WO2021022258A1 - Tetracycline compounds for the treatment of hematological cancers - Google Patents

Abstract

This invention relates to a method of treating hematological cancer comprising administering a compound of Formula (I) or a salt thereof in combination with venetoclax. Methods of treating hematological cancer comprising administering a compound of Formula (I) in venetoclax-refractory subjects are also disclosed.

Description

TETRACYCLINE COMPOUNDS FOR THE TREATMENT OF

HEMATOLOGICAL CANCERS

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No.

62/881,794, filed on 01 August 2019. The entire teachings of the above application are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Hematological malignancies are cancers that affect the blood and lymph system. Some types of hematologic malignancies include: Multiple myeloma, Hodgkin lymphoma, Non-Hodgkin lymphoma and Leukemia. The cancer may begin in blood-forming tissue (e.g., bone marrow), or in the cells of the immune system. For example, leukemia originates in blood-forming tissue. Leukemia is characterized by the uncontrolled growth of blood cells, usually white blood cells (leukocytes), in the bone marrow. White blood cells are a fundamental component of the body's immune response. The leukemia cells crowd out and replace normal blood and marrow cells.

[0003] There are four main types of leukemia: Acute myeloid leukemia (AML);

Chronic myeloid leukemia (CML); Acute lymphocytic leukemia (ALL); and Chronic lymphocytic leukemia (CLL). The primary differences between the four main types of leukemia have to do with their rates of progression and where the cancer develops. Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, is a fast-growing form of cancer of the blood and bone marrow. AML is the most common type of acute leukemia. It occurs when the bone marrow begins to make blasts, cells that have not yet completely matured. These blasts normally develop into white blood cells. However, in AML, these cells do not develop and are unable to ward off infections. In AML, the bone marrow may also make abnormal red blood cells and platelets. The number of these abnormal cells increases rapidly, and the abnormal (leukemia) cells begin to crowd out the normal white blood cells, red blood cells and platelets that the body needs.

[0004] The standard treatment for AML includes remission-induction treatment consisting of administration of the chemotherapeutic agents cytarabine and daunorubicin (7+3). This treatment has been the standard of care for decades. Few other therapeutic approaches for malignant disease have remained so unchanged for such a long period. In addition, the co-morbidities and high susceptibility to treatment-related toxicity still limit treatment success. Despite advances in treatment strategies for hematological cancer there remains a need to identify novel, potent and well-tolerated therapies, particularly for the treatment of leukemias, such as AML, either a single agent therapy or a combination therapy in order to maximize the therapeutic benefit and minimize treatment-related toxicity.

SUMMARY OF THE INVENTION

[0005] This invention relates to a method of treating hematological cancers comprising administering a compound of Formula (I) or a salt thereof in combination with a Bcl-2 inhibitor, such as venetoclax.

[0006] One embodiment is a method of treating hematological cancers in a subject in need thereof. The method comprises administering to the subject a combination of a first amount of a Bcl-2 inhibitor, such as venetoclax, and a second amount of a compound represented by Formula (I)

R 403 R403

I

or a pharmaceutically acceptable salt thereof, wherein the first and second amounts together comprise an effective amount. In some embodiments, the subject is a venetocl ax-refractory subject. In other embodiments, the subject is not refractory to venetoclax.

[0007] Another embodiment is a method of treating hematological cancers in a venetocl ax-refractory subject in need thereof, comprising administering to the subject a compound represented by Formula (I)

R 403 R403

I

or a pharmaceutically acceptable salt thereof. [0008] Another embodiment of the invention is pharmaceutical composition comprising a first amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt, a second amount of a Bcl-2 inhibitor, for example venetoclax, and optionally a pharmaceutically acceptable carrier.

[0009] Another embodiment of the invention is the use of a pharmaceutical

composition comprising a first amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt, a second amount of a Bcl-2 inhibitor, for example venetoclax and optionally a pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of a hematological cancer.

[0010] Another embodiment of the invention is a pharmaceutical composition comprising a first amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt and a second amount of a Bcl-2 inhibitor, for example venetoclax for use in treating a hematological cancer.

[0011] Yet another embodiment is the use of a first amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt and a second amount of a Bcl-2 inhibitor, for example venetoclax for the manufacture of a medicament for the treatment of a hematological cancer.

[0012] Yet another embodiment is a first amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt and a second amount of a Bcl-2 inhibitor, for example venetoclax for use in treating hematological cancer.

[0013] Another embodiment is the use of a of a compound represented by Formula (I) or a pharmaceutically acceptable salt for the manufacture of a medicament for the treatment of a hematological cancer, wherein the cancer is refractory to venetoclax.

[0014] Yet another embodiment is a first amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt for use in treating hematological cancer, wherein the cancer is refractory to venetoclax.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A depicts comparative antiproliferative activity of TP-2846 and venetoclax against a venetoclax-sensitive cell line, OCI-AML-2.

[0016] FIG. IB depicts comparative antiproliferative activity of TP -2846 and venetoclax against a venetoclax-resistant cell line, OCI- AML-3. [0017] FIG. 2A depicts one view of the synergy score for the combination of TP -2846 and venetoclax in the OCI-AML-3 antiproliferative assays, assessed by the ZIP

methodology.

[0018] FIG. 2B depicts a second view of the synergy score for the combination of TP- 2846 and venetoclax in the OCI-AML-3 antiproliferative assays, assessed by the ZIP methodology.

[0019] FIG. 3 A depicts one view of the synergy score for the combination of TP -2846 and venetoclax in the OCI-AML-2 antiproliferative assays, assessed by the ZIP

methodology.

[0020] FIG. 3B depicts a second view of the synergy score for the combination of TP- 2846 and venetoclax in the OCI-AML-2 antiproliferative assays, assessed by the ZIP methodology.

[0021]

DETAILED DESCRIPTION OF THE INVENTION

[0022] A description of example embodiments of the invention follows.

[0023] The compound represented by Formula I

or a pharmaceutically acceptable salt thereof is defined as follows:

R⁸⁰³ is a Ci-₆ alkyl, H, a Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, a C3-12 carbocyclyl-(Co- 3)alkylenyl, an amino-(Ci-C4) alkyl, a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl, or a (4- 13 member)heterocyclyl-(Co-C3)alkylenyl, wherein the heterocyclyl portion is optionally substituted with a C1-3 alkyl;

R⁷⁰¹ is a Ci-4 alkyloxy, H, -OH, Ci-4 alkyl, a Ci-4 haloalkyl, Ci-4 hydroxyalkyl, or Ci- 4 haloalkoxy;

R⁴⁰³ and R^403’, each independently, are H; a Ci-4 alkyl; a C1-C4 haloalkyl; a C1-C4 hydroxyalkyl; a (C1-C4 alkoxy)-(Ci-4)alkyl; an amino-(Ci-C4) alkyl; a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl; or a C₃-12 carbocyclyl-(Co-C₃)alkylenyl, wherein the carbocyclyl portion is optionally substituted with a hydroxyl group; a (Ci-4 alkyl)C(O)-, a (Ci-4 alkyl)S(0)i-2-; a (CM alkyl)C(0)NH(Ci-₄ alkylenyl)-; a (CM alkyl)S(0)i-₂NH(Ci-4 alkylenyl)-; a H0C(0)-(Ci-C3)alkylenyl; a H2NC(0)-(Ci-C3)alkylenyl; or a (Ci-4 alkyloxy)C(0)-( Ci-C₃)alkylenyl.

[0024] Venetoclax is an FDA approved Bcl-2 inhibitor for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), sold under the brand names Venclexta and Venclyxto (4-[4-[[2-(4-chlorophenyi)-4,4-dimethylcyclohexen-l- yl]methyl]piperazin-l-yi]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfony!-2-(]H- pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) and represented by the following structural formula:

Venetoclax is a BH3 mimetic that selectively blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of cancer cells. Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is a member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. The pro-apoptotic proteins in the BCL-2 family, including Bax and Bak, normally act on the mitochondrial membrane to promote permeabilization and release of cytochrome C and ROS, that are important signals in the apoptosis cascade. These pro- apoptotic proteins are in turn activated by BH3-only proteins, and are inhibited by the function of BCL-2 and its relative BCL-X1. By inhibiting Bcl-2, which can be

overexpressed in cancer cells, venetoclax reduces the anti-apoptotic effects of the Bcl-2 protein. Venetoclax does not exhibit the same levels of thrombocytopenia that are observed with other Bcl-2 inhibitors, such as navitoclax, such that it is more well tolerated in subjects. However, hematological cancers, such as AML, can become resistant to venetoclax.

Definitions [0025] “Alkyl” means an optionally substituted saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms. Thus,“(Ci-C6) alkyl” means a radical having from 1- 6 carbon atoms in a linear or branched arrangement.“(Ci-C6)alkyl” includes methyl, ethyl, propyl, butyl, pentyl and hexyl. “(C1-C12 ) alkyl” means a radical having from 1- 12 carbon atoms in a linear or branched arrangement.“(Ci-Ci2)alkyl” includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl. Unless otherwise specified, suitable substitutions for a“substituted alkyl” include halogen, -OH, -O-C1-C4 alkyl, C1-C4 alkyl, fluoro-substituted-Ci-C4 alkyl, -O-C1-C4 fluoroalkyl, -NH2, -NH(CI-C4 alkyl), -N(CI-C4 alkyl)2, C3-C12 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or naphthalenyl), a (4-13 membered) heterocyclyl (e.g., pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran or morpholine) or -N(R^X)(R^X ), wherein R^x and R^x are independently hydrogen or C1-C4 alkyl, or taken together with the nitrogen atom to which they are bound form a (4-7 membered) heterocylic ring optionally comprising one additional heteroatom selected from N, S and O, wherein the (4-7 membered) heterocylic ring is optionally substituted with fluoro, chloro, -OH, fluoro-substituted C1-C4

alkyl, -C1-C4 alkyl, or -C₀-C4 alkylene-0-Ci-C4 alkyl, and is optionally benzofused.

[0026] “Benzofused,” when referring to a ring system, means fused to a phenyl ring, forming a fused bicyclyl ring.

[0027] “Alkylene” or“alkylenyl” (used interchangeably) mean an optionally substituted saturated aliphatic branched or straight-chain divalent hydrocarbon radical having the specified number of carbon atoms. An alkyl moiety of an alkylene group can be a part of a larger moiety such as alkoxy, alkylammonium, and the like. Thus,“(Ci-Ce)alkylene” means a divalent saturated aliphatic radical having from 1- 6 carbon atoms in a linear arrangement, e.g., -[(CH2)n]-, where n is an integer from 1 to 6, “(Ci-Ce)alkylene” includes methylene, ethylene, propylene, butylene, pentylene and hexylene. Alternatively,“(Ci- C6)alkylene” means a divalent saturated radical having from 1-6 carbon atoms in a branched arrangement, for

example: -[(CH2CH2CH2CH2CH(CH3)]-, -[(CH2CH2CH2CH₂C(CH3)2]-, -[(CH₂C(CH3)₂C H (CH3))]-, and the like. A“(Ci-Ci2)alkylene” includes methyl, ethyl, «-propyl, Ao-propyl, «-butyl, sec-butyl, /er/-butyl, pentyl, hexyl, heptyl or octyl. A specific branched C3-alkylene Other examples of a divalent Ci-₆ alkyl group include, for example, a methylene group, an ethylene group, an ethylidene group, an n-propylene group, an isopropylene group, an isobutylene group, an s- butylene group, an n-butylene group, and a t-butylene group.

[0028] A“Co alkylenyl” is a covalent bond.

[0029] “Alkoxy” means an alkyl radical attached through an oxygen linking atom. “(Ci-C4)-alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.

[0030] “Alkylthio” means an alkyl radical attached through a sulfur linking atom. “(Ci-C4)alkylthio” include methylthio, ethylthio, propylthio and butylthio.

[0031] “Alkyl sulfmyl” means an alkyl radical attached through a -S(O)- linking group. “(Ci-C4)alkylsulfmyl” include methylsulfmyl, ethylsulfmyl, propyl sulfmyl and

butyl sulfmyl.

[0032] “Alkyl sulfonyl” means an alkyl radical attached through a -S(0)2- linking group.“(Ci-C4)alkylsulfonyl” include methylsulfonyl, ethylsulfonyl, propyl sulfonyl and butyl sulfonyl.

[0033] “Aryl” or“aromatic” means an aromatic 6-18 membered monocyclic or polycyclic (e.g. bicyclic or tricyclic) carbocyclic ring system. In one embodiment,“aryl” is a 6-18 membered monocylic or bicyclic system. Aryl systems include, but not limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.

[0034] “Aryloxy” means an aryl moiety attached through an oxygen linking atom. Aