-3.57 (m, 4H), 2.56-2.53 (m, 1H), 2.20-2.14 (m, 2H), 2.11 -2.10 (m, 1H), 1.81 (m, 1H), 1.62-1.56 (m, 2H), 1.21-1.17 (m, 6H), 1.01 (s , 3H), 0.91 (s, 3H).

Intermediate 20

Benzyl 2-bromo-4,4-dimethylcyclohex-1-ene-1-carboxylate

[0328] Step 1. A solution of NaClO ₂ (11.08 g, 122.5 mmol) in water (100 ml) was added dropwise to a stirred mixture of 2-bromo-4,4-dimethylcyclohex-1-en-1-carbaldehyde ( 19 g, 87.5 mmol), CH ₃ CN (100 ml), NaH ₂ PO ₄ (2.72 g, 22.75 mmol), water (40 ml) and 30% H ₂ O ₂ (aq) ( 15 ml) at 10°C. Upon completion, the reaction mixture was poured into sat. aq. Na ₂ CO ₃ (200 ml) and washed with Et ₂ O (200 ml). The aqueous phase was poured into 1N HCl solution (500 ml) and extracted with Et ₂ O (3×200 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude compound was further washed with water and dried to give 2-bromo-4,4-dimethylcyclohex-1-en-1-carboxylic acid ( Intermediate 20-1 ) (15 g, 73% yield) as a white solid. LC/MS (ESI) m/z 231.0 [MH]-.

[0329] Step 2 To a stirred solution of intermediate 20-1 (10 g, 42.9 mmol) in DMF (100 mL) was added K ₂ CO ₃ (17.79 g, 128.7 mmol) followed by benzyl bromide (14.67 g, 85.8 mmol) at 0°C and heated the reaction mixture to rt. After 16 h, water (200 ml) was added and the reaction mixture was extracted with EtOAc (3×200 ml). The combined organic layers were washed with water (3 x 200 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give Intermediate 20 (11 g, 79% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.32 (m, 5H), 5.22 (s, 2H), 2.45-2.38 (m, 4H), 1.44 ( t, J = 5.6 Hz, 2H), 0.97 (s, 6H); GC/MS m/z 322.1 [M] ⁺ .

Intermediate 21

3-(Difluoromethyl)-N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide

[0330] Step 1 A stirred solution of methyl 3-formylbicyclo[1.1.1]pentane-1-carboxylate (7.5 g, 48.7 mmol) in DCM (100 ml) was cooled to -78°C and treated with DAST (19, 3 ml, 146.1 mmol) dropwise and heated to rt. After 6 h the reaction mixture was cooled to -78°C and quenched sat. aq. NaHCO₃ (100 ml) and extracted using DCM (3×100 ml). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give methyl 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylate (intermediate 21-1) (7 g) as a viscous oil. It was used in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 5.71 (t,J = 56.1 Hz, 1H), 3.70 (s, 3H), 2.15 (s, 6H).

[0331] Step 2 To a stirred solution of intermediate 21-1 (7 g, 39.74 mmol) in anhydrous THF (70 mL) was added N , O -dimethylhydroxylamine hydrochloride (3.89 g, 39.74 mmol) at - 78°C followed by i -PrMgCl (2 M in THF, 79.5 ml, 159 mmol). The reaction mixture was heated to -50° C. and stirred for 2 h. The reaction mixture was then quenched with sat. aq. NH ₄ Cl solution (100 ml) and extracted with EtOAc (3 × 100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give intermediate 21 (4 g, 40% yield over two steps). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.72 (t, J = 56.4 Hz, 1H), 3.68 (s, 3H), 3.19 (s, 3H), 2.20 (s , 6H); LC/MS (ESI) m/z 206.1 [M+H]+.

Intermediate 22

4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-carbaldehyde

[0332] Step 1. A solution of 1-iodo-3-methylbicyclo[1.1.1]pentane (30 g, 144.20 mmol) in THF (225 ml) was cooled to -78°C and sec-butyllithium (1 ,4 M in cyclohexane, 154.50 ml, 216.30 mmol) for 1 hour. The resulting pale yellow suspension was stirred at -78°C for 10 minutes and then warmed to 0°C and stirred for 80 minutes. The reaction mixture was then cooled to -78°C and a solution of intermediate 19 (24.67 g, 108.15 mmol) in THF (75 ml) was added dropwise over 20 min. After 10 min, the reaction mixture was heated to 0° C. for 1 h. The reaction mixture was then quenched with sat. aq. NH ₄ Cl (300 ml) and extracted with Et ₂ O (2×450 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(diethoxymethyl)-5,5-dimethyl-1-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohexan-1-ol ( intermediate 22-1 ) (31 g, crude) as a pale yellow oil. It was used in the next step without further purification.

[0333] Stage 2. SolutionIntermediate 22-1(62 g, 199.69 mmol) in 1,4-dioxane (1.24 L) was treated with 2N HCl (aq.) (299.5 ml, 599.2 mmol) at rt and then heated to 70°C. After 16 h the reaction mixture was cooled to rt, poured into water (1.24 L) and extracted with Et₂O (2 × 750 ml). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, EtOAc / Petr. ether) with the formationIntermediate 22(23 g, 36% yield over 2 steps) as a yellow oil.¹H NMR (400 MHz, CDCl₃): δ 10.28 (s, 1H), 2.25-2.22 (m, 2H), 1.94 (s, 6H), 1.92 (br. s, 2H), 1.35-1 .32 (m, 2H), 1.19 (s, 3H), 0.90 (s, 6H).

Intermediate 23

2-(3-Ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-carbaldehyde

[0334] Step 1: EtI ( _18.7 g, 257.38 mmol ). The reaction mixture was heated to rt and stirred for 3 days in the dark. The reaction mixture was then concentrated at 0°C to give 1-ethyl-3-iodobicyclo[1.1.1]pentane ( intermediate 23-1) (21.2 g, 74% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.17 (s, 6H), 1.52 (q, J = 8.0 Hz, 2H), 0.84 (t, J = 7.2 Hz, 3H ).

[0335] Step 2. To a stirred solution of intermediate 23-1 (10.90 g, 49.1 mmol) in Et ₂ O (75 ml) at -78°C was added sec -BuLi (1.4 M in cyclohexane, 50 ml, 70.0 mmol). After 10 min, the reaction mixture was heated to rt and stirred for 1 h. The reaction mixture was then cooled to -78°C and treated with a solution of 2-(diethoxymethyl)-5,5-dimethylcyclohexan-1-one (8 g, 35.0 mmol ) in Et ₂ O (25 ml). After 1 h, the reaction mixture was heated to 0° C. and stirred for 2 h. The reaction mixture was quenched with sat. aq. NH ₄ Cl (20 ml) and extracted with EtOAc (3×70 ml). The combined organic layers were then dried over Na ₂ SO ₄ , filtered and concentrated to give 8.5 g of crude 2-(diethoxymethyl)-1-(3-ethylbicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohexane -1-ol ( Intermediate 23-2 ). It was used in the next step without further purification.

[0336] Step 3. A solution of intermediate 23-2 (8.5 g, crude) in acetone (80 ml) was treated with 2N HCl (aq) (20 ml) at rt and then heated to 75°C. After 24 h the reaction mixture was concentrated and then diluted with water (50 ml) and was extracted with Et ₂ O (3×250 ml). The combined organic layers were washed with sat. aq. NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (SiO ₂ , Et ₂ O/pet. ether) to give intermediate 23 (3.9 g, 48% yield over 2 steps) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.30 (s, 1H), 2.26-2.22 (m, 2H), 1.93-1.92 (m, 2H), 1.89 ( s, 6H), 1.49 (k, J = 7.2 Hz, 2H), 1.33 (t, J = 6.4 Hz, 2H), 0.89 (s, 6H), 0.87 ( t, J = 7.6 Hz, 3H).

Intermediate 24

2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-ene-1-carbaldehyde

[0337] Step 1: Preparation of CF ₂ HI (based on the procedure described by Cao, P. et. al. J. Chem. Soc., Chem. Commun. 1994, 737-738): performed in two parallel batches. A mixture of KI (94 g, 568 mol), MeCN (228 ml) and water (18 ml) was heated to 45°C and treated dropwise with 2,2-difluoro-2-(fluorosulfonyl)acetic acid (50 g, 284 mmol) in MeCN (50 ml) for 4 h. The reaction mixture was then cooled to 0° C. and diluted with pentane (150 ml) and water (125 ml). The aqueous layer was washed with pentane (150 ml) and the combined organic layers of both reactions were washed with sat. aq. NaHCO ₃ (200 ml) and dried over Na ₂ SO ₄ to give 500 ml difluoromethyl iodide solution. The solution was washed with additional water (2 x 200 ml) to remove residual acetonitrile and dried over Na ₂ SO ₄ to give difluoroiodomethane ( intermediate 24-1) (0.15 M in pentane, 400 ml, 11% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (t, J = 56.0 Hz, 1H).

[0338] Step 2 To a stirred solution of [1.1.1]propellane (0.53 M in Et ₂ O, 52 ml, 27.56 mmol) at -40°C was added intermediate 24-1 (0.15 M in pentane, 200 ml, 30 mmol). The reaction mixture was heated to rt under protection from light and stirred for 2 days. The reaction mixture was then concentrated at 0-10°C to give 1-(difluoromethyl)-3-iodobicyclo[1.1.1]pentane ( intermediate 24-2) (5 g, 20.5 mmol, 74% yield) as white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.65 (t, J = 56.0 Hz, 1H), 2.40 (s, 6H).

[0339] Step 3. A solution of intermediate 24-2 (30 g, 122.94 mmol) in THF (225 ml) was cooled to -78°C and sec-butyllithium (1.4 M in cyclohexane, 219 ml) was added dropwise , 306.7 mmol) for 1 hour. The resulting pale yellow suspension was stirred at -78°C for 10 minutes, the temperature was raised to 0°C and stirred for 80 minutes. The reaction mixture was then cooled to -78°C and a solution of intermediate 19 (21 g, 92.20 mmol) in THF (75 ml) was added dropwise to the reaction mixture over 20 min. After 10 min, the reaction mixture was heated to 0° C. for 1 h. The reaction mixture was quenched with sat. aq. NH ₄ Cl (450 ml) and extracted with Et ₂ O (2×300 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(diethoxymethyl)-1-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohexane-1- ol ( intermediate 24-3 ) (31 g, crude) as a pale yellow oil. The crude product was used in the next step without further purification.

[0340] Step 4 Intermediate 24 was prepared according to the procedure described in Step 2 for Intermediate 22 using Intermediate 24-3 instead of Intermediate 22-1 (38% over 2 steps). ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.26 (s, 1H), 5.73 (t, J= 56.0 Hz , 1H), 2.29-2.25 (m, 2H), 2.18 (s, 6H), 1.94-1.93 (m, 2H), 1.37 (t, J = 6.8 Hz , 2H), 0.91 (s, 6H).

Intermediate 25

4,4-Dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-carbaldehyde

[0341] Step 1 To a stirred solution of 1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (5.00 g, 19.1 mmol) in Et ₂ O (100 ml) at -78°C was added sec-BuLi (1.4 M in cyclohexane, 13.63 mL, 19.08 mmol). After 10 minutes at -78°C, the reaction mixture was heated to 0°C and stirred for 1 h. The reaction mixture was then cooled to -78°C and then a solution of intermediate 19 (3.63 g, 15.90 mmol) in Et ₂ O (50 ml). After 1 h, the reaction mixture was heated to 0° C. and stirred for 2 h and then heated to rt for 1 h. The reaction mixture was quenched with sat. aq. NH ₄ Cl (100 ml) and extracted with Et ₂ O (3×150 ml). The organic layers were then dried over Na ₂ SO ₄ , filtered and concentrated to give 2-(diethoxymethyl)-5,5-dimethyl-1-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohexanol ( intermediate compound 25-1) (7 g, crude) as a brown oil. The crude product was used in the next step without further purification.

[0342] Step 2 Intermediate 25 was prepared according to the procedure described in Step 3 for Intermediate 23 using Intermediate 25-1 instead of Intermediate 23-2 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.23 (s, 1H), 2.29 (s, 6H), 2.28-2.26 (m, 2H), 1.92 (t, J = 2.0 Hz, 2H), 1.36 (t, J = 6.8 Hz, 2H), 0.91 (s, 6H).

Intermediate 26

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0343] Stage 1 A solution of 5-iodo-4,4-dimethylpent-1-ene (9.85 g, 44.0 mmol) in pentane (100 ml) was treated with t-BuLi (64.6 ml, 1.7 M inn-pentane, 109.9 mmol) at -78°C in an inert atmosphere. After 1 h, a solution was addedIntermediate 1 (5 g, 26.4 mmol) in THF (20 ml) and the mixture was stirred at -78°C for 1 h. The reaction mixture was then heated to -30°C for 30 min. and stirred for 1 h. The reaction mixture was quenched with sat. aq. NH₄Cl at -30°C, heated to rt and extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with water, dried over Na₂SO₄, filtered and concentrated. The product was purified by column chromatography (SiO₂, EtOAc / Petr. ether) to give 1-(3-chlorobicyclo[1.1.1]pentan-1-yl)-3,3-dimethylhex-5-en-1-one (intermediate 26-1) (7 g, 70%) as an oil.¹H NMR (300 MHz, CDCl₃) δ 5.83-5.69 (m, 1H), 5.05-4.96 (m, 2H), 2.36 (s, 6H), 2.30 (s, 2H), 2.09 ( d,J = 7.5 Hz, 2H), 0.98 (s, 6H).

[0344] Step 2: A solution of intermediate 26-1 (3.1 g, 13.7 mmol) and acrylonitrile (2.18 g, 41.0 mmol) in degassed DCM (120 ml) was treated dropwise over 2 hours ^2nd generation Hoveyda-Grubbs Catalyst™ (343 mg, 0.55 mmol) in DCM (5 ml) at 45°C. The reaction mixture was stirred at 45° C. for 48 h, cooled to rt, concentrated and taken up in celite. The residue was purified by column chromatography (SiO ₂ , EtOAc/petr. ether) to give 7-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxohept-2-ennitrile ( intermediate compound 26-2 ) as a mixture of E/Z isomers (1.3 g, 38%) as a clear colorless oil. LC/MS (ESI) m/z 252.1 [M+H] ⁺ .

[0345] Step 3: A solution of intermediate 26-2 (700 mg, 2.78 mmol) in MeOH (20 mL) was treated with Pd/C (10 wt%, 170 mg) and stirred under H ₂ (1 atm) for 2 h. The reaction mixture was purged with N ₂ and the reaction mixture was filtered through celite and concentrated to give 7-(3-chlorobicyclo[1.1.1]pentan-1- yl )-5,5-dimethyl-7-oxoheptanenitrile ( intermediate 26-3 ) (550 mg, 77%) as a clear colorless oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.37 (s, 6H), 2.35-2.30 (m, 4H), 1.66-1.55 (m, 2H), 1.52- 1.44 (m, 2H), 0.98 (s, 6H).

[0346] Step 4. A solution of intermediate 26-3 (1.1 g, 4.34 mmol, 1 eq.) in THF (20 ml) was treated with 4 Å molecular sieves (100 mg) and 15-crown-5 (956 mg, 4.34 mmol) and placed in an oil bath preheated to 70°C. After 2 minutes, the reaction mixture was treated with t-BuONa (2.09 g, 21.7 mmol) in one go. After 5 h, the reaction mixture was cooled to rt and poured into a stirred solution of sat. aq. _NH4Cl . The aqueous phase was washed with DCM (3×25 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give 2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbonitrile ( intermediate 26- 4 ) (800 mg, 39%) as a clear colorless oil. LC/MS (ESI) m/z 236.3 [M+H] ⁺ .

[0347] Stage 5 To the mixed solutionIntermediate 26-4 (400 mg, 1.70 mmol) in anhydrous DCM (20 ml) at -78°C was added DIBAL-H (2.55 ml, 1 M in toluene, 2.55 mmol). The reaction mixture was heated to rt. After 4 h, the reaction mixture was cooled to 0°C, quenched with 2 M HCl (aq.) (40 ml) and heated to rt. The reaction mixture was diluted with water and extracted with DCM (2×40 ml) and the combined organic layers were dried over Na₂SO₄, filtered and concentrated to give 2-(3-chlorobicyclo[1.1.1]pentan-1-silt)-4,4-dimethyl cyclohex-1-enecarbaldehyde (intermediate 26-5) (400 mg, quantitatively). This compound was used directly in the next step without further purification.¹H NMR (300 MHz, CDCl₃) δ 10.19 (s, 1H), 2.44 (s, 6H), 2.30-2.22 (m, 2H), 1.90 (s, 2H), 1.35 (t,J = 6 Hz, 2H), 0.90 (s, 6H).

[0348] Stage 6. To the mixed solutionIntermediate 26-5 (300 mg, 1.26 mmol) in DCM (10 ml) was added intermediate 2 (544 mg, 1.38 mmol) and NaBH (OAc)₃ (347 mg, 1.64 mmol) at rt. After 16 hours additional NaBH (OAc) was added₃ (347 mg, 1.64 mmol). After 48 h the reaction mixture was quenched with MeOH (0.2 ml) at 0°C, warmed to rt and concentrated. The residue was diluted with DCM and washed with sat. aq. NaHCO₃. The aqueous layer was washed with DCM (3×25 ml) and the combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (SiO₂, EtOAc / Petr. ether) to receivetert-butyl 2-(1H-pyrrolo[2,3-b]pyridine-5-silt-hydroxy)-4-(4-((2-(3-chlorobicyclo [1.1.1]pentane-1-silt)-4,4-dimethylcyclohex-1-en-silt)methyl)piperazin-1-yl)benzoate (intermediate 26-6) (220 mg, 44.6 mmol; 28%) as a white solid. LC/MS (ESI)m/z 617.3 [M+H]⁺.

[0349] Step 7 To a solution of intermediate 26-6 (125 mg, 0.20 mmol) in DCM (2 ml) at 0°C was added TFA (139 mg, 1.22 mmol). The mixture was heated to rt and stirred for 3 h, concentrated to give the TFA salt 2-( 1H -pyrrolo[2,3- b ]pyridin-5- yl- oxy)-4-(4-((2-( 3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-yl)methyl)piperazin-1-yl)benzoic acid (140 mg, quantitative) as white solid LC/ MS (ESI) m/z 561.3 [C ₃₂ H ₃₇ ClN ₄ O ₃ +H] ⁺ .

Intermediate 27

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0350] Step 1. 1-(3-Fluorobicyclo[1.1.1]pentan-1-yl)-3,3-dimethylhex-5-en-1-one ( intermediate 27-1 ) was prepared according to the procedure described in Step 1 for Intermediate 26 using Intermediate 11 instead of Intermediate 1 . ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.84-5.69 (m, 1H), 5.06-4.96 (m, 2H), 2.34 (s, 2H), 2.29 ( d, J = 2.4 Hz, 6H), 2.10 (d, J = 7.2 Hz, 2H), 0.99 (s, 6H).

[0351] Step 2 E / Z -7-(3-Fluorobicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxohept-2-ennitrile ( intermediate 27-2) was obtained in according to the procedure described in Step 2 for Intermediate 26 using Intermediate 27-1 instead of Intermediate 26-1 . LC/MS (ESI) m/z 236.3 [M+H] ⁺ .

[0352] Step 3. 7-(3-Fluoro-bicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxoheptanenitrile ( Intermediate 27-3 ) was prepared according to the procedure described in Step 3 for Intermediate 26 using Intermediate 27-2 instead of Intermediate 26-2 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.36 (s, 2H), 2.32 (t, J = 6.8 Hz, 2H), 2.31 (d, J = 2.8 Hz, 6H ), 1.64-1.58 (m, 2H), 1.51-1.47 (m, 2H), 0.99 (s, 6H).

[0353] Step 4 2-(3-Fluoro-bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbonitrile ( intermediate 27-4) was prepared according to the procedure described in step 4 for Intermediate 26 using Intermediate 27-3 instead of Intermediate 26-3 . LC/MS (ESI) m/z 220.4 [M+H] ⁺ .

[0354] Step 5 2-(3-Fluoro-bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbaldehyde ( intermediate 27-5) was prepared according to the procedure described in step 5 for Intermediate 26 using Intermediate 27-4 instead of Intermediate 26-4 . ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.19 (s, 1H), 2.37-2.34 (m, 6H), 2.30-2.25 (m, 2H), 1.93 ( br s, 2H), 1.40-1.35 (m, 2H), 0.91 (s, 6H).

[0355] Step 6 To a stirred solution of intermediate 27-5 (100 mg, 0.45 mmol) in EtOH (4 mL) was added intermediate 2 (195 mg, 0.49 mmol) and AcOH ( cat. ) at rt and stirred for 15 min. The resulting reaction mixture was cooled to 0°C, NaCNBH ₃ (42 mg, 0.675 mmol) was added and the reaction mixture was heated to rt. After 16 hours the reaction mixture was concentrated and the residue was diluted with sat. aq. NaHCO ₃ (10 ml) and extracted with DCM (3×10 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude compound was purified by column chromatography ( SiO ₂ , EtOAc/pet. ether ) to give tert -butyl 2-( 1H -pyrrolo[2,3- b ]pyridin-5- yl -oxy)-4-(4-( (2-(3-Fluorobicyclo[1.1.1]pentan-1- yl )-4,4-dimethylcyclohex-1-en- yl )methyl)piperazin-1- yl )benzoate ( intermediate 27-6 ) as white solid (40 mg, 15% yield). LC/MS (ESI) m/z 601.7 [M+H] ⁺ .

[ 0356 ] Step 7 -yl)-4,4-dimethylcyclohex-1-en-yl)methyl)piperazin-1-yl)benzoic acid as TFA salt was prepared according to the procedure described in Step 7 for Intermediate 26 using Intermediate 27 -6 instead of the 26-6 intermediate . LC/MS (ESI) m/z 545.4 [C ₃₂ H ₃₇ FN ₄ O ₃ +H] ⁺ .

Intermediate 28

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1 -yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

Path A

[0357] Step 1. 3,3-Dimethyl-1-(3-methylbicyclo[1.1.1]pentan-1-yl)hex-5-en-1-one ( intermediate 28-1 ) was prepared according to the procedure described in Step 1 for Intermediate 26 using Intermediate 10 instead of Intermediate 1 . ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.86-5.71 (m, 1H), 5.04-4.97 (m, 2H), 2.28 (s, 2H), 2.09 ( e, J = 7.8 Hz, 2H), 1.85 (s, 6H), 1.12 (s, 3H), 0.97 (s, 6H).

[0358] Step 2 E / Z -5,5-Dimethyl-7-(3-methylbicyclo[1.1.1]pentan-1-yl)-7-oxohept-2-ennitrile ( intermediate 28-2 ) was obtained in according to the procedure described in Step 2 for Intermediate 26 using Intermediate 28-1 instead of Intermediate 26-1 . LC/MS (ESI) m/z 232.3 [M+H] ⁺ .

[0359] Step 3. 5,5-Dimethyl-7-(3-methylbicyclo[1.1.1]pentan-1-yl)-7-oxoheptanenitrile ( Intermediate 28-3 ) was prepared according to the procedure described in Step 3 for Intermediate 26 using Intermediate 28-2 instead of Intermediate 26-2 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.33-2.29 (m, 4H), 1.86 (s, 6H), 1.64-1.56 (m, 2H), 1.50- 1.45 (m, 2H), 1.18 (s, 3H), 0.98 (s, 6H).

[0360] Step 4. 4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-enecarbonitrile ( intermediate 28-4 ) was prepared according to the procedure described in step 4 for Intermediate 26 using Intermediate 28-3 instead of Intermediate 26-3 . LC/MS (ESI) m/z 216.4 [M+H] ⁺ .

[0361] Step 5 Intermediate 22 was prepared according to the procedure described in Step 5 for Intermediate 26 using Intermediate 28-4 instead of Intermediate 26-4 . LC/MS (ESI) m/z 219.3 [M+H] ⁺ .

[0362] Step 6 To a stirred solution of intermediate 22 (70 mg, 0.32 mmol) in EtOH (4 mL) was added intermediate 2 (190 mg, 0.48 mmol) and AcOH (cat) at rt. After 15 min the mixture was cooled to 0°C, NaCNBH ₃ (31 mg, 0.48 mmol) was added and the reaction mixture was heated to rt. After 16 h the reaction mixture was concentrated, the residue was diluted with sat. aq. NaHCO ₃ (10 ml) and extracted with DCM (3 x 10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give tert- butyl 2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4 ,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate ( intermediate 28-5 ) (80 mg, 42% ) as a white solid. LC/MS (ESI) m/z 597.4 [M+H] ⁺ .

[0363] Step 7. 2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1. 1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid was prepared according to the procedure described in Step 7 for Intermediate 26 using Intermediate 28-5 instead of Intermediate 26- 6 . LC/MS (ESI) m/z 541.4 [C ₃₃ H ₄₀ N ₄ O ₃ +H] ⁺ .

Path B

[0364] Step 1. A solution of t -butyl lithium (1.3 M in pentane, 60 mL, 78 mmol) was added dropwise to a solution of 1-iodo-3-methylbicyclo[1.1.1]pentane (6.5 g, 31. 2 mmol) in MTBE (60 ml) at -78° C. under N ₂ atmosphere. The reaction mixture was stirred for 1 h at -78°C. Lithium 2-thienylcyanocuprate (0.25 M in THF, 125 ml, 31.2 mmol) was added at -78°C and the addition was monitored to keep the temperature below -60°C. After the addition, the reaction mixture was warmed to 0° C. and stirred for 30 min. The reaction mixture was then cooled to -78°C and was added intermediate compound 20 (5 g, 15.5 mmol) in MTBE (5 ml) and then BF ₃ ⋅OEt ₂ (3.5 ml, 15.5 mmol). The reaction mixture was stirred for 30 min at -78°C and then heated to rt. After 16 h, the reaction mixture was cooled to 0°C and quenched with sat. aq. NH ₄ Cl (50 ml) and H ₂ O (50 ml). Then MTBE (50 ml) was added and the reaction mixture was stirred for 20 min at rt. The organic layer was separated and the aqueous layer was extracted with MTBE (100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by column chromatography (SiO ₂ , EtOAc/heptane) followed by column chromatography (C18, CH ₃ CN : H ₂ O) gave benzyl 4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentane- 1-yl)cyclohex-1-ene-1-carboxylate (3.6 g, 70%). ¹ H NMR (400 MHz, DMSO) δ 7.41-7.34 (m, 5H), 5.13 (s, 2H), 2.17-2.12 (m, 2H), 1.72-1 .70 (m, 2H), 1.64 (s, 6H), 1.31-1.27 (m, 2H), 1.08 (s, 3H), 0.86 (s, 6H).

[0365] Step 2. To a stirred solution of benzyl 4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-carboxylate (1.1 g, 3. 39 mmol) in THF (40 ml) at 0°C was added lithium aluminum hydride (386.6 mg, 10.2 mmol). The reaction mixture was heated to rt and stirred for 3 hours. The reaction mixture was then cooled to 0°C, diluted with Et ₂ O (40 ml) and treated with H ₂ O (0.386 ml), 0.386 ml of 15% NaOH (aq.), and then H ₂ O (1.15 ml). The reaction mixture was heated to rt, stirred for 15 min and then treated with anhydrous MgSO ₄ . After 15 min the reaction mixture was filtered, concentrated and purified by column chromatography (SiO ₂ , EtOAc/petr. ether) to give (4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex -1-en-1-yl)methanol (1.1 g, 68% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.15 (d, J = 5.2 Hz, 2H), 2.16-2.12 (m, 2H), 1.81 (s, 6H), 1 .68 (s, 2H), 1.32 (t, J = 6.4 Hz, 2H), 1.15 (s, 3H), 0.86 (s, 6H).

[0366] Step 3. To a stirred solution of (4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methanol (500 mg, 2, 27 mmol) in DCM (20 ml) SOCl ₂ (0.537 ml, 4.54 mmol) was added dropwise at 0°C. The reaction mixture was heated to rt and stirred for 2 h. The reaction mixture was concentrated, diluted with DCM and concentrated again to give 1-(2-(chloromethyl)-5,5-dimethylcyclohex-1-en-1-yl)-3- methylbicyclo[1.1.1]pentane (540 mg, quantitative) as a clear oil. It was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.19 (s, 2H), 2.15-2.11 (m, 2H), 1.85 (s, 6H), 1.70 (s, 2H) , 1.34 (t, J = 6.4 Hz, 2H), 1.16 (s, 3H), 0.87 (s, 6H).

[0367] Step 4. To a stirred solution of 1-(2-(chloromethyl)-5,5-dimethylcyclohex-1-en-1-yl)-3-methylbicyclo[1.1.1]pentane (540 mg, 2.26 mmol ) in acetone (20 ml) was added methyl 2-(( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (798 mg, 2.26 mmol), NaI (33.90 mg, 0.22 mmol) and K ₂ CO ₃ (938.9 mg, 6.80 mmol) at rt. The reaction mixture was then heated at reflux for 6 hours. The reaction mixture was further cooled to rt, diluted with 50 ml of acetone and filtered. The collected solid was washed with acetone (150 mL) and the combined filtrates were concentrated to give methyl 2-(( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(4-((4.4 -dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (1.15 g, 91% yield) in form of a white solid. LC/MS (ESI) m/z 555.3 [M+H] ⁺ .

[0368] Step 5. To the stirred solution of methyl 2-(( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-( 3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate (1.15 g, 2.075 mmol) in MeOH : THF : H ₂ O (1 : 1 : 1) (36 ml) was added LiOH⋅H ₂ O (261.30 mg, 6.23 mmol) at rt. The reaction mixture was heated to 30°C and stirred for 16 h. The volatile solvents were then removed and the reaction mixture was neutralized with 1 N HCl and extracted with DCM (3×70 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 28 (940 mg, 84% yield) as a white solid. LC/MS (ESI) m/z 541.3 [M+H] ⁺ .

Path C

[0369] Step 1. Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate solution (35 g, 99.3 mmol) and intermediate 22 (26.0 g, 119.2 mmol) in THF (700 mL) was stirred at rt for 20 min. The reaction mixture was then cooled to 0°C and NaBH(OAc) ₃ (63.15 g, 297.96 mmol) was added. After the addition, the reaction mixture was heated to rt. After 16 h the reaction mixture was poured into ice water (1 L) and extracted with EtOAc (2×500 ml). The combined organic layers were washed with 10% NaHCO ₃ (aq.) (500 ml) and brine (500 ml). The organic layer was then dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was first purified by column chromatography (SiO ₂ , EtOAc/petr. ether) and then triturated with MeOH and filtered to give methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate in as an off-white solid (38 g, 70%). LC/MS (ESI) m/z 555.1 [M+H] ⁺ .

[0370] Step 2 Intermediate 28 was prepared according to the procedure described in Step 5, Route B for Intermediate 28 . LC/MS (ESI) m/z 541.3 [M+H] ⁺ .

Intermediate 29

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0371] Stage 1. To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (1.89 g, 5.38 mmol) in DMSO (25 ml) was added a solutionIntermediate 23 (1.5 g, 6.46 mmol) in THF (25 ml) at rt and the reaction mixture was stirred for 1 h. The reaction mixture was then cooled to 0°C and treated with Na(OAc)₃BH (3.42 g, 16.14 mmol) and heated to rt. After 24 h, the reaction mixture was diluted with sat. aq. NaHCO₃ and extracted with 10% MeOH in DCM (4 x 50 ml). The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, Et₂O/n-pentane) to give methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzoate (intermediate 29-1) (1.4 g, 46% yield) as an off-white solid. LC/MS (ESI)m/z 569.4 [M+H]⁺.

[0372] Step 2. Intermediate 29 was prepared according to the procedure described in Step 5, Route B for Intermediate 28, using Intermediate 29-1 in place of methyl 2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl) piperazin-1-yl)benzoate. LC/MS (ESI) m/z 555.3 [M+H] ⁺ .

Intermediate 30

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0373] Step 1. Methyl 2-(( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1. 1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate ( intermediate 30-1 ) was prepared according to the procedure described in step 1, path C for intermediate 28 , using intermediate 24 instead of intermediate 22 . LC/MS (ESI) m/z 591.2 [M+H] ⁺ .

[0374] Step 2. Intermediate 30 was prepared according to the procedure described in Step 5, Route B for Intermediate 26 using Intermediate 30-1 in place of methyl 2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl) piperazin-1-yl)benzoate. LC/MS (ESI) m/z 577.5[M+H] ⁺ .

Intermediate 31

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0375] Step 1. Sample procedure (reaction run in 3 parallel batches). To a stirred solution of methyl 2-(( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(piperazin-1-yl)benzoate (2 g, 5.68 mmol) in DMSO ( 0.2 M, 30 ml) a solution of intermediate 25 (1.72 g, 6.22 mmol) in THF (30 ml) was added at rt. After 1 h the reaction mixture was cooled to 0°C and treated with NaBH(OAc) ₃ (1.70 g, 17.04 mmol). The reaction mixture was heated to rt and stirred for 24 h. The reaction mixture was diluted with sat. aq. NaHCO ₃ and extracted with 10% MeOH in DCM (4 x 150 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ EtOAc/pet. ether) to give methyl 2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4- dimethyl 2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate ( intermediate 31-1 ) (8.7 g, 14.29 mmol, 84% in total for three lots) as a white solid. LC/MS (ESI) m/z 609.3 [M+H] ⁺ .

[0376] Step 2 To a stirred solution of intermediate 31-1 (8.3 g, 13.65 mmol) in MeOH : THF : H ₂ O (1 : 1 : 1) (100 mL) was added LiOH⋅H ₂ O (1.7 g, 40.95 mmol) at rt. The reaction mixture was then heated to 35° C. and stirred for 16 hours. The reaction mixture was concentrated, diluted with water and neutralized with 1N HCl. The product was then extracted with 10% MeOH-DCM (3×150 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 31 (7.6 g, 90% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.91 (br. s, 1H), 11.59 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7 .70 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 2.8 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 6.73 -6.71 (m, 1H), 6.36-6.34 (m, 2H), 3.14-3.05 (m, 4H), 2.94 (s, 2H), 2.40-2 .28 (m, 4H), 2.12 (s, 6H), 2.09-1.99 (m, 2H), 1.68 (s, 2H), 1.29-1.19 (m, 2H ), 0.84 (s, 6H); ¹⁹ F NMR (376 MHz, DMSO- d ₆ , no internal standard) δ -71.55; LC/MS (ESI) m/z 595.3 [M+H] ⁺ .

Intermediate 32

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-isopropylbicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0377] Step 1 3,3-Dimethyl-1-(3-isopropylbicyclo[1.1.1]pentan-1-yl)hex-5-en-1-one ( Intermediate 32-1 ) was prepared according to the procedure described in Step 1 from Intermediate 26 using Intermediate 12 instead of Intermediate 1 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.81-5.74 (m, 1H), 5.04-4.97 (m, 2H), 2.31 (s, 2H), 2.10 ( d, J = 7.6 Hz, 2H), 1.76 (s, 6H), 1.69-1.65 (m, 1H), 0.99 (s, 6H), 0.83 (d, J = 6.8 Hz, 6H).

[0378] Step 2 E / Z -7-(3-Isopropylbicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxohept-2-ennitrile ( intermediate 32-2 ) was obtained in following the procedure described in Step 2 from Intermediate 26 using Intermediate 32-1 instead of Intermediate 26-1 . LC/MS (ESI) m/z 260.4 [M+H] ⁺ .

[0379] Step 3. 7-(3-Isopropylbicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxoheptanenitrile ( intermediate 32-3 ) was prepared according to the procedure described in step 3 from Intermediate 26 using Intermediate 32-2 instead of Intermediate 26-2 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.34-2.30 (m, 4H), 1.78 (s, 6H), 1.70-1.57 (m, 4H), 1.51- 1.46 (m, 1H), 0.98 (s, 6H), 0.84 (d, J = 7.2 Hz, 6H).

[0380] Step 4 2-(3-Isopropylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbonitrile ( intermediate 32-4 ) was prepared according to the procedure described in Step 4 from Intermediate 26 using Intermediate 32-3 instead of Intermediate 26-3 . LC/MS (ESI) m/z 244.4 [M+H] ⁺ .

[0381] Step 5 2-(3-Isopropylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbaldehyde ( intermediate 32-5 ) was prepared according to the procedure described in step 5 from Intermediate 26 using Intermediate 32-4 instead of Intermediate 26-4 . LC/MS (ESI) m/z 247.4 [M+H] ⁺ .

[0382] Step 6. tert -Butyl 2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((2-(3-isopropylbicyclo[1.1.1]pentan- 1-yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate ( intermediate 32-6 ) was prepared according to the procedure described in step 6, route A for intermediate 28 using intermediate 32-5 instead of intermediate 28-5 . LC/MS (ESI) m/z 625.7 [M+H] ⁺ .

[0383] Step 7 To a solution of intermediate 32-6 (160 mg, 0.26 mmol) in DCM (5 ml) at 0°C was added TFA (176 mg, 1.54 mmol). The mixture was heated to rt and stirred for 3 h. The reaction mixture was then diluted with sat. aq. NaHCO ₃ (10 ml) and extracted with DCM (3×10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 32 as an off-white solid. LC/MS (ESI) m/z 569.6 [M+H] ⁺ .

Intermediate 33

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((2-(3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1- yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid

[0384] Step 1. 1-(3-(1,1-Difluoroethyl)bicyclo[1.1.1]pentan-1-yl)-3,3-dimethylhex-5-en-1-one ( Intermediate 33-1 ) was prepared according to the procedure described in Step 1 for Intermediate 26 using Intermediate 13 instead of Intermediate 1 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.85-5.69 (m, 1H), 5.03-4.95 (m, 2H), 2.30 (s, 2H), 2.08 ( e, J = 8.0 Hz, 2H), 2.03 (s, 6H), 1.53 (t, J = 18.0 Hz, 3H), 0.97 (s, 6H).

[0385] Stage 2E/Z-7-(3-(1,1-Difluoroethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxohept-2-ennitrile (intermediate 33-2) received in accordance with the procedure described in step 2 forIntermediate 26usingintermediate 33-1 instead ofIntermediate 26-1. LC/MS (ESI)m/z 282.5[M+H]⁺.

[0386] Step 3. 7-(3-(1,1-Difluoroethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethyl-7-oxoheptanenitrile (intermediate 33-3) received in accordance with the procedure described in step 3 forIntermediate 26usingintermediate 33-2instead ofIntermediate 26-2.¹H NMR (400 MHz, CDCl₃) δ 2.34-2.31 (m, 4H), 2.06 (s, 6H), 1.66-1.57 (m, 2H), 1.55 (t,J=18.0 Hz, 3H), 1.51-1.46 (m, 2H), 0.99 (s, 6H).

[0387] Step 4. 2-(3-(1,1-Difluoroethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbonitrile (intermediate 33-4) was obtained in accordance with the procedure described in step 4 forIntermediate 26usingintermediate 33-3instead ofIntermediate 26-3. LC/MS (ESI)m/z 266.1 [M+H]⁺.

[0388] Step 5. 2-(3-(1,1-Difluoroethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enecarbaldehyde (intermediate 33-5) received in accordance with the procedure described in step 5 forIntermediate 26usingintermediate 33-4 instead ofIntermediate 26-4. LC/MS (ESI)m/z 269.5[M+H]⁺.

[0389] Stage 6tert-Butyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enyl) methyl)piperazin-1-yl)benzoate (intermediate 33-6) was obtained in accordance with the procedure described in step 6, route A forintermediate connection 28usingintermediate 33-5 instead ofIntermediate 28-5. LC/MS (ESI)m/z 647.3 [M+H]⁺.

[0390] Step 7 Intermediate 33 was prepared according to the procedure described in Step 7 for Intermediate 32 using Intermediate 33-6 instead of Intermediate 32-6 . LC/MS (ESI) m/z 591.3 [M+H] ⁺ .

Intermediate 34

(S)-4-(((1,4-Dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0391] A solution of (S)-(1,4-dioxan-2-yl)methanamine hydrochloride (500 mg, 3.25 mmol) in THF (5 mL) was treated with 4-fluoro-3-nitrobenzenesulfonamide (501 mg, 2. 20 mmol) and DIPEA (1.65 g, 13 mmol) and heated the mixture to 45°C. After 16 h the reaction mixture was concentrated, triturated with MeOH and filtered to give intermediate 34 (500 mg, 48%) as a yellow solid. LC/MS (ESI) m/z 318.4 [M+H] ⁺ .

Intermediate 35

(R)-4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide

[0392] Intermediate 35 was prepared according to the procedure described in WO2012/017251A1. LCMS (ESI) m/z 780.6 [M+H] ⁺ .

Intermediate 36

4-(4-((2-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0393] Step 1 To a stirred solution of 3,3-dimethylpent-4-en-1-ol (18.5 g, 162.01 mmol) in DCM (100 ml) was added MsCl (13.54 ml, 175.0 mmol) and then NEt ₃ (33.87 ml, 243.0 mmol) at 0°C and heated the reaction mixture to rt. After 4 hours sat. aq. NaHCO ₃ solution (100 ml) and the reaction mixture was extracted with DCM (3 x 100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 3,3-dimethylpent-4-enyl methanesulfonate ( Intermediate 36-1 ) (20.0 g, 64% yield) as a clear colorless oil. It was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.80-5.72 (m, 1H), 5.01-4.94 (m, 2H), 4.22-4.18 (m, 2H), 2.99 (s, 3H), 1.81-1.77 (m, 2H), 1.06 (s, 6H).

[0394] Step 2 Into a pressure flask was added intermediate 36-1 (20 g, 104.01 mmol) and NaI (46.77 g, 312.04 mmol) in acetone (100 ml). The flask was sealed and the reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was cooled to rt, diluted with water (250 ml) and extracted with Et ₂ O (3×200 ml). The combined organic layers were washed with sat. aq. Na ₂ S ₂ O ₃ , dried over Na ₂ SO ₄ and evaporated to give 5-iodo-3,3-dimethylpent-1-ene ( intermediate 36-2 ) (18 g, 77% yield) as a clear colorless oil . ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.75-5.68 (m, 1H), 5.01-4.92 (m, 2H), 3.09-3.05 (m, 2H), 1.99-1.95 (m, 2H), 1.01 (s, 6H).

[0395] Step 3. 1-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylhex-5-en-1-one ( Intermediate 36-3 ) was prepared according to the procedure described in step 1 for intermediate 26 using 36-2 instead of 5-iodo-4,4-dimethylpent-1-ene. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.71-5.63 (m, 1H), 4.97-4.88 (m, 2H), 2.38 (s, 6H), 2.34- 2.30 (m, 2H), 1.57-1.52 (m, 2H), 0.98 (s, 6H).

[0396] Step 4 Ozone gas was bubbled into a solution of intermediate 36-3 (1.5 g, 6.63 mmol) in DCM (40 mL) at -78° C. until the solution turned blue (~30 min). The reaction mixture was then sparged with gaseous N ₂ until the color disappeared. Added PPh ₃ (2.6 g, 9.94 mmol) in one step and heated the reaction mixture to rt. After 3 h the reaction mixture was diluted with DCM (100 ml), washed with water (2×25 ml) and brine (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give 5-(3-chlorobicyclo[1.1.1]pentan-1-yl)-2,2-dimethyl-5-oxopentanal ( intermediate 36- 4 ) as a clear colorless oil (800 mg, 53% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.41 (s, 1H), 2.39 (s, 6H), 2.38-2.33 (m, 2H), 1.77-1.72 ( m, 2H), 1.05 (s, 6H).

[0397] Step 5 To a stirred solution of diethylcyanomethylphosphonate (619 mg, 3.50 mmol) in toluene (10 ml) at 0°C was added LiHMDS (1 M in toluene, 3.5 ml, 3.50 mmol). The reaction mixture was then heated to rt. After 30 minutes, this solution was added dropwise at -78°C to a solution of intermediate 36-4 (800 mg, 3.50 mmol) in toluene (10 ml). The reaction mixture was heated to rt and stirred for 16 h at which point it was cooled to 0° C. and quenched with sat. aq. NH ₄ Cl (20 ml). The organic phase was separated and the aqueous phase was further extracted with DCM (3 x 50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/petr. ether) to give ( E )-7-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethyl-7-oxohept- 2-ennitrile ( intermediate 36-5 ) as a clear colorless oil (440 mg, 50% yield). LC/MS (ESI) m/z 252.4 [M+H] ⁺ .

[0398] Step 6: A solution of intermediate 36-5 (440 mg, 1.75 mmol) in MeOH (10 mL) was treated with Pd/C (25 wt%, 110 mg) and stirred under H ₂ (1 atm) within 2 hours the Reaction mixture was then purged with N ₂ and filtered through celite. The Celite layer was washed with MeOH (3 x 25 mL) and the combined organic layers were concentrated to give 7-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethyl-7-oxoheptanenitrile ( Intermediate 36-6 ) as a clear colorless oil (360 mg, 81% yield). ¹ H NMR (400 MHz, CDCl ₃ ) 2.41 (s, 6H), δ 2.40-2.36 (m, 2H), 2.30-2.25 (m, 2H), 1.63- 1.56 (m, 2H), 1.50-1.46 (m, 2H), 0.89 (s, 6H).

[0399] Step 7 2-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-en-1-carbonitrile ( intermediate 36-7 ) was prepared according to the procedure described in Step 4 for Intermediate 26 using Intermediate 36-6 instead of Intermediate 26-3 . LC/MS (ESI) m/z 236.4 [M+H] ⁺ .

[0400] Step 8. 5,5-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-ene-1-carbaldehyde ( intermediate 36-8 ) was obtained according to the procedure described in Step 5 for Intermediate 26 using Intermediate 36-7 instead of Intermediate 26-4 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.17 (s, 1H), 2.46 (s, 6H), 2.44 (s, 2H), 2.03 (t, J = 7.6 Hz , 2H), 1.42-1.37 (m, 2H), 0.86 (s, 6H).

[0401] Step 9 To a stirred solution of intermediate 36-8 (85 mg, 0.361 mmol) in EtOH (3 mL) was added tert- butyl 4-(piperazin-1-yl)benzoate (104 mg, 0.397 mmol) and AcOH ( cat. ). After 15 min the reaction mixture was cooled to 0°C, treated with NaCNBH ₃ (33.6 mg, 0.535 mmol) and heated to rt. After 16 h, the reaction mixture was diluted with sat. aq. NaHCO ₃ and extracted with DCM (3×15 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give tert- butyl 4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-5,5- dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate ( Intermediate 36-9 ) as a white solid (80 mg, 50% yield). LC/MS (ESI) m/z 485.6 [M+H] ⁺ .

[0402] Step 10 To a stirred solution of intermediate 36-9 (80 mg, 0.165 mmol) in DCM (3 mL) at 0°C was added TFA (113 mg, 0.99 mmol). The reaction mixture was heated to rt and stirred for 3 h. The reaction mixture was concentrated and then diluted with sat. aq. NaHCO ₃ and extracted with DCM (3×10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give intermediate 36 as an off-white solid (60 mg, 85%). LC/MS (ESI) m/z 429.5 [M+H] ⁺ .

Intermediate 37

( R )-4-(4-(4-Hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

[0403] Step 1. To a stirred solution of ( R )-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(phenylthio)butanoic acid (6.8 g, 15.7 mmol) in DCM (70 ml) and DMF (10 ml) was added HATU (9.5 g, 25.12 mmol) followed by DIPEA (8.3 ml, 47.1 mmol) at 0°C. After 10 minutes, 4-hydroxypiperidine (2.4 g, 23.55 mmol) was added and the temperature was brought to rt. After 16 hours the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ MeOH/DCM) to give ( R )-( 9H- fluoren-9-yl)methyl-4-(4-hydroxypiperidin-1-yl)-4-oxo-1-( phenylthio)butan-2-ylcarbamate ( Intermediate 37-1 ) (5.5 g, 68% yield) as a brown oil. LC/MS (ESI) m/z 517.6 [M+H] ⁺ .

[0404] Step 2 To a stirred solution of intermediate 37-1 (2.75 g, 5.32 mmol) in CH ₃ CN (20 mL) was added diethylamine (3.3 mL, 31.92 mmol) at rt and stirred at ct. After 16 hours, the reaction mixture was concentrated and purified by column chromatography (neutral alumina, MeOH/DCM) to give ( R )-3-amino-1-(4-hydroxypiperidin-1-yl)-4-(phenylthio)butane-1 -one ( intermediate 37-2 ) (900 mg, 57% yield) as a brown liquid. LC/MS (ESI) m/z 295.1 [M+H] ⁺ .

[0405] Step 3. To a stirred solution of intermediate 37-2 (0.9 g, 3.06 mmol) in anhydrous THF (12 ml) at 0°C was added BH ₃ (1 M in THF, 9.18 ml, 9.18 mmol) and brought the temperature to 45°C. After 16 h the reaction mixture was cooled to 0°C and was added MeOH (30 ml). After 1 hour, the reaction mixture was concentrated and purified by column chromatography (C18, CH ₃ CN/water) to give ( R )-1-(3-amino-4-(phenylthio)butyl)piperidin-4-ol ( intermediate 37- 3 ) (305 mg, 36% yield) as an off-white semi-solid. LC/MS (ESI) m/z 281.2 [M+H] ⁺ .

[0406] Step 4 To a stirred solution of intermediate 37-3 (100 mg, 0.357 mmol) in DMF (1 mL) was added 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (99 mg, 0.32 mmol) followed by DIPEA (140 mg, 1.07 mmol) and the resulting reaction mixture was stirred at rt. After 16 h the reaction mixture was concentrated, diluted with water and extracted with 9 : 1 DCM : MeOH (2 × 10 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by trituration with EtOAc/Et ₂ O to give Intermediate 37 (105 mg, 51% yield) as a white solid. LC/MS (ESI) m/z 568.1 [M+H] ⁺ .

Intermediate 38

4-(4-((5,5-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0407] Step 1 4,4-Dimethyl-1-(3-methylbicyclo[1.1.1]pentan-1-yl)hex-5-en-1-one ( intermediate 38-1) was prepared according to the procedure described in Step 1 for Intermediate 26 using Intermediate 10 and Intermediate 36-2 in place of Intermediate 1 and 5-iodo-4,4-dimethylpent-1-ene. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.73-5.66 (m, 1H), 4.95-4.88 (m, 2H), 2.33-2.28 (m, 2H), 1.88 (s, 6H), 1.55-1.51 (m, 2H), 1.21 (s, 3H), 0.99 (s, 6H).

[0408] Step 2. 2,2-Dimethyl-5-(3-methylbicyclo[1.1.1]pentan-1-yl)-5-oxopentanal (intermediate 38-2 ) was prepared according to the procedure described in step 4 for Intermediate 36 , using Intermediate 38-1 instead of Intermediate 36-3 . 1H NMR (300 MHz, CDCl3) δ 9.41 (s, 1H), 2.36-2.30 (m, 2H), 1.88 (s, 6H), 1.79-1.71 (m, 2H), 1.18 (s, 3H), 1.05 (s, 6H).

[0409] Step 3. 4,4-Dimethyl-7-(3-methylbicyclo[1.1.1]pentan-1-yl)-7-oxohept-2-ennitrile (intermediate 38-3 ) was prepared according to the procedure described in Step 5 for Intermediate 36 using Intermediate 38-2 instead of Intermediate 36-4 . LC/MS (ESI) m/z 232.5 [M+H] ⁺ .

[0410] Step 4. 4,4-Dimethyl-7-(3-methylbicyclo[1.1.1]pentan-1-yl)-7-oxoheptanenitrile ( intermediate 38-4 ) was prepared according to the procedure described in step 6 for Intermediate 36 using Intermediate 38-3 instead of Intermediate 36-5 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.38-2.33 (m, 2H), 2.29-2.25 (m, 2H), 1.90 (s, 6H), 1.62- 1.58 (m, 2H), 1.48-1.44 (m, 2H), 1.19 (s, 3H), 0.90 (s, 6H).

[0411] Step 5. 5,5-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-ene-1-carbonitrile (intermediate 38-5 ) was obtained according to the procedure described in Step 4 for Intermediate 26 using Intermediate 38-4 instead of Intermediate 26-3 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.11-2.06 (m, 2H), 2.00-1.98 (m, 2H), 1.93 (s, 6H), 1.35 ( t, J = 6.4 Hz, 2H), 1.18 (s, 3H), 0.90 (s, 6H).

[0412] Step 6 5,5-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-carbaldehyde (intermediate 38-6 ) was prepared according to the procedure described in Step 5 for Intermediate 26 using Intermediate 38-5 instead of Intermediate 26-4 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.28 (s, 1H), 2.21-2.17 (m, 2H), 2.14 (br. s, 2H), 2.00 (s, 6H), 1.35 (t, J = 6.4 Hz, 2H), 1.20 (s, 3H), 0.88 (s, 6H).

[0413] Step 7. tert-Butyl 4-(4-((5,5-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzoate ( Intermediate 38-7 ) was prepared according to the procedure described in Step 9 from Intermediate 36 using Intermediate 38-6 instead of Intermediate 36-8 . LC/MS (ESI) m/z 465.6 [M+H] ⁺ .

[0414] Step 8 Intermediate 38 was prepared according to the procedure described in Step 10 from Intermediate 36 using Intermediate 38-7 instead of Intermediate 36-9 . LC/MS (ESI) m/z 409.6 [M+H] ⁺ .

Intermediate 39

4-(4-((4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0415] Step 1. To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (1.68 g, 7.6 mmol) and intermediate 22 (2.0 g, 9.15 mmol) in THF (20 ml) Na(OAc) ₃ BH (4.8 g, 22.8 mmol) was added at rt. After 16 hours, the reaction mixture was placed in an ice bath and quenched with sat. aq. NaHCO ₃ (25 ml). The reaction mixture was extracted with EtOAc (3×50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give methyl 4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex -1-en-1-yl)methyl)piperazin-1-yl)benzoate ( Intermediate 39-1 ) as a white solid (1.5 g, 46% yield). LC/MS (ESI) m/z 423.2 [M+H] ⁺ .

[0416] Step 2. Intermediate 39 was prepared according to the procedure described in Step 5, Route B for Intermediate 28, using Intermediate 39-1 in place of methyl 2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl) piperazin-1-yl)benzoate. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.25 (br. s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9, 0 Hz, 2H), 3.32-3.25(m, 4H), 3.03(s, 2H), 2.45-2.35(m, 4H), 2.06-2.04(m , 2H), 1.79 (s, 6H), 1.68 (s, 2H), 1.26 (t, J = 6.3 Hz, 2H), 1.12 (s, 3H), 0.85 (s, 6H); LC/MS (ESI) m/z 409.5 [M+H] ⁺ .

Intermediate 40

4-(4-((2-(3-Ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0417] Step 1. Methyl 4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)benzoate (Intermediate 40-1) was prepared according to the procedure described in Step 1 for Intermediate 39 using Intermediate 23 in place of Intermediate 22. LC/MS (ESI) m/z 437.3 [M +H] ⁺ .

[0418] Step 1. Intermediate 40 was prepared according to the procedure described in Step 2 for Intermediate 39, using Intermediate 40-1 instead of Intermediate 39-1 . LC/MS (ESI) m/z 423.3 [M+H] ⁺ .

Intermediate 41

4-(4-((4,4-Dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl )benzoic acid

[0419] Step 1 To a stirred solution of intermediate 25 (3.5 g, 12.85 mmol) in toluene was added titanium(IV) ethoxide (3.73 g, 16.36 mmol). After 30 min, a solution of methyl 4-(piperazin-1-yl)benzoate (2.35 g, 10.71 mmol) in toluene (20 ml) was added and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then cooled to 0°C, Na(OAc) ₃ BH (6.9 g, 32.72 mmol) was added and the reaction mixture was heated to rt. After 16 h the reaction mixture was quenched with water (100 ml) at 0°C and MTBE (200 ml) was added after 30 min. The reaction mixture was filtered through celite and the collected solid was washed with DCM (2 x 100 ml). The combined organic layers were washed with sat. aq. NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give methyl 4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate ( Intermediate 41-1) (3.2 g, 63% yield) as a white solid. LC/MS (ESI) m/z 477.3 [M+H] ⁺ .

[0420] Step 2 Intermediate 41 was prepared according to the procedure described in Step 2 for Intermediate 39 using Intermediate 41-1 instead of Intermediate 39-1 . LC/MS (ESI) m/z 463.2 [M+H] ⁺ .

Intermediate 42

4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl) benzoic acid

[0421] Step 1. Methyl 4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)benzoate (Intermediate 42-1) was obtained in accordance with the procedure described in step 1 forintermediate connection 39,usingintermediate connection 24 instead ofIntermediate 22.¹H NMR (400 MHz, DMSO-d ₆ ) δ 7.77 (d,J = 8.8 Hz, 2H), 6.97 (d,J = 8.8 Hz, 2H), 6.01 (t,J = 56.4 Hz, 1H), 3.77 (s, 3H), 3.35-3.20 (m, 4H), 3.00 (s, 2H), 2.42 (t,J = 4.4 Hz, 4H), 2.10-2.01 (m, 2H), 1.90 (s, 6H), 1.71 (s, 2H), 1.27 (t,J = 6.0 Hz, 2H), 0.86 (s, 6H); LC/MS (ESI)m/z 459.6 [M+H]⁺.

[0422] Step 1 Intermediate 42 was prepared according to the procedure described in Step 2 for Intermediate 39 using Intermediate 42-1 instead of Intermediate 39-1 . LC/MS (ESI) m/z 445.6 [M+H] ⁺ .

Intermediate 43

(R)-4-((4-Morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrobenzenesulfonamide

[0423] To a solution of ( R )-4-morpholino-1-(phenylthio)butan-2-amine dihydrochloride (900 mg, 2.6 mmol) in DMF (10 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (56 mg , 2.53 mmol) followed by DIPEA (5.8 ml, 33.8 mmol) at rt. The reaction mixture was then heated to 50°C for 4 h. The reaction mixture was cooled to rt, quenched with ice water (150 ml) and stirred at rt for 15 min. The mixture was then filtered and the collected solid washed with n -pentane to give Intermediate 43 (800 mg, 66%) as a yellow solid. LCMS (ESI) m/z 467.1 [M+H] ⁺ .

Intermediate 44

(R)-4-((4-(Dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

[0424] Intermediate 44 was prepared according to the procedure described in WO200861208A2. LC/MS (ESI) m/z 512.2 [M+H] ⁺ .

Intermediate 45

(R)-4-((4-(4-(Dimethylamino)piperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

[0425] Step 1 To a stirred solution of N,N -dimethylpiperidin-4-amine (462.5 mg, 3.61 mmol), DMAP (367.80 mg, 3.01 mmol) and EDC⋅HCl (863.75 mg, 4.51 mmol) in DCM (20 ml) was added (R)-4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butanoic acid (prepared according to with the procedure described in WO2012017251A1) (1.5 g, 3.01 mmol) and Et ₃ N (0.84 ml, 6.02 mmol) at rt. After 15 min, the reaction mixture was heated to 35°C and stirred for 16 h. The reaction mixture was then cooled to rt, diluted with DCM (100 ml) and MeOH (10 ml) and washed with 10% CH ₃ CO ₂ H (aq.) ( 2 × 20 ml). The organic layer was then washed with 5% NaHCO ₃ (aq.) (20 ml) and 5% NaCl (aq.) (20 ml) and concentrated. The crude product was purified by column chromatography (C18, CH ₃ CN/H ₂ O) to give (R)-4-((4-(4-(dimethylamino)piperidin-1-yl)-4-oxo-1-(phenylthio )butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide ( Intermediate 45-1 ) (686 mg, 37% yield). LC/MS (ESI) m/z 609.3 [M+H] ⁺ .

[0426] Step 2 To a stirred solution of intermediate 45-1 (800 mg, 1.31 mmol) in THF (15 ml) was added BH ₃ ⋅THF (1 M in THF, 6.57 ml, 6.57 mmol) at ct. The resulting reaction mixture was heated to 55°C for 24 h in a sealed tube. The reaction mixture was then cooled to rt and treated with MeOH (8 ml) and conc. HCl (2 ml) and heated to 65°C. After 10 hours the reaction mixture was concentrated, diluted with 2N NaOH and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (C18, CH ₃ CN/H ₂ O) to give intermediate 45 (490 mg, 62% yield). LC/MS (ESI) m/z 595.3 [M+H] ⁺ .

Intermediate 46

tert-Butyl (R)-4-(4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butyl)piperazine-1-carboxylate

[0427] Step 1. ( R ) -tert -Butyl 4-(4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)-amino)butanoyl)piperazine-1-carboxylate ( Intermediate 46-1 ) was prepared according to the procedure described in Step 1 for Intermediate 45 using tert- butyl piperazine-1-carboxylate instead of N,N -dimethylpiperidine-4-amine. LC/MS (ESI) m/z 665.4 [MH] ^- .

[0428] Step 2 Intermediate 46 was prepared according to the procedure described in Step 2 for Intermediate 45 using Intermediate 46-1 instead of Intermediate 45-1 . LC/MS (ESI) m/z 653.2 [M+H] ⁺ .

Intermediate 47

7-(Diethoxymethyl)spiro[3,5]nonan-6-one

[0429] To a solution of triethyl orthoformate (7.28 ml, 43.79 mmol) in DCM (10 ml) at -30° C.₃⋅OEt₂ (6.75 ml, 54.72 mmol) for 20 minutes. The reaction mixture was heated to 0°C and stirred for 20 min. The reaction mixture was then cooled to -78°C, spiro[3,5]nonan-6-one (3.0 g, 21.89 mmol) was added andN,N-diisopropylethylamine (11.4 ml, 35.7 mmol) and stirred for 90 minutes at the same temperature. The reaction mixture was then carefully poured into a mixture of sat. aq. NaHCO₃ (20 ml) and DCM (30 ml). The resulting mixture was stirred for 15 min at rt and the organic layer was separated. The organic layer was washed with cold 1 M H₂SO₄ (2 × 20 ml) and water. The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, Et₂O / petr. ether) to receiveIntermediate 47 (3.00 g, 57% yield) as a colorless oil. 1H NMR (400 MHz, CDCl₃) δ 4.78 (d,J = 6.4 Hz, 1H), 3.72-3.56 (m, 4H), 2.48-2.45 (m, 1H), 2.38 (d,J = 1.2 Hz, 1H), 2.35 (d,J = 0.8 Hz, 1H), 1.90-1.64 (m, 10H), 1.18 (t,J = 6.8 Hz, 6H).

Intermediate 48

7-(Diethoxymethyl)-6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)spiro[3,5]nonan-6-ol

[0430] Stage 1. To the mixed solutionIntermediate 24-2(4.67 g, 19.15 mmol) in Et₂O (30 ml) under argon atmosphere was added sec-BuLi (1.4 M in cyclohexane, 20.8 ml, 29.12 mmol) at -78°C and the reaction mixture was stirred for 10 minutes at the same temperature. The temperature was then heated to 0°C and stirred for 1 h. The reaction mixture was cooled to -78°C and a solution ofIntermediate 47 (2 g, 8.32 mmol) in Et₂O (20 ml) for 5 minutes. The reaction mixture was stirred at -78° C. for 1 h and then warmed to 0° C. and stirred for 1 h. The reaction mixture was quenched with sat. aq. NH solution₄Cl (50 ml) at 0°C and extracted with Et₂O (3 × 150 ml). The combined organic layers were dried over Na₂SO₄, filtered and concentrated to give 7-(diethoxymethyl)-6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)spiro[3,5]nonan-6-ol (Intermediate 48-1) (1.5 g, crude) as a yellow oil. It was used in the next step without further purification.

[0431] Step 2 To a stirred solution of intermediate 48-1 (1.5 g crude, 4.18 mmol) in 1,4-dioxane (30 ml) was added 2N HCl (aq.) (7 ml) and stirred the resulting the reaction mixture at 65-70°C for 16 hours the Reaction mixture was diluted with ice water (15 ml) and was extracted with Et ₂ O (3 × 100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by column chromatography (SiO ₂ , Et ₂ O/petr. ether) to give Intermediate 48 (1 g, 45% yield over 2 steps) as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.21 (s, 1H), 5.74 (t, J = 56.4 Hz, 1H), 2.22-2.19 (m, 2H), 2 .18 (s, 6H), 1.93-1.86 (m, 4H), 1.83-1.65 (m, 4H), 1.63-1.56 (m, 2H).

Intermediate 49

7-(Diethoxymethyl)-6-(3-methylbicyclo[1.1.1]pentan-1-yl)spiro[3,5]nonan-6-ol

[0432] Stage 1. 7-(Diethoxymethyl)-6-(3-methylbicyclo[1.1.1]pentan-1-yl)spiro[3,5]nonan-6-ol (intermediate 49-1) was obtained according to the procedure described in step 1 forintermediate connection 48using 1-iodo-3-methylbicyclo[1.1.1]pentane instead ofIntermediate 24-2.

[0433] Step 2 Intermediate 49 was prepared according to the procedure described in Step 2 for Intermediate 49 using Intermediate 49-1 instead of Intermediate 48-1 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.23 (s, 1H), 2.23-2.20 (m, 2H), 1.96 (s, 6H), 1.89-1.71 ( m, 8H), 1.58-1.55 (m, 2H), 1.16 (s, 3H).

Intermediate 50

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) spiro[3,5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid

[0434] Stage 1. Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)spiro[3.5]non-6-en-7 -yl)methyl)piperazin-1-yl)benzoate (intermediate 50-1) was obtained according to the procedure described in step 1, route C forintermediate connection 28usingintermediate connection 48 instead ofIntermediate 22. LC/MS (ESI)m/z 603.5 [M+H]⁺.

[0435] Step 2. Intermediate 50 was prepared according to the procedure described in Step 5, Route B for Intermediate 28, using Intermediate 50-1 in place of methyl 2-(( 1H -pyrrolo[2,3- b ] pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzoate. LC/MS (ESI) m/z 589.3.

Intermediate 51

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(3-methylbicyclo[1.1.1]pentan-1-yl)spiro[3 ,5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoic acid

[0436] Step 1. Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(3-methylbicyclo[1.1.1]pentan-1-yl )spiro[3,5]non-6-en-7-yl)methyl)piperazin-1-yl)benzoate (intermediate connection 51-1) was obtained according to the procedure described in step 1, route C forintermediate connection 28usingintermediate connection 49 instead ofIntermediate 22. LC/MS (ESI)m/z 567.3 [M+H]⁺.

[0437] Step 2. Intermediate 50 was prepared according to the procedure described in Step 5, Route B for Intermediate 28, using Intermediate 51-1 in place of methyl 2-(( 1H -pyrrolo[2,3- b ] pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzoate. LC/MS (ESI) m/z 553.3.

Intermediate 52

4-(((4-Fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide

[0438] To a stirred solution of (4-fluorotetrahydro- 2H -pyran-4-yl)methanamine (450 mg, 3.38 mmol) in THF (25 ml) was added 4-fluoro-3-nitrobenzenesulfonamide (669 mg, 3.38 mmol) 04 mmol) followed by triethylamine (1.37 g, 13.52 mmol) at rt. After 16 h, the reaction mixture was concentrated and triturated with EtOAc and Et ₂ O. The crude product was purified by column chromatography (C18, 0.1 μM NH ₄ CO ₃ H (aq.): CH ₃ CN) to give intermediate 52 (220 mg , 21% yield) as a yellow solid. LC/MS (ESI) m/z 334.3 [M+H] ⁺ .

Intermediate 53

4-((4-Fluoro-tetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

[0439] Intermediate 53received in accordance with the procedure described in step 3 forintermediate 7,using (4-fluorotetrahydro-2H-pyran-4-yl)methanol instead ofintermediate compound 7-2.LC/MS (ESI)m/z 333.5[M-H]^-.

Intermediate 54

4-((2-Morpholinoethyl)amino)-3-nitrobenzenesulfonamide

[0440] Intermediate 54 was prepared according to the procedure described in WO2010/065824. LC/MS (ESI) m/z 331.2 [M+H] ⁺ .

Intermediate 55

3-Nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

[0441] Intermediate 55received in accordance with the procedure described in step 3 forintermediate 7,using (tetrahydro-2H-pyran-4-yl)methanol instead ofintermediate compound 7-2.LC/MS (ESI) m/z 315.1 [M-H]^-.

Intermediate 56

4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl) benzoic acid

[0442] Step 1. 2-(Diethoxymethyl)-1-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohexanol ( Intermediate 56-1 ) was obtained according to the procedure described in Step 1 for Intermediate 25 using Intermediate 24-2 in place of 1-iodo-3(trifluoromethyl)bicyclo[1.1.1]pentane and 2-(diethoxymethyl)-4,4-dimethylcyclohexanone in place of Intermediate 19 . The crude product was used in the next step without purification.

[0443] Step 2. 2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-enecarbaldehyde (intermediate 56-2) received in accordance with the procedure described in step 2 forIntermediate 22usingintermediate 56-1 instead ofIntermediate 22-1.¹H NMR (400 MHz, CDCl₃) δ 10.25 (br. s, 1H), 5.74 (t,J=56.0 Hz, 1H), 2.23-2.21 (m, 2H), 2.20 (s, 6H), 2.03 (br. s, 2H), 1.38 (t,J=6.4 Hz, 2H), 0.89 (s, 6H).

[0444] Step 3 To a stirred solution of methyl 4-(piperazin-1-yl)benzoate (389 mg, 1.77 mmol) in THF (10 mL) was added a solution of Intermediate 56-2 (450 mg, 1.77 mmol ) in THF (5 ml) at rt. The reaction mixture was stirred for 1 h, treated with Na(OAc) ₃ BH (1.12 g, 5.31 mmol) at 0°C and then heated to rt. After 16 hours, MeOH (10 ml) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in DCM (20 ml) and washed with sat. aq. NaHCO ₃ (3 × 10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , EtOAc/pet. ether) to give methyl 4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5.5 -dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoate ( Intermediate 56-3 ) (400 mg, 49% yield) as off-white solid. LC/MS (ESI) m/z 459.2 [M+H] ⁺ .

[0445] Step 4. Intermediate 56 was prepared according to the procedure described in Step 5, Route B for Intermediate 28 using Intermediate 56-3 instead of methyl 2-(( 1H -pyrrolo[2,3- b ] pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzoate. LC/MS (ESI) m/z 445.4 [M+H] ⁺ .

Intermediate 57

(R)-4-((4-(3-Hydroxyazetidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

[0446] Step 1. To a solution of ( R )-4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butanoic acid (1.5 g, 3.01 mmol N -methylmorpholine (1.3 ml, 9.3 mmol) and DMF (1.5 ml). The reaction mixture was heated to rt and stirred for 0.5 h. The reaction mixture was then cooled to 0°C, azetidin-3-ol (264 mg, 3.61 mmol) was added and the reaction mixture was heated to rt. After 16 hours the reaction mixture was quenched with sat. aq. NaHCO ₃ (50 ml) and extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , MeOH/DCM) to give ( R )-4-((4-(3-hydroxyazetidin-1-yl)-4-oxo-1-(phenylthio)butan-2-yl )amino)-3-((trifluoro-methyl)sulfonyl)benzenesulfonamide ( intermediate 57-1 ) (1.00 g, 60% yield) as an off-white solid. LC/MS (ESI) m/z 554.1.

[0447] Step 2. To a stirred solution of intermediate 57-1 (1.0 g, 1.80 mmol) in THF (20 ml) at 0°C was added BH ₃ ⋅THF (1 M in THF, 5.0 ml , 5 mmol) and heated the reaction mixture to rt. After 1 h, the reaction mixture was heated to 55°C and stirred for 16 h in a sealed tube. The reaction mixture was then cooled to 0°C, quenched with NH ₃ (7.0 M in MeOH, 5 ml) at 0°C and heated to rt. After 16 hours, the reaction mixture was concentrated and purified by column chromatography (SiO ₂ , MeOH/DCM) to give Intermediate 57 (500 mg, 51% yield) as an off-white solid. LC/MS (ESI) m/z 540.3 [M+H] ⁺ .

Intermediate 58

4-(4-((6-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)spiro[3,5]non-6-en-7-yl)methyl)piperazin-1-yl )benzoic acid

[0448] Step 1. Methyl 4-(4-((6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)spiro[3.5]non-6-en-7-yl) methyl)piperazin-1-yl)benzoate ( Intermediate 58-1 ) was prepared according to the procedure described in Step 3 for Intermediate 56 using Intermediate 48 instead of Intermediate 56-2. LC/MS (ESI) m/z 471.3 [M+H] ⁺ .

[0449] Step 2. Intermediate 58 was prepared according to the procedure described in Step 5, Route B for Intermediate 28 using Intermediate 58-1 in place of methyl 2-((1 H -pyrrolo[2,3- b ] pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzoate. LC/MS (ESI) m/z 457.5 [M+H] ⁺ .

Intermediate 59

(R)-4-((4-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-( (trifluoromethyl)sulfonyl)benzenesulfonamide

[0450] Step 1. (R )-4-((4-(4-(2-(( tert- Butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)-4-oxo-1-(phenylthio)butan- 2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide ( Intermediate 59-1 ) was prepared according to the procedure described in Step 1 for Intermediate 45 using 1-(2-(( tert- butyldiphenylsilyl) hydroxy)ethyl)piperazine instead of N,N -dimethylpiperidin-4-amine. LC/MS (ESI) m/z 849.3 [M+H] ⁺ .

[0451] Step 2 Intermediate 59 was prepared according to the procedure described in Step 2 for Intermediate 57 using Intermediate 59-1 instead of Intermediate 57-1 . LC/MS (ESI) m/z 835.0 [M+H] ⁺ .

Intermediate 60

(R)-4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide

[0452] Step 1 2-((tert-Butyldiphenylsilyl)oxy) -N -ethylethanamine ( intermediate 60-1 ) was prepared according to the procedure described in WO2012/017251A1. LC/MS (ESI) m/z 328.4 [M+H] ⁺ .

[0453] Stage 2. To the mixed solution (R)-4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butanoic acid (500 mg, 1.0 mmol) in CH₃CN (10 ml) at 0°C was addedintermediate 60-1 (328 mg, 1.01 mmol) in CH₃CN (2 ml) followed byN-methyl imidazole (250 mg, 3.1 mmol) and hexafluorophosphateN,N,N',N'-tetramethylchloroformamidinium (TCFH) (308 mg, 1.1 mmol). The reaction mixture was heated to rt and stirred for 16 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×100 ml). The combined organic layers were washed with sat. aq. NaHCO₃ (2 x 20 ml), water (2 x 10 ml) and then saline (2 x 20 ml). The organic layer was dried over Na₂SO₄, filtered and concentrated. The crude product was purified by column chromatography (SiO₂, EtOAc / Petr. ether) with receiving (R)-N-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-N-ethyl-4-(phenylthio)-3-((4-sulfamoyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)butanamide (intermediate 60-2) (500 mg, 65% yield) as a yellow oil. LC/MS (ESI)m/z 808.4 [M+H]⁺.

[0454] Step 2 Intermediate 60 was prepared according to the procedure described in Step 2 for Intermediate 57 using Intermediate 60-2 instead of Intermediate 57-1 . LC/MS (ESI) m/z 794.8 [M+H] ⁺ .

Intermediate 61

4-(((2 R )-4-(3-Hydroxypyrrolidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide

[0455] Step 1. 4-(((2 R )-4-(3-Hydroxypyrrolidin-1-yl)-4-oxo-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl )sulfonyl)benzenesulfonamide ( Intermediate 61-1 ) was prepared according to the procedure described in Step 1 for Intermediate 45 using pyrrolidin-3-ol instead of N,N -dimethylpiperidin-4-amine. LC/MS (ESI) m/z 568.1 [M+H] ⁺ .

[0456] Step 2 Intermediate 61 was prepared according to the procedure described in Step 2 for Intermediate 57 using Intermediate 61-1 instead of Intermediate 57-1 . LC/MS (ESI) m/z 554.4 [M+H] ⁺ .

Intermediate 62

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)cyclohex-1 -en-1-yl)methyl)piperazin-1-yl)benzoic acid

[0457] Step 1. 1-(3-Chlorobicyclo[1.1.1]pentan-1-yl)hex-5-en-1-one ( Intermediate 62-1 ) was prepared according to the procedure described in Step 1 for intermediate 26 using 5-bromopent-1-ene instead of 5-iodo-3,3-dimethylpent-1-ene. ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.84-5.66 (m, 1H), 5.03-4.97 (m, 2H), 2.48 (s, 6H), 2.44 ( t, J = 7.2 Hz, 2H), 2.08-2.01 (m, 2H), 1.71-1.61 (m, 2H).

[0458] Step 2 E/Z- 7-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-7-oxohept-2-ennitrile (intermediate 62-2) was prepared according to the procedure described on step 2 for intermediate 26 , using intermediate 62-1 instead of intermediate 26-1 . LC/MS (ESI) m/z 236.3 [M+H] ⁺ .

[0459] Step 3. 7-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-7-oxoheptanenitrile ( intermediate 62-3) was prepared according to the procedure described in step 3 for intermediate 26 using intermediate 62-2 instead of intermediate 26-2 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.47 (t, J = 7.2 Hz, 2H), 2.40 (s, 6H), 2.35 (t, J = 6.8 Hz, 2H ), 1.70-1.62(m, 2H), 1.61-1.55(m, 2H), 1.48-1.41(m, 2H).

[0460] Step 4. 2-(3-Chlorobicyclo[1.1.1]pentan-1-yl)cyclohex-1-enecarbonitrile ( intermediate 62-4 ) was prepared according to the procedure described in step 4 for intermediate 26 , using Intermediate 62-3 instead of Intermediate 26-3 . LC/MS (ESI) m/z 208.1 [M+H] ⁺ .

[0461] Step 5. 2-(3-Chlorobicyclo[1.1.1]pentan-1-yl)cyclohex-1-enecarbaldehyde ( intermediate 62-5) was prepared according to the procedure described in step 5 for intermediate 26 , using Intermediate 62-4 instead of Intermediate 26-4 . ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.16 (s, 1H), 2.46 (s, 6H), 2.23-2.21 (m, 2H), 2.15-2.13 ( m, 2H), 1.64-1.54 (m, 4H).

[0462] Stage 6tert-Butyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate (intermediate 62-6) received in accordance with the procedure described in step 6, route A forintermediate connection 28usingintermediate connection 62-5instead ofIntermediate 22. LC/MS (ESI)m/z 589.3 [M+H]⁺.

[0463] Step 7. Intermediate 62 was prepared according to the procedure described in Step 7 for Intermediate 32 using Intermediate 62-6 instead of Intermediate 32-6. LC/MS (ESI) m/z 533.3 [M+H] ⁺ .

General Procedure A. Preparation of Acylsulfonamide

[0464] EDC⋅HCl (1-2 , 5 equiv.), followed by DMAP (1-2 equiv.). After 10 minutes, the appropriate acid A or sulfonamide B (1-1.5 equiv. note 1) and N- methylmorpholine (2-4 equiv. note 2) were added at 0°C and the reaction mixture was heated to rt or 35°C. After completion of the reaction according to LCMS (or TLC), water was added and the reaction mixture was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude product C was purified either by 1) column chromatography (SiO ₂ ), 2) HPLC (10 mM NH ₄ CO ₃ H(aq): CH ₃ CN or MeOH) or 3) trituration with an organic solvent.

[0465] Note 1: TFA salt of acid A was used in some cases.

[0466] Note 2: In some cases, N- methylmorpholine was not added.

General Procedure B. Preparation of Acylsulfonamide

[0467] EDC⋅HCl (1.5-1.75 equiv.) and DMAP (1-2, 5 equiv.). In a separate flask, the appropriate acid A (1-1.1 equiv.) was dissolved in DCM (0.02-0.1 M) and treated with Et ₃ N (2 equiv.). Note 1). After 15 min, the acid solution was added to the sulfonamide suspension and either stirred at rt or heated to 35°C. After completion of the reaction according to LCMS, N , N -dimethylethylenediamine (2-2.5 equiv., note 2) was added to the reaction mixture and the reaction mixture was stirred for 90 minutes. The reaction mixture was further washed with 10% aq. AcOH (Note 3), 5% NaHCO ₃ (aq) and then 5% NaCl (aq). The organic layer was concentrated and the crude product C was purified either by 1) column chromatography (SiO ₂ ), 2) HPLC (10 mM NH ₄ CO ₃ H (aq): CH ₃ CN or MeOH) or 3) trituration with an organic solvent.

[0468] Note 1: In some cases, Et ₃ N was added to the flask containing sulfonamide B.

[0469] Note 2: In some cases, N , N -dimethylethylenediamine was not added during processing.

[0470] Note 3: In some cases, the organic layer was diluted with DCM and MeOH to solubilize the crude product.

Example 1

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yl-oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-yl)methyl)piperazin-1-yl)- N -(3-nitro-4-((tetrahydro- 2H- pyran-4-yl)methylamino)phenylsulfonyl)benzamide

[0471] Representative Example of General Procedure A. To a solution of 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (63 mg, 0.20 mmol) in DCM (20 mL) EDC⋅HCl (58 mg, 0.30 mmol) was added followed by DMAP (49 mg, 0.40 mmol) at 0°C. After 10 min , intermediate 26 (140 mg, 0.20 mmol) and N -methylmorpholine (0.07 ml, 0.60 mmol) were added and the reaction mixture was heated to rt. After 16 hours, water was added and the mixture was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by HPLC (10:90-99:1 10 mM NH ₄ CO ₃ H(aq)/CH ₃ CN) to give Example 1 (69 mg, 39%) as a yellow solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.68 (br. s, 1H), 11.42 (br. s, 1H), 8.58 (br. s, 1H), 8.53 ( s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.54-7.46 (m, 3H), 7.10-7.02(m, 1H), 6.74-6.68(m, 1H), 6.38(s, 1H), 6.25(s, 1H), 3.89-3, 82 (m, 2H), 3.33-3.22 (m, 4H), 3.19-3.05 (m, 4H), 2.90 (s, 2H), 2.33 (br. s, 4H), 2.29 (s, 6H), 2.05-1.95 (m, 2H), 1.95-1.82 (m, 1H), 1.69-1.57 (m, 4H) , 1.32-1.18 (m, 4H), 0.82 (s, 6H); LC/MS (ESI) m/z 858.4 [M+H] ⁺ .

Example 2

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yl-oxy)- N -(4-(2-oxaspiro[3,3]heptan-6-yl-methylamino)-3-nitrophenylsulfonyl) -4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-yl)methyl)piperazin-1-yl)benzamide

[0472] Example 2 was prepared according to General Procedure A using Intermediate 26 and Intermediate 3 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.13 (br. s, 1H), 8.89 (d, J = 2 Hz, 1H), 8.82 (br. s, 1H), 8.33 (t, J = 5.2 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 9.4, 1.6 Hz, 1H), 7 .98 (d, J = 9.6 Hz, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.44 (br. s, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.59-6.56 (m, 2H), 6.02 (s, 1H), 4.74 (s, 2H), 4.63 (s, 2H), 3, 32 (t, J = 5.2 Hz, 2H), 3.15-3.05 (m, 4H), 2.89 (s, 2H), 2.55-2.45 (m, 2H), 2 .38-2.28 (m, 4H), 2.25 (s, 6H), 2.08-1.95 (br. s, 4H), 1.64 (s, 2H), 1.33-1 .25 (m, 2H), 0.84 (s, 6H); LC/MS (ESI) m/z 870.6 [M+H] ⁺ .

Example 3

2-((1 H -Pyrrolo[2,3- b ]pyridin-5-yl)oxy)- N -((4-((2-(2-oxa-8-azaspiro[4,5]decan-8 -yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en- 1-yl)methyl)piperazin-1-yl)benzamide

[0473] Example 3 was prepared according to General Procedure A using Intermediate 26 and Intermediate 4 . ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.18 (br. s, 1H), 9.21 (br. s, 1H), 8.99 (br. s, 1H), 8.88 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.16 (dd, J = 9.0, 1.8 Hz, 1H), 7.97 ( d, J = 8.7 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.45 (t, J = 3.0 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.60-6.54 (m, 2H), 6.03 (d, J = 1.8 Hz, 1H), 3.85 (t, J = 7.2 Hz, 2H), 3.57 (s, 2H), 3.42-3.36 (m, 2H), 3.10 (br. s, 4H), 2.89 (s, 2H), 2.71 (t, J = 5.7 Hz, 2H), 2.58-2.38 (m, 4H), 2.38-2.29 (m, 4H), 2.24 (s, 6H), 2, 06-1.95 (m, 2H), 1.77-1.63 (m, 8H), 1.27-1.23 (m, 2H), 0.83 (s, 6H); LC/MS (ESI) m/z 927.6 [M+H] ⁺ .

Example 4

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)- N -(4-(2-(7-oxa-2-azaspiro[3,5]nonan-2-yl)ethylamino) -3-nitrophenylsulfonyl)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

[0474] Example 4 was prepared according to General Procedure A using Intermediate 26 and Intermediate 5 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.50 (br. s, 1H), 8.46 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.45 (t, J = 2, 4 Hz, 1H), 7.38 (br. s, 1H), 6.93 (d, J = 9.2 Hz, 1H), 6.69 (dd, J = 9.4, 2.0 Hz, 1H), 6.34 (dd, J = 3.2, 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 3.60-3.38 (m, 10H ), 3.16-2.95 (m, 6H), 2.89 (s, 2H), 3.38-2.30 (m, 4H), 2.29 (s, 6H), 2.05- 1.98 (m, 2H), 1.71-1.66 (m, 6H), 1.23 (t, J = 6.4 Hz, 2H), 0.82 (s, 6H), one NH proton not observed; ¹ H NMR (400 MHz, DMSO-d ₆ ) LC/MS (ESI) m/z 913.5 [M+H] ⁺ .

Example 5

2-((1 H -Pyrrolo[2,3- b ]pyridin-5-yl)oxy)- N -((4-(((7-oxaspiro[3,5]nonan-2-yl)methyl)amino )-3-nitrophenyl)sulfonyl)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl) piperazin-1-yl)benzamide

[0475] Example 5 was prepared according to General Procedure A using Intermediate 26 and Intermediate 6 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.13 (br. s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.81 (br. s, 1H), 8 .37 (t, J = 4.8 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 9.6, 2.4 Hz, 1H) , 7.97 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.8 Hz, 1H), 7.44 (t, J = 2.8 Hz, 1H), 6 .88 (d, J = 9.6 Hz, 1H), 6.59-6.54 (m, 2H), 6.01 (d, J = 2.0 Hz, 1H), 3.64 (t, J = 4.8 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.39-3.36 (m, 2H), 3.10 (br. s, 4H), 2.89 (s, 2H), 2.70-2.65 (m, 1H), 2.32 (br. s, 4H), 2.24 (s, 6H), 2.14-2.09 ( m, 2H), 2.01 (br. s, 2H), 1.68 (t, J = 5.2 Hz, 2H), 1.63-1.56 (m, 6H), 1.25 (t , J = 6.0 Hz, 2H), 0.83 (s, 6H); LC/MS (ESI) m/z 898.4 [M+H] ⁺ .

Example 6

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((4-oxaspiro[2,4]heptan-6-yl)oxy)-3- nitrophenyl)sulfonyl)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1- yl)benzamide

[0476] Example 6 was prepared according to General Procedure A using Intermediate 26 and Intermediate 7 . LC/MS (ESI) m/z 857.4 [M+H] ⁺ .

Example 7

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)- N -(4-(2-(2-oxa-6-azaspiro[3,3]heptan-6-yl)ethoxy) -3-nitrophenylsulfonyl)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

[0477] Example 7 was prepared according to General Procedure A using Intermediate 26 and Intermediate 8 . LC/MS (ESI) m/z 886.5 [M+H] ⁺ .

Example 8

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)- N -(4-(2-oxaspiro[3,3]heptan-6-ylmethoxy)-3-nitrophenylsulfonyl)-4-( 4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

[0478] Example 8 was prepared according to General Procedure A using Intermediate 26 and Intermediate 9 . LC/MS (ESI) m/z 871.6 [M+H] ⁺ .

Example 9

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl )cyclohex-1-enyl)methyl)piperazin-1-yl)- N -(3-nitro-4-((tetrahydro- 2H -pyran-4-yl)methylamino)phenylsulfonyl)benzamide

[0479] Example 9 was prepared according to general procedure A using intermediate 28 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 11.42 (br. s, 1H), 8.58 (br. s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.80-7.76 (m, 1H), 7.53-7.48 (m, 3H), 7.12-7.05 (m, 1H) , 6.74-6.70(m, 1H), 6.38(s, 1H), 6.25(s, 1H), 3.85-3.83(m, 2H), 3.30-3 .23 (m, 4H), 3.19-3.05 (m, 4H), 2.99 (br. s, 2H), 2.38-2.32 (m, 4H), 2.05-1 .95 (m, 2H), 1.93-1.85 (m, 1H), 1.75 (s, 6H), 1.67-1.58 (m, 4H), 1.30-1.20 (m, 4H), 1.10 (s, 3H), 0.81 (s, 6H); LC/MS (ESI) m/z 838.5 [M+H] ⁺ .

Example 10

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((2-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4,4- dimethylcyclohex-1-enyl)methyl)piperazin-1-yl) -N- (3-nitro-4-((tetrahydro- 2H -pyran-4-yl)methylamino)phenylsulfonyl)benzamide

[0480] Example 10 was prepared according to general procedure A using intermediate 27 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.20 (br. s, 2H), 9.09 (br. s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8 .52 (t, J = 5.7 Hz, 1H), 8.22-8.15 (m, 2H), 7.98 (d, J = 9.3 Hz, 1H), 7.71 (d, J = 9.3 Hz, 1H), 7.45 (t, J = 3.0 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 6.60-6.54 ( m, 2H), 6.03-6.01 (m, 1H), 4.03 (dd, J = 11.5, 3.9 Hz, 2H), 3.46-3.38 (m, 2H) , 3.27 (t, J = 6.0 Hz, 2H), 3.12-3.09 (m, 4H), 2.91 (s, 2H), 2.35-2.33 (m, 4H ), 2.15 (d, J = 2.4 Hz, 6H), 2.09-1.95 (m, 3H), 1.77-1.62 (m, 4H), 1.51-1, 38 (m, 2H), 1.27 (t, J = 6.3 Hz, 2H), 0.84 (s, 6H); LC/MS (ESI) m/z 842.4 [M+H] ⁺ .

Example 11

2-((1 H -Pyrrolo[2,3- b ]pyridin-5-yl)oxy)- N -((4-(((7-oxaspiro[3,5]nonan-2-yl)methyl)amino )-3-nitrophenyl)sulfonyl)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl )piperazin-1-yl)benzamide

[0481] Example 11 was prepared according to General Procedure A using Intermediate 28 and Intermediate 6 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.15 (br. s, 1H), 9.16 (br. s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8 .37 (t, J = 4.8 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.17 (dd, J = 9.0, 2.0 Hz, 1H) , 7.97 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 6 .89 (d, J = 9.6 Hz, 1H), 6.60-6.54 (m, 2H), 6.02 (d, J = 2.0 Hz, 1H), 3.64 (t, J = 5.2 Hz, 2H), 3.56 (t, J = 5.2 Hz, 2H), 3.38 (dd, J = 7.0, 5.2 Hz, 2H), 3.10 ( t, J = 4.8 Hz, 4H), 3.00 (s, 2H), 2.71-2.64 (m, 1H), 2.35 (t, J = 4.8 Hz, 4H), 2.15-2.09 (m, 2H), 2.01-1.98 (m, 2H), 1.73 (s, 6H), 1.68 (t, J = 5.2 Hz, 2H) , 1.66-1.56 (m, 6H), 1.24 (t, J = 6.4 Hz, 2H), 1.10 (s, 3H), 0.82 (s, 6H); LC/MS (ESI) m/z 878.6 [M+H] ⁺ .

Example 12

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1 -yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl) benzamide

[0482] To a stirred solution of intermediate 28 (150 mg, 0.277 mmol) in DMF (1 ml) at 0°C was added EDC⋅HCl (106.2 mg, 0.554 mmol) and 1-hydroxy-7-azabenzotriazole (75, 4 mg, 0.554 mmol). After 10 min , intermediate 14 (92 mg, 0.277 mmol) and DIPEA (108 mg, 0.83 mmol) were added and the reaction mixture was heated to rt. After 48 h, water (10 ml) was added and the reaction mixture was extracted with DCM (3 x 10 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by HPLC (30:70-1:99, 10 mM NH ₄ CO ₃ H(aq) : CH ₃ CN) to give Example 12 as a yellow solid (6 mg, 3% yield). LC/MS (ESI) m/z 851.4 [M+H] ⁺ .

Example 13

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo [1.1.1]pentan-1 -yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluoro-1-methylpiperidin-4-yl)methyl)amino)-3- nitrophenyl)sulfonyl)benzamide

[0483] Example 13 was prepared according to General Procedure A using Intermediate 28 and Intermediate 15 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (br. s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.66 (t, J = 5.2, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 9.2, 1.6 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 6.59 (dd, J = 9.2, 2.4 Hz, 1H), 6.54 (dd, J = 3.6, 2.0 Hz, 1H), 6.04 (d, J = 2.4 Hz, 1H), 3.52 (dd, J = 19.6, 6.0 Hz, 2H), 3.11 (t, J = 4.8 Hz, 4H), 2.99 (s , 2H), 2.82-2.75 (m, 2H), 2.41-2.31 (m, 8H), 2.06-1.97 (m, 4H), 1.74 (s, 6H ), 1.65 (s, 2H), 1.33-1.22 (s, 5H), 1.10 (s, 3H), 0.82 (s, 6H). One NH proton was not observed; LC/MS (ESI) m/z 869.5 [M+H] ⁺ .

Example 14

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1 -yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-3-nitrophenyl) sulfonyl)benzamide

[0484] Example 14 was prepared according to General Procedure A using Intermediate 28 and Intermediate 16 . LC/MS (ESI) m/z 865.5 [M+H] ⁺ .

Example 15

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo

[1.1.1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl) -N- (4-((4-fluorotetrahydro- 2H- pyran-4-yl)methylamino)-3 -nitrophenylsulfonyl)benzamide

[0485] Example 15 was prepared according to General Procedure A using Intermediate 28 and Intermediate 52 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.16 (br. s, 1H), 8.97 (br. s, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8 .67 (t, J = 5.6 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 9.0, 2.4 Hz, 1H) , 7.97 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 6 .98 (d, J = 9.2 Hz, 1H), 6.59 (dd, J = 9.0, 2.4 Hz, 1H), 6.55 (dd, J = 3.2, 2.0 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 3.89 (dd, J = 11.8, 4.0 Hz, 2H), 3.79-3.72 (m , 2H), 3.55 (dd, J = 19.6, 6.0 Hz, 2H), 3.11-3.09 (m, 4H), 3.00 (s, 2H), 2.36- 2.33 (m, 4H), 2.05-1.95 (m, 2H), 1.94-1.75 (m, 4H), 1.74 (s, 6H), 1.64 (s, 2H), 1.24 (t, J = 6.4 Hz, 2H), 1.10 (s, 3H), 0.82 (s, 6H); LC/MS (ESI) m/z 856.5 [M+H] ⁺ .

Example 16

2-((1 H -Pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan- 1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)- N -((4-((4-fluorotetrahydro-2 H -pyran-4-yl)methoxy)-3-nitrophenyl )sulfonyl)benzamide

[0486] Example 16 was prepared according to General Procedure A using Intermediate 28 and Intermediate 53 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.16 (br. s, 1H), 8.85 (br. s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8 .38 (dd, J = 9.2, 2.4 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H) , 7.70 (d, J = 2.8 Hz, 1H), 7.45 (t, J = 2.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6 .60-6.54 (m, 2H), 6.01 (d, J = 2.0 Hz, 1H), 4.18 (d, J = 18.0 Hz, 2H), 3.91-3, 87 (m, 2H), 3.81-3.74 (m, 2H), 3.12-3.10 (m, 4H), 2.99 (s, 2H), 2.36-2.34 ( m, 4H), 2.01-1.83 (m, 6H), 1.74 (s, 6H), 1.65 (s, 2H), 1.24 (t, J = 6.0 Hz, 2H ), 1.10 (s, 3H), 0.82 (s, 6H); LC/MS (ESI) m/z 857.5 [M+H] ⁺ .

Example 17

2-((1 H -Pyrrolo[2,3- b ]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan- 1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)- N -((4-(((4-methylmorpholin-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl )benzamide

[0487] Example 17 was prepared according to General Procedure A using Intermediate 28 and Intermediate 17 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.16 (br. s, 1H), 8.97 (br. s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8 .65 (t, J = 5.6 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 9.0, 2.4 Hz, 1H) , 7.96 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.43 (t, J = 2.8 Hz, 1H), 6 .88 (d, J = 9.2 Hz, 1H), 6.58 (dd, J = 9.2, 2.0 Hz, 1H), 6.55 (dd, J = 3.6, 2.0 Hz, 1H), 6.03 (d, J = 2.0 Hz, 1H), 3.95 (d, J = 10.4 Hz, 1H), 3.90-3.84 (m, 1H), 3.73 (dt, J = 11.4, 2.4 Hz, 1H), 3.49-3.36 (m, 2H), 3.12-3.09 (m, 4H), 2.99 ( s, 2H), 2.77 (d, J = 11.2 Hz, 1H), 2.67 (d, J = 11.6 Hz, 1H), 2.36-2.33 (m, 4H), 2.32 (s, 3H), 2.19 (dt, J = 11.4, 3.2 Hz, 1H), 2.03-1.98 (m, 3H), 1.74 (s, 6H) , 1.65 (s, 2H), 1.24 (t, J = 6.4 Hz, 2H), 1.10 (s, 3H), 0.82 (s, 6H); LC/MS (ESI) m/z 853.5 [M+H] ⁺ .

Example 18

(R)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1 ]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3- nitrophenyl)sulfonyl)benzamide

[0488] Example 18 was prepared according to General Procedure A using Intermediate 28 and Intermediate 17A . LC/MS (ESI) m/z 853.5 [M+H] ⁺ . The absolute stereochemistry is set arbitrarily.

Example 19

(S)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1 ]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)-3- nitrophenyl)sulfonyl)benzamide

[0489] Example 19 was prepared according to General Procedure A using Intermediate 28 and Intermediate 17B . LC/MS (ESI) m/z 853.6 [M+H] ⁺ . The absolute stereochemistry is set arbitrarily.

Example 20

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl )cyclohex-1-enyl)methyl)piperazin-1-yl)- N -(4-((( 1r , 4r )-4-hydroxy-4-methylcyclohexyl)methylamino)-3-nitrophenylsulfonyl)benzamide

[0490] Example 19 was prepared according to General Procedure A using Intermediate 28 and Intermediate 18 . LC/MS (ESI) m/z 866.5 [M+H] ⁺ .

Example 21

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl )cyclohex-1-enyl)methyl)piperazin-1-yl) -N- (4-(2-morpholinoethylamino)-3-nitrophenylsulfonyl)benzamide

[0491] Example 21 was prepared according to General Procedure A using Intermediate 28 and Intermediate 54 . LC/MS (ESI) m/z 853.6 [M+H] ⁺ .

Example 22

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl )cyclohex-1-enyl)methyl)piperazin-1-yl)- N -(3-nitro-4-((tetrahydro- 2H -pyran-4-yl)methoxy)phenylsulfonyl)benzamide

[0492] Representative Example of General Procedure B. To a stirred solution of intermediate 55 (70.03 mg, 0.22 mmol) in DCM (5 ml) was added DMAP (54.02 mg, 0.44 mmol) and EDC⋅HCl ( 63.15 mg, 0.33 mmol) and DCM (5 ml). In a separate flask , intermediate 28 (120 mg, 0.222 mmol), Et ₃ N (0.046 ml, 0.44 mmol) and DCM (3 ml) were combined and stirred for 15 minutes. The solution containing the acid was then slowly added to the sulfonamide suspension and the reaction mixture was stirred at rt. After 20 hours , N,N- dimethylethylenediamine (0.055 ml) was added to the reaction mixture and stirring was continued for 90 minutes. The reaction mixture was then washed with 10% acetic acid solution (2×10 ml). Note. The organic layer was diluted with DCM (10 ml) and MeOH (3 ml) before the final separation of the aqueous layer. The organic layer was washed with 5% NaHCO ₃ (aq.) (10 ml), 5% NaCl(aq.) (10 ml) and concentrated the organic layer. The crude product was purified by HPLC (30:70-1:99 10 mM NH ₄ CO ₃ H (aq): CH ₃ CN) to give Example 22 (55 mg, 30% yield) as a white solid. LC/MS (ESI) m/z 839.6 [M+H] ⁺ .

Example 23

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4,4- dimethylcyclohex-1-enyl)methyl)piperazin-1-yl) -N- (3-nitro-4-((tetrahydro- 2H -pyran-4-yl)methylamino)phenylsulfonyl)benzamide

[0493] Example 23 was prepared according to General Procedure B using intermediate 29 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.69 (s, 1H), 11.40 (br. s, 1H), 8.59 (br. s, 1H), 8.54 (s, 1H), 8.03 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.56-7.48 (m, 3H), 7.07 (d, J = 8 .8 Hz, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.26 (s, 1H), 3.85 (d, J = 11 .2 Hz, 2H), 3.33-3.23 (m, 4H), 3.20-3.05 (m, 4H), 3.05-2.94 (m, 2H), 2.41- 2.28 (m, 4H), 2.05-1.95 (m, 2H), 1.94-1.81 (m, 1H), 1.70 (s, 6H), 1.66-1, 59 (m, 4H), 1.38 (k, J = 7.6 Hz, 2H), 1.31-1.19 (m, 4H), 0.82 (s, 6H), 0.78 (t , J = 8.0 Hz, 3H); LC/MS (ESI) m/z 852.5 [M+H] ⁺ .

Example 24

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4,4- dimethylcyclohex-1-enyl)methyl)piperazin-1-yl) -N- (4-((4-fluoro-1-methylpiperidin-4-yl)methylamino)-3-nitrophenylsulfonyl)benzamide

[0494] Example 24 was prepared according to General Procedure B using Intermediate 29 and Intermediate 15 . LC/MS (ESI) m/z 883.9 [M+H] ⁺ .

Example 25

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl )sulfonyl)benzamide

[0495] Example 25 was prepared according to General Procedure B using Intermediate 29 and Intermediate 52 . LC/MS (ESI) m/z 870.8 [M+H] ⁺ .

Example 26

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl)sulfonyl) benzamide

[0496] Example 26 was prepared according to General Procedure B using Intermediate 29 and Intermediate 53 . LC/MS (ESI) m/z 871.7 [M+H] ⁺ .

Example 27

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3 -nitrophenyl)sulfonyl)benzamide

[0497] Example 27 was prepared according to General Procedure B using Intermediate 29 and Intermediate 18 . LC/MS (ESI) m/z 880.6 [M+H] ⁺ .

Example 28

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide

[0498] Example 28 was prepared according to general procedure A using intermediate 31 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.68 (s, 1H), 11.50 (br. s, 1H), 8.60 (br. s, 1H), 8.55 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.82-7.77 (m, 1H), 7.53-7.49 (m, 3H), 7.12-7 .08 (m, 1H), 6.73-6.70 (m, 1H), 6.39-6.38 (m, 1H), 6.25-6.23 (m, 1H), 3.87 -3.83 (m, 2H), 3.38-3.24 (m, 4H), 3.14-3.09 (m, 4H), 2.94 (br. s, 2H), 2.39 -2.31 (m, 4H), 2.11 (s, 6H), 2.04-1.98 (m, 2H), 1.90-1.85 (m, 1H), 1.68 (s , 2H), 1.64-1.59 (m, 2H), 1.31-1.22 (m, 4H), 0.83 (s, 6H); ¹⁹ F NMR (376 MHz, DMSO- d ₆ , no internal standard) δ -71.53; LC/MS (ESI) m/z 892.6 [M+H] ⁺ .

Example 29

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluoro-1-methylpiperidin-4-yl)methyl)amino) -3-nitrophenyl)sulfonyl)benzamide

[0499] Example 29 was prepared according to General Procedure B using Intermediate 31 and Intermediate 15 . LC/MS (ESI) m/z 923.9 [M+H] ⁺ .

Example 30

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino) -3-nitrophenyl)sulfonyl)benzamide

[0500] Example 30 was prepared according to General Procedure B using Intermediate 31 and Intermediate 52 . LC/MS (ESI) m/z 910.6 [M+H] ⁺ .

Example 31

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3- nitrophenyl)sulfonyl)benzamide

[0501] Example 31 was prepared according to General Procedure B using Intermediate 31 and Intermediate 53 . LC/MS (ESI) m/z 911.6 [M+H] ⁺ .

Example 32

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1] pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl) amino)-3-nitrophenyl)sulfonyl)benzamide

[0502] Example 32 was prepared according to General Procedure B using Intermediate 31 and Intermediate 18 . LC/MS (ESI) m/z 920.7 [M+H] ⁺ .

Example 33

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino )phenyl)sulfonyl)benzamide

[0503] Example 33 was prepared according to general procedure A using intermediate 30 and 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.06 (br. s, 1H), 8.94 (br. s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8 .53 (t, J = 5.6 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.18 (dd, J = 9.6, 2.0 Hz, 1H) , 7.98 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.45 (t, J = 3.2 Hz, 1H), 6 .92 (d, J = 9.6 Hz, 1H), 6.60-6.55 (m, 2H), 6.02 (d, J = 2.0 Hz, 1H), 5.65 (t, J = 56.8 Hz, 1H), 4.03 (dd, J = 11.2, 3.2 Hz, 2H), 3.46-3.39 (m, 2H), 3.27 (t, J = 6.4 Hz, 2H), 3.12-3.09 (m, 4H), 2.96 (s, 2H), 2.35-2.32 (m, 4H), 2.05-1, 98 (m, 3H), 1.96 (s, 6H), 1.76-1.72 (m, 2H), 1.66 (s, 2H), 1.49-1.38 (m, 2H) , 1.26 (t, J = 6.4 Hz, 2H), 0.84 (s, 6H); LC/MS (ESI) m/z 874.4 [M+H] ⁺ .

Example 34

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino )-3-nitrophenyl)sulfonyl)benzamide

[0504] Example 34 was prepared according to General Procedure A using Intermediate 30 and Intermediate 18 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 11.40 (br. s, 1H), 8.59-8.49 (m, 2H), 8.04 ( d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.53-7.48 (m, 3H), 7.06 (d, J = 9 .2 Hz, 1H), 6.72 (d, J = 7.2 Hz, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 5.99 (t, J = 56 .8 Hz, 1H), 4.25 (s, 1H), 3.33-3.25 (m, 2H), 3.18-3.05 (m, 4H), 2.97 (s, 2H) , 2.40-2.28 (m, 4H), 2.05-1.95 (m, 2H), 1.94 (s, 6H), 1.71-1.59 (m, 5H), 1 .58-1.49 (m, 2H), 1.39-1.28 (m, 2H), 1.27-1.20 (m, 2H), 1.18-1.09 (m, 2H) , 1.10 (s, 3H), 0.83 (s, 6H); LC/MS (ESI) m/z 902.6 [M+H] ⁺ .

Example 35

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)- 3-nitrophenyl)sulfonyl)benzamide

[0505] Example 35 was prepared according to General Procedure A using Intermediate 30 and Intermediate 52 . LC/MS (ESI) m/z 892.5 [M+H] ⁺ .

Example 36

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenyl )sulfonyl)benzamide

[0506] Example 36 was prepared according to General Procedure A using Intermediate 30 and Intermediate 53 . LC/MS (ESI) m/z 893.5 [M+H] ⁺ .

Example 37

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((7-oxaspiro[3,5]nonan-2-yl)methyl)amino) -3-nitrophenyl)sulfonyl)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl) methyl)piperazin-1-yl)benzamide

[0507] Example 37 was prepared according to General Procedure A using Intermediate 30 and Intermediate 6 . LC/MS (ESI) m/z 914.5 [M+H] ⁺ .

Example 38

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) -4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-fluoro-1-methylpiperidin-4-yl)methyl)amino)- 3-nitrophenyl)sulfonyl)benzamide

[0508] Example 38 was prepared according to General Procedure A using Intermediate 30 and Intermediate 15 . LC/MS (ESI) m/z 905.5 [M+H] ⁺ .

Example 39

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-isopropylbicyclo[1.1.1]pentan-1-yl)-4, 4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl) sulfonyl)benzamide

[0509] Example 39 was prepared according to general procedure A using intermediate 32 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ10.18 (br. s, 1H), 8.92 (br. s, 1H), 8.90 (d, J = 1.6 Hz, 1H), 8, 53 (t, J = 5.6 Hz, 1H), 8.23 (d, J = 2.8 Hz, 1H), 8.18 (dd, J = 9.0, 2.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.44 (t, J = 2.8 Hz, 1H), 6, 91 (d, J = 9.6 Hz, 1H), 6.59 (dd, J = 9.2, 2.4 Hz, 1H), 6.56 (dd, J = 3.4, 2.4 Hz , 1H), 6.02 (d, J = 2.0 Hz, 1H), 4.03 (dd, J = 11.2, 4.0 Hz, 2H), 3.46-3.39 (m, 2H), 3.27 (t, J = 6.4 Hz, 2H), 3.12-3.09 (m, 4H), 3.02 (s, 2H), 2.37-2.34 (m , 4H), 2.05-1.95 (m, 3H), 1.78-1.71 (m, 2H), 1.66 (s, 2H), 1.65 (s, 6H), 1, 62-1.56 (m, 1H), 1.49-1.39 (m, 2H), 1.25 (t, J = 6.4 Hz, 2H), 0.83 (s, 6H), 0 .78 (d, J = 6.8 Hz, 6H); LC/MS (ESI) m/z 866.4 [M+H] ⁺ .

Example 40

2-(1 H -Pyrrolo[2,3- b ]pyridin-5-yloxy)-4-(4-((2-(3-(1,1-difluoroethyl)bicyclo[1.1.1]pentan-1- yl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl) -N- (3-nitro-4-((tetrahydro- 2H -pyran-4-yl)methylamino)phenylsulfonyl)benzamide

[0510] Example 40 was prepared according to General Procedure B using intermediate 33 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 11.50 (br. s, 1H), 8.61-8.49 (m, 2H), 8.03 ( s, 1H), 7.80-7.70 (m, 1H), 7.54-7.45 (m, 3H), 7.04 (br. s, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 6.25 (s, 1H), 3.87-3.83 (m, 2H), 3.33-3.21 (m, 4H ), 3.15-3.05 (m, 4H), 2.97 (s, 2H), 2.40-2.25 (m, 4H), 2.04-1.97 (m, 2H), 1.94 (s, 6H), 1.93-1.82 (m, 1H), 1.67-1.57 (m, 4H), 1.53 (t, J = 18.8 Hz, 3H) , 1.30-1.15 (m, 4H), 0.83 (s, 6H); LC/MS (ESI) m/z 888.7 [M+H] ⁺ .

Example 41

(S)-N-((4-(((1,4-Dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl) methyl)piperazin-1-yl)benzamide

[0511] Example 41 was prepared according to General Procedure B using Intermediate 30 and Intermediate 34 . LC/MS (ESI) m/z 876.5 [M+H] ⁺ .

Example 42

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) spiro[3,5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl) amino)phenyl)sulfonyl)benzamide

[0512] Example 42 was prepared according to General Procedure B using intermediate 50 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.63 (s, 1H), 11.38 (br. s, 1H), 8.61-8.54 (m, 2H), 8.04 ( d, J = 2.8 Hz, 1H), 7.78 (dd, J = 9.6, 1.6 Hz, 1H), 7.53-7.50 (m, 3H), 7.10 (d , J = 9.2 Hz, 1H), 6.71 (dd, J = 9.2, 1.6 Hz, 1H), 6.39-6.38 (m, 1H), 6.25-6, 24 (m, 1H), 5.99 (t, J = 56.4 Hz, 1H), 3.84 (dd, J = 11.2, 3.2 Hz, 2H), 3.32-3.23 (m, 4H), 3.11 (br. s, 4H), 2.94 (s, 2H), 2.33 (br. s, 4H), 2.09-1.73 (m, 13H), 1.71-1.60 (m, 6H), 1.46 (t, J = 5.6 Hz, 2H), 1.30-1.20 (m, 2H); LC/MS (ESI) m/z 886.3 [M+H] ⁺ .

Example 43

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3 -nitrophenyl)sulfonyl)-4-(4-((6-(3-methylbicyclo[1.1.1]pentan-1-yl)spiro[3.5]non-6-en-7-yl)methyl)piperazin- 1-yl)benzamide

[0513] Example 43 was prepared according to General Procedure B using Intermediate 51 and Intermediate 52 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 11.40 (br. s, 1H), 8.57-8.53 (m, 2H), 8.01 ( d, J = 2.4 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.53-7.48 (m, 3H), 7.19-7.17 (m, 1H ), 6.70 (dd, J = 8.8, 1.6 Hz, 1H), 6.36 (br. s, 1H), 6.26-6.25 (m, 1H), 3.76- 3.68 (m, 4H), 3.55-3.50 (m, 2H), 3.09 (br. s, 4H), 2.95 (br. s, 2H), 2.32-2, 32 (br s, 4H), 1.98-1.92 (m, 4H), 1.83-1.58 (m, 16H), 1.45 (t, J = 5.6 Hz, 2H) , 1.10 (s, 3H); LC/MS (ESI) m/z 868.4 [M+H] ⁺ .

Example 44

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl) spiro[3,5]non-6-en-7-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl) amino)-3-nitrophenyl)sulfonyl)benzamide

[0514] Example 44 was prepared according to General Procedure B using Intermediate 50 and Intermediate 18 . LC/MS (ESI) m/z 914.5 [M+H] ⁺ .

Example 45

( R )-4-(4-((2-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl )- N -((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0515] To a stirred solution of intermediate 36 (45 mg, 0.105 mmol) in DCM (5 mL) was added EDC⋅HCl (21 mg, 0.0252 mmol) followed by DMAP (26 mg, 0.21 mmol) at 0 °C After 10 min, ( R )-4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (70 mg, 0.126 mmol) was added and the reaction mixture was heated to ct. After 48 h, water (10 ml) was added and the reaction mixture was extracted with DCM (3×20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The product was purified by HPLC (45:55-1:99 10 mM NH ₄ CO ₃ H (aq)/CH ₃ CN) to give Example 45 (4 mg, 4% yield) as a white solid. LC/MS (ESI) m/z 964.4 [M+H] ⁺ .

Example 46

( R )-4-(4-((2-(3-Chlorobicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl) -N- (4-(4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

[0516] Example 46 was prepared according to the procedure described for example 45 using intermediate 37 instead of ( R )-4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-( (trifluoromethyl)sulfonyl)benzenesulfonamide. LC/MS (ESI) m/z 978.4 [M+H] ⁺ .

Example 47

( R )-4-(4-((5,5-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl) -N -(4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

[0517] Example 47 was prepared according to the procedure described for example 45 using intermediate 38 instead of intermediate 36 . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 9.4, 1.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 6.8 Hz, 2H), 7.33-7.26 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 10.0 Hz, 1H), 3.95-3.85 (m, 1H), 3.71-3.60 (m, 4H), 3.36-3.24 (m, 4H), 3.14 (s, 2H), 3.13-2.98 (m, 2H) , 2.61-2.50 (m, 4H), 2.49-2.28 (m, 6H), 2.19-2.08 (m, 1H), 1.99-1.92 (m, 2H), 1.86 (s, 2H), 1.81 (s, 6H), 1.71-1.61 (m, 1H), 1.30 (t, J = 6.4 Hz, 2H), 1.13 (s, 3H), 0.86 (s, 6H). One -NH proton was not observed; LC/MS (ESI) m/z 944.6 [M+H] ⁺ .

Example 48

( R )-4-(4-((5,5-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-enyl)methyl)piperazin-1-yl) -N -(4-(4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide

[0518] Example 48 was prepared according to the procedure described for example 46 using intermediate 38 instead of intermediate 36 . LC/MS (ESI) m/z 958.3 [M+H] ⁺ .

Example 49

(R)-4-(4-((4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1- yl)-N-((4-((4-((2-hydroxyethyl)(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl )benzamide

[0519] Step 1. (R)-N-((4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-yl )amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4,4-dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1 -en-1-yl)methyl)piperazin-1-yl)benzamide ( Example 49-1) was prepared according to General Procedure B using Intermediate 39 and Intermediate 35 . LC/MS (ESI) m/z 1170.9 [M+H] ⁺ .

[0520] Step 2 To a stirred solution of Example 49-1 (375 mg, 0.32 mmol) in THF (15 mL) at 0°C was added TBAF (1 M in THF, 0.48 mL). After 5 min the reaction mixture was heated to rt. After 2 h the reaction mixture was quenched with water (25 ml) and extracted with 9:1 DCM/MeOH (3×35 ml) and concentrated. The crude compound was purified by HPLC (50:50-0:100 10 mM NH ₄ CO ₃ H (aq)/CH ₃ CN) to give Example 49 as a white solid. LC/MS (ESI) m/z 932.6 [M+H] ⁺ .

Example 50

( R )-4-(4-((2-(3-Ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl )- N -((4-((4-((2-hydroxyethyl)(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl) benzamide

[0521] Step 1. (R)-N-((4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-yl )amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1- en-1-yl)methyl)piperazin-1-yl)benzamide ( Example 50-1 ) was prepared according to General Procedure B using Intermediate 40 and Intermediate 35 . LC/MS (ESI) m/z 1186.0 [M+H] ⁺ .

[0522] Step 2 Example 50 was prepared according to the procedure described in Step 2 for Example 49 using Example 50-1 instead of Example 49-1 . LC/MS (ESI) m/z 946.7 [M+H] ⁺ .

Example 51

(R)-4-(4-((4,4-Dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazine -1-yl)-N-((4-((4-((2-hydroxyethyl)(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl) phenyl)sulfonyl)benzamide

[0523] Step 1. (R)-N-((4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-yl )amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((2-(3-ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1- en-1-yl)methyl)piperazin-1-yl)benzamide ( Example 51-1 ) was prepared according to General Procedure B using Intermediate 41 and Intermediate 35. LC/MS (ESI m/z 1225.9 [ M+2H] ⁺ .

[0524] Step 2 To a stirred solution of Example 51-1 (500 mg, 0.4 mmol) in THF at 0°C was added TBAF (1 M in THF, 0.49 ml). After 5 min the reaction mixture was heated to rt. After 5 h, the reaction mixture was quenched with water (25 ml) and 9 : 1 DCM/MeOH (3 × 50 ml). The combined organic layers were washed with brine (2×15 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude compound was purified by column chromatography (SiO ₂ , 7-10% MeOH in DCM) to give Example 51 (101 mg, 20%, over 2 steps) as a white solid. LC/MS (ESI) m/z 986.7 [M+H] ⁺ .

Example 52

( R )-4-(4-((4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1- yl)- N -((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0525] Example 52 was prepared according to General Procedure B using Intermediate 39 and ( R )-4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide. LC/MS (ESI) m/z 944.9 [M+H] ⁺ .

Example 53

( R )-4-(4-((2-(3-Ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl )- N -((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0526] Example 53 was prepared according to General Procedure B using Intermediate 40 and ( R )-4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide. LC/MS (ESI) m/z 958.8 [M+H] ⁺ .

Example 54

( R )-4-(4-((4,4-Dimethyl-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazine -1-yl)- N -((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0527] Example 54 was prepared according to General Procedure B using Intermediate 41 and ( R )-4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide. LC/MS (ESI) m/z 998.9 [M+H] ⁺ .

Example 55

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0528] Example 55 was prepared according to General Procedure B using Intermediate 42 and ( R )-4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)benzenesulfonamide. LC/MS (ESI) m/z 980.9 [M+H] ⁺ .

Example 56

(R)-4-(4-((4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1- yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0529] Example 56 was prepared according to General Procedure B using Intermediate 39 and Intermediate 43 . LC/MS (ESI) m/z 857.8 [M+H] ⁺ .

Example 57

(R)-4-(4-((2-(3-Ethylbicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl )-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0530] Example 57 was prepared according to General Procedure B using Intermediate 40 and Intermediate 43 . LC/MS (ESI) m/z 871.8 [M+H] ⁺ .

Example 58

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0531] Example 58 was prepared according to General Procedure B using Intermediate 42 and Intermediate 43 . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.40-8.30 (m, 1H), 7.78 (d, J = 9.2 Hz, 1H) , 7.73 (d, J = 8.8 Hz, 2H), 7.31-7.28 (m, 2H), 7.25-7.20 (m, 2H), 7.17-7.13 (m, 1H), 7.05-6.95 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.01 (t, J = 56.0 Hz, 1H) , 4.19-4.09 (m, 1H), 3.60-3.45 (m, 4H), 3.30-3.15 (m, 6H), 3.10-2.90 (m, 2H), 2.55-2.10(m, 10H), 2.10-2.01(m, 3H), 1.99(s, 6H), 1.90-1.80(m, 1H) , 1.71 (s, 2H), 1.30-1.21 (m, 2H), 0.86 (s, 6H). One -NH proton was not observed; LC/MS (ESI) m/z 893.6 [M+H] ⁺ .

Example 59

(R)-4-(4-((4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1- yl)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0532] Example 59 was prepared according to General Procedure B using Intermediate 39 and Intermediate 44 . LC/MS (ESI) m/z 902.6 [M+H] ⁺ .

Example 60

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-((2-hydroxyethyl)(methyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl )sulfonyl)benzamide

[0533] Step 1. (R)-N-((4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-yl )amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex -1-en-1-yl)methyl)piperazin-1-yl)benzamide ( Example 60-1 ) was prepared according to General Procedure B using Intermediate 42 and Intermediate 35 . LC/MS (ESI) m/z 1206.5 [M+H] ⁺ .

[0534] Step 2 To a stirred solution of Example 60-1 (130 mg, 0.10 mmol) in 1,4-dioxane (5 ml) was added HCl (4 M in 1,4 dioxane, 1 ml) followed by 3 drops of water at 0°C. The reaction mixture was heated to rt, stirred for 16 h and then concentrated. The crude reaction mixture was diluted with sat. aq. NaHCO ₃ and extracted with EtOAc (3×25 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , MeOH/DCM) to give Example 60 (30 mg, 29% yield) as an off-white solid. LC/MS (ESI) m/z 968.2 [M+H] ⁺ .

Example 61

( R )-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)- N -((4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl )benzamide

[0535] Example 61 was prepared according to General Procedure B using Intermediate 42 and Intermediate 37 . LC/MS (ESI) m/z 994.6 M+H] ⁺ .

Example 62

( R )-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl) -N -((4-((4-(4-(dimethylamino)piperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl) phenyl)sulfonyl)benzamide

[0536] Example 62 was prepared according to General Procedure B using Intermediate 42 and Intermediate 45 . LC/MS (ESI) m/z 1021.2 [M+H] ⁺ .

Example 63

( R )-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)- N -((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0537] Example 63 was prepared according to General Procedure B using Intermediate 42 and Intermediate 44 . LC/MS (ESI) m/z 938.4 [M+H] ⁺ .

Example 64

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0538] Step 1. ( R ) -tert- Butyl 4-(3-((4-( N- (4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentane-1 -yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-((trifluoro-methyl)sulfonyl)phenyl)amino)-4-(phenylthio )Butyl)piperazine-1-carboxylate ( Example 64-1 ) was prepared according to General Procedure B using Intermediate 42 and Intermediate 46 . LC/MS (ESI) m/z 1079.3 [M+H] ⁺ .

[0539] Step 2 To a stirred solution of Example 64-1 (350 mg, 0.32 mmol) in Et ₂ O (5 ml) at 0°C, was added HCl (2 M in Et ₂ O, 2.0 ml) . The reaction mixture was heated to rt and stirred for 16 h. The reaction mixture was concentrated, diluted with ice water, basified with sat. aq. NaHCO ₃ (10 ml) and extracted with 10% MeOH in DCM (3×30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by HPLC (30:70-1:99 10 mM NH ₄ CO ₃ H (aq)/CH ₃ CN) to give Example 64 (14 mg, 4% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (br. s, 2H), 8.02 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7 .68 (d, J = 8.8 Hz, 2H), 7.34-7.23 (m, 4H), 7.19-7.15 (m, 1H), 6.83-6.75 (m , 3H), 6.66 (d, J = 8.8 Hz, 1H), 5.97 (t, J = 56.8 Hz, 1H), 3.97 (br. s, 1H), 3.26 -3.23(m, 2H), 3.15-3.10(m, 4H), 3.02-2.90(m, 6H), 2.52-2.50(m, 2H), 2 .40-2.23 (m, 8H), 2.10-1.83 (m, 9H), 1.67 (s, 3H), 1.23 (t, J = 6.4 Hz, 2H), 0.82 (s, 6H); LC/MS (ESI) m/z 979.4 [M+H] ⁺ .

Example 65

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl )benzamide

[0540] Example 65 was prepared according to General Procedure B using Intermediate 56 and Intermediate 37 . LC/MS (ESI) m/z 994.4 [M+H] ⁺ .

Example 66

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-(3-hydroxyazetidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl )benzamide

[0541] Example 66 was prepared according to General Procedure B using Intermediate 42 and Intermediate 57 . LC/MS (ESI) m/z 966.5 [M+H] ⁺ .

Example 67

( R )-4-(4-((6-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)spiro[3,5]non-6-en-7-yl)methyl)piperazine -1-yl)- N -((4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl) sulfonyl)benzamide

[0542] Example 67 was prepared according to General Procedure B using Intermediate 58 and Intermediate 37 . LC/MS (ESI) m/z 1006.5 [M+H] ⁺ .

Example 68

(R)-4-(4-((4,4-Dimethyl-2-(3-methylbicyclo[1.1.1]pentan-1-yl)cyclohex-1-en-1-yl)methyl)piperazin-1- yl)-N-((4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide

[0543] Example 68 was prepared according to General Procedure B using Intermediate 37 and Intermediate 39 . LC/MS (ESI) m/z 958.2 [M+H] ⁺ .

Example 69

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)phenyl)sulfonyl)benzamide

[0544] Step 1: ( R )-N-((4-((4-(4-(2-(( tert- Butyldiphenylsilyl)oxy)ethyl)piperazin-1-yl)-1-(phenylthio)butan- 2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4, 4-Dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzamide ( Example 69-1 ) was prepared according to General Procedure B using Intermediate 42 and Intermediate 59 . LC/MS (ESI) m/z 631.6 [M+2H] ⁺ .

[0545] Step 2 To a stirred solution of Example 69-1 (250 mg, 0.198 mmol) in 1,4-dioxane was added HCl (4 M in 1,4-dioxane, 1.5 ml) followed by 3 drops of water at 0 °C The reaction mixture was heated to rt, stirred for 16 h and then concentrated. The crude reaction mixture was diluted with sat. aq. NaHCO ₃ and extracted with 9 : 1 DCM : MeOH (3 × 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by HPLC (10 mM NH ₄ OAc (aq): CH ₃ CN) to give the title compound (22 mg, 11% yield) as an off-white solid. LC/MS (ESI) m/z 1023.3 [M+H] ⁺ .

Example 70

(R)-4-(4-((2-(3-(Difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin- 1-yl)-N-((4-((4-(ethyl(2-hydroxyethyl)amino)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl )benzamide

[0546] Step 1. ( R ) -N -((4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-yl )amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex -1-en-1-yl)methyl)piperazin-1-yl)benzamide ( Example 70-1 ) was prepared according to General Procedure B using Intermediate 42 and Intermediate 60 . LC/MS (ESI) m/z 611.3 [M+2H] ⁺ .

[0547] Step 2. Example 70 was prepared in accordance with the procedure described in example 69, using example 70-1 instead of example 69-1 . LC/MS (ESI) m/z 982.5 [M+H] ⁺ .

Example 71

( R )- N -((4-((4-((2-((tert-Butyldiphenylsilyl)oxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl)-4,4-dimethylcyclohex-1-en-1 -yl)methyl)piperazin-1-yl)benzamide

[0548] Example 71 was prepared according to General Procedure B using Intermediate 42 and Intermediate 61 . LC/MS (ESI) m/z 980.4 [M+H] ⁺ .

Example 72

2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-chlorobicyclo[1.1.1]pentan-1-yl)cyclohex-1 -en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide

[0549] Example 72 was prepared according to general procedure A using intermediate 62 and 3-nitro-4-(((tetrahydro- 2H -pyran-4-yl)methyl)amino)benzenesulfonamide. LC/MS (ESI) m/z 830.8 [M+H] ⁺ .

Example 73

(R)-2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((2-(3-(difluoromethyl)bicyclo[1.1.1]pentan- 1-yl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-methylmorpholin-2-yl)methyl)amino)- 3-nitrophenyl)sulfonyl)benzamide

[0550] Example 73 was prepared according to General Procedure B using Intermediate 30 and Intermediate 17A . The absolute stereochemistry is set arbitrarily. LC/MS (ESI) m/z 445.5 [M+2H] ⁺ .

Examples 74-97

[0551] Examples 74-97 having the chemical names and structures shown in FIG. 3, 4A and 4B were obtained in accordance with the methods described herein. Similar results were obtained.

Example A

Bcl-2 family protein binding assay

[0552] Bcl-2-Bcl-2 and Bcl-X _L family protein binding was assessed using Bcl2scan™: T7 phage strains displaying BCL2 proteins were grown in parallel in 24-well plates in E. coli host cells derived from strain BL21. E. coli were grown to logarithmic phase and infected with T7 phage from a frozen stock solution (multiplicity of infection = 0.4) and incubated with shaking at 32° C. until lysed (90-150 minutes). Lysates were centrifuged (5000 xg) and filtered (0.2 µm) to remove debris. Streptavidin-coated magnetic beads were treated with biotinylated BIM peptide ligand for 30 minutes at room temperature to generate affinity resins for BCL2 assays. Ligand-coated beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce non-specific phage binding. Binding reactions were prepared by combining BCL2 proteins, ligand-coated affinity beads and test compounds in 1x binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were obtained as 100X stock solutions in 100% DMSO. Kd values were determined using an 11-point 3-fold dilution series with one control point, DMSO. All compounds for Kd measurement were applied by acoustic transfer in 100% DMSO. The compounds were then diluted directly into the assay wells such that the final DMSO concentration was 0.9%. All reactions were performed in polypropylene 384-well plates. The final volume in each case was 0.02 ml. The assay plates were incubated at room temperature and with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1x PBS, 0.05% Tween 20, 2 μM non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The concentration of BCL2 in the eluates was measured by quantitative PCR. Binding constants (Kd) were calculated using a standard dose-response curve using the Hill equation:

.

The Hill slope was set to -1.

The curves were approximated by means of a non-linear least squares approximation using the Levenberg-Marquardt algorithm. The results are shown in Table 1.

Table 1

Example Bcl-2 Kd (nm) Bcl-X _L Kd (nm) 1 A C 9 A C 10 A C eleven A C 13 A C 15 A C 16 A C 17 A B 20 A C 23 A C 25 A C 26 A C 27 A C 28 A C thirty A C 31 A C 32 A C 33 A C 34 A C 35 A C 36 A B 38 A B 39 B C 40 A C 47 C B 48 B B ABT-199 A B ABT-263 B B

Bcl-2 binding assay (Kd): A = one Kd ≤ 10 nM; B = one Kd > 10 nM and < 100 nM; C = one Kd ≥ 100 nM

Example B

Bcl-2/Bcl-X _L Analysis by Homogeneous Time Resolved Fluorescence (HTRF)

[0553] Binding to Bcl-2 family proteins such as Bcl-2 and Bcl-X _L was also assessed using HTRF analysis. Basic information. FAM-Bak/Bad binds to a pocket on the surface of the Bcl-2 family proteins. This binding can be monitored by HTRF signals between the anti-GST-Tb antibody and the FAM peptide using GST-tagged Bcl proteins. Assay conditions: Bcl-2: 4 nM Bcl-2, 100 nM FAM-Bak peptide, Bcl-X _L : 3 nM Bcl-X _L , 40 nM FAM-Bad peptide in 20 mM K Phosphate, pH 7.5, 50 mM NaCl, 1 mM EDTA, 0.005% Triton X-100 and 1% DMSO (final). Assay Procedure: Compounds were tested in a 10-dose IC ₅₀ regimen, in single replication, with 3-fold serial dilutions starting at 10 μM or 1 μM. Compound stock solutions were added to the protein solution using acoustic technology. Compounds were then incubated with protein for 10 min at room temperature. The corresponding FAM-labeled peptide was added and incubated for another 10 min, and then the anti-GST-Tb antibody was added. After 60 min at rt, the ratio of the HTRF fluorescent signals was measured. Curve fitting was performed in GraphPad Prism 4 in the "sigmoid dose-response curve (variable slope)"mode; 4 parameters with hill slope. The results are shown in Table 2.

table 2

Example Bcl-2 IC ₅₀ (nM) Bcl-X _L IC ₅₀ (nM) 15 A C 20 A C 34 A B 46 A A 48 A A 49 A A 50 A A 55 A A 58 A A 59 A A 60 A A 61 A A 62 A A 63 A A 64 A A 67 A A 69 A A 70 A A ABT-199 A B ABT-263 A A

Bcl-2 binding assay (IC ₅₀ ): A = one IC ₅₀ ≤ 10 nM; B = one IC ₅₀ > 10 nM and < 100 nM; C = one IC ₅₀ ≥ 100 nM.

Example C

Cell proliferation assay RS4;11 and NCI-H1963

[0554] Cell proliferation was measured using the CellTiter-Glo® Luminescent Cell Viability Assay. The assay involved adding a single reagent (CellTiter-Glo® Reagent) directly to cells cultured in serum-enriched medium. RS4;11 cells (ATC, CRL-1873) were cultured according to ATCC recommendations and seeded at 50,000 cells per well. NCI-H1963 cells (ATCC CRL-5982) were cultured according to ATCC recommendations and seeded at 12,000 cells per well.

[0555] Each analyte was obtained as a stock solution in DMSO (10 mM). Compounds were tested in duplicate on each plate using a 10-point serial dilution curve (1:3 dilution). Injectable compound (1.0 μl) was added from the compound dilution plates to the cell plate. The highest compound concentration was 10 μM (final) with a final DMSO concentration of 0.1%. Next, the plates were incubated at 37°C, 5% CO ₂ . After 48 hours of compound exposure to RS4 cells; 11 or 72 hours to NCI-H1963 cells, the cell plates were equilibrated at RT for approximately 30 minutes. An equal volume of CellTiter-Glo® Reagent (40 µl) was added to each well. The plates were stirred for 2 min on an orbital shaker to induce cell lysis and then incubated at RT for 10 min to stabilize the luminescent signal. Luminescence was recorded using an Envision plate scanner according to the CellTiter-Glo protocol. IC ₅₀ for each compound was calculated using GraphPad Prism using non-linear regression analysis. IC ₅₀ values are presented in Table 3.

Table 3

Example No. RS4;11 (nM) H1963 (nM) Example No. RS4;11 (nM) H1963 (nM) 1 A 39 A 2 A 40 A 3 B 41 4 B 42 A 5 B 43 B 6 C 44 7 C 45 C 8 B 46 B 9 A 47 C 10 A 48 B eleven A 49 B 12 A 50 B 13 A 51 B 14 A 52 B 15 A 53 C 16 A 54 C 17 A 55 B 18 A 56 C B 19 A 57 C C 20 A 58 B 21 B 59 B B 22 A 60 A B 23 A 61 A A 24 A 62 B A 25 A 63 A A 26 A 64 B C 27 A 65 B 28 A 66 29 A 67 B thirty A 68 B A 31 A 69 B 32 A 70 B C 33 A 71 B 34 A 72 C 35 A 73 36 A ABT-199 A C 37 A ABT-263 A A 38 A

For RS4;11 CTG IC ₅₀ : A = single IC ₅₀ ≤ 100 nM; B = one IC ₅₀ > 100 nM and < 1000 nM; C = one IC ₅₀ ≥ 1000 nM. For H1963 CTG IC ₅₀ : A = single IC ₅₀ ≤ 500 nM; B = one IC ₅₀ > 500 nM and < 1000 nM; C = one IC ₅₀ ≥ 1000 nM.

Example D

Caspase release in CD4 cells prone to spoof agent and HIV-1 (strain IIIB)

[0556] Primary CD4 T cells were purified by negative selection with the RosetteSep human CD4 ⁺ T cell enrichment reagent (Stemcell Technologies) or the EasySep human CD4 ⁺ T cell isolation kit (Stemcell Technologies) according to the manufacturer's instructions. Primary CD4 T cells were isolated and activated with IL-2 50 IU/ml and phytohemagglutinin (PHA) 1 μg/ml for 48 hours. Cells were then infected with stock solution of HIV-1 _IIIb virus (NIH AIDS Reagent Program) for 3-6 h with 6 μg/ml Polybrene (Sigma-Aldrich), washed and resuspended with complete RPMI and IL-2 for 48 h. Cells were treated with compounds as 100 μM and 300 μM stock solutions in DMSO or pure DMSO. Cell death was measured using an IncuCyte system (Essen BioScience) and an IncuCyte Caspase 3/7 apoptosis assay reagent (Cat. No. 4440, Essen BioScience). Data analysis was performed using IncuCyte Zoom software (2018A). Statistical analysis was performed using GraphPad Prism. The results are presented with a standard error (std. osh.). The fold change in the analysis of the area under the graph was compared using multiple t-tests. P values less than 0.05 were considered statistically significant. The results of this analysis are summarized in FIG. 5 and they show that Examples 34 and 36 show selectivity in killing HIV-infected cells over mock-infected cells.

[0557] Moreover, although the foregoing has been described in more detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art that numerous and varied changes can be implemented without departing from the spirit or scope of the present invention. Therefore, it should be clearly understood that the forms described herein are illustrative only, and are intended not to limit the scope of the present description, but, on the contrary, to cover all modifications and alternatives within the true scope and spirit of the invention.

Claims (93)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, having the structure (I) where R ¹ is selected from the group consisting of hydrogen, halogen, unsubstituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ haloalkyl; each R ² is independently unsubstituted C ₁ -C ₆ alkyl; or, when m is 2, each R ² is independently unsubstituted C ₁ -C ₆ alkyl, or two R ² groups taken together with the atom(s) to which they are attached form an unsubstituted C ₃ -C ₆ cycloalkyl; R ³ is XR ^3A ; R ^3A is an unsubstituted 5-10 membered heteroaryl such as ; R ⁴ is NO ₂ ; R ⁵ is -X ¹ -(Alk ¹ ) _n -R ⁷ ; Alk ¹ is selected from unsubstituted C ₁ -C ₄ alkylene and C ₁ -C ₄ alkylene substituted with 1, 2 or 3 substituents independently selected from fluorine, chlorine, unsubstituted C ₁ -C ₃ alkyl and unsubstituted C ₁ -C ₃ haloalkyl; R ⁷ is selected from substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl and substituted or unsubstituted 3-10 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen; m is 0, 1 or 2; n is selected from 0 and 1; X ¹ represents -NH-; And X is -O-; however, when it is indicated that the group is "substituted", the specified group may be substituted by one or more groups that are individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino group and disubstituted amino group. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CH ₂ F or -CF ₃ . 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -CHF ₂ . 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is not -CH ₂ F, -CHF ₂ or -CF ₃ . 5. Connection according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2. 6. Connection according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof, wherein each R ² is independently unsubstituted C ₁ -C ₆ alkyl. 7. The connection according to any one of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof, wherein m is 2 and each R ² is unsubstituted methyl. 8. Connection according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof, wherein the two R ² groups taken together with the atom(s) to which they are attached form an unsubstituted C ₃ -C ₆ cycloalkyl, preferably an unsubstituted cyclopropyl. 9. Connection according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, wherein m is 0. 10. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt thereof, which is also a compound of formula (Ia), formula (Ib), formula (Ic) or formula (Id): or a pharmaceutically acceptable salt of any of the above compounds. 11. The connection according to any one of paragraphs. 1-10 or a pharmaceutically acceptable salt thereof, wherein R ^3A is . 12. Connection according to any one of paragraphs. 1-11 or a pharmaceutically acceptable salt thereof, in which Alk ¹ is unsubstituted -(CH ₂ ) _1-4 -*, for which "*" denotes the point of attachment to R ⁷ where Alk ¹ is selected from , , , And ; and R ⁷ is a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, such as a substituted or unsubstituted C ₆ -C ₁₀ spirocycloalkyl, or a substituted or unsubstituted 3-10 membered heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen, such as a substituted or unsubstituted 6- to 10-membered spiro-heterocyclyl containing 1-2 heteroatoms selected from nitrogen and oxygen, wherein when a group is said to be "substituted", said group may be substituted by one or more groups which are individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino group and disubstituted amino group. 13. Connection according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt thereof, in which R ⁷ is substituted with 1 or 2 substituents independently selected from unsubstituted C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ alkoxy, fluorine, chlorine, hydroxy and -SO ₂ - (unsubstituted C ₁ -C ₆ alkyl). 14. Connection according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And ; or R ⁷ is selected from: , , , And . 15. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , . , , , , , , , , , , , , , , , , , And or a pharmaceutically acceptable salt of any of the above compounds. 16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, where the compound is selected from the group consisting of: And , or a pharmaceutically acceptable salt of any of the above compounds. 17. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 18. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 19. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 20. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 21. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 22. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 23. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 24. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 25. The compound according to claim 15, where the compound is or a pharmaceutically acceptable salt of said compound. 26. Pharmaceutical composition for the treatment of a disease or condition mediated by Bcl-2, containing an effective amount of a compound according to any one of paragraphs. 1-25 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. 27. A method for treating cancer or tumors mediated by Bcl-2, comprising administering an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 to a subject having a cancer or tumor, wherein the cancer or tumor is selected from bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancer (including oral cancer), cancer ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma , Ewing's tumors and Wilm's tumors. 28. A method of inhibiting the replication of a malignant formation or tumor mediated by Bcl-2, including bringing the formation or tumor into contact with an effective amount of the compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, wherein the malignancy or tumor selected from Ewing's tumor and Wilm's tumor, or the malignancy of the tumor is due to a cancer selected from bladder cancer, brain cancer, cancer breast, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer head and neck (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer , bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma. 29. A method for treating Bcl-2 mediated cancer, comprising bringing the cancer or tumor into contact with an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, wherein the malignancy or tumor selected from Ewing's tumor and Wilm's tumor, or the malignancy of the tumor is due to a cancer selected from bladder cancer, brain cancer, cancer breast, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer head and neck (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer , bile duct cancer, testicular cancer, neuroblastoma, or osteosarcoma. 30. A method of inhibiting Bcl-2 activity, comprising providing an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 for a Bcl-2 mediated cancer cell or tumor, wherein the cancer cell or tumor is caused by a cancer selected from bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid malignancy, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer, bile duct cancer ducts, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilm's tumor. 31. A method for inhibiting Bcl-2 activity in a subject, comprising providing an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 for a subject having a Bcl-2 mediated cancer or tumor, wherein the cancer or tumor is selected from bladder cancer, brain cancer, breast cancer, bone cancer brain, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid malignancy, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilm's tumor. 32. The use of an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 for the manufacture of a medicament for the treatment of a cancer or tumor mediated by Bcl-2, wherein the cancer or tumor is selected from bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, T-cell or B-cell lymphoid malignancy, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer, bile duct cancer ducts, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilm's tumor. 33. The use of an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 for the manufacture of a medicament for inhibiting the replication of a Bcl-2 mediated malignancy or tumor, wherein the malignancy or tumor is due to a cancer selected from bladder cancer, brain cancer brain, breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, gallbladder cancer, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilm's tumor. 34. The use of an effective amount of a compound according to any one of paragraphs. 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26 for the manufacture of a medicament for the treatment of a Bcl-2 mediated malignancy or tumor, wherein the malignancy or tumor is due to a cancer selected from bladder cancer, brain cancer , breast cancer, bone marrow cancer, cervical cancer, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancy of T-cell or B-cell origin, melanoma, myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma , head and neck cancer (including oral cancer), ovarian cancer, non-small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostate cancer, small cell lung cancer, spleen cancer, polycythemia vera, thyroid cancer, endometrial cancer, gastric cancer, cancer gallbladder, bile duct cancer, testicular cancer, neuroblastoma, osteosarcoma, Ewing's tumor and Wilm's tumor. 35. A compound of formula (I), or a pharmaceutically acceptable salt thereof, having the structure (I) where R ¹ is selected from the group consisting of hydrogen, halogen, unsubstituted C ₁ -C ₆ alkyl and unsubstituted C ₁ -C ₆ haloalkyl; each R ² is independently unsubstituted C ₁ -C ₆ alkyl; or, when m is 2, each R ² is independently an unsubstituted C ₁ -C ₆ alkyl, or two R ² groups taken together with the atom(s) to which they are attached form an unsubstituted C ₃ -C ₆ cycloalkyl; R ³ is hydrogen; R ⁴ is selected from the group consisting of NO ₂ , S(O)R ⁶ and SO ₂ R ⁶ ; R ⁵ is -X ² (CHR ⁸ )-(Alk ² ) _p -X ³ -R ⁹ ; Alk ² is independently unsubstituted C ₁ -C ₄ alkylene; R ⁶ is an unsubstituted C ₁ -C ₆ haloalkyl; R ⁸ is selected from substituted or unsubstituted 3-10 membered heterocyclyl(C ₁ -C ₆ alkyl) containing 1-2 heteroatoms selected from nitrogen and oxygen, substituted or unsubstituted di-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl) and substituted or unsubstituted mono-C ₁ -C ₆ alkylamine(C ₁ -C ₆ alkyl); R ⁹ is unsubstituted C ₆ -C ₁₀ aryl; m is 2; p is 1; X ² is -NH-; and X ³ is -S-; however, when it is indicated that the group is "substituted", the specified group may be substituted by one or more groups that are individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, amino, monosubstituted amino group and disubstituted amino group.

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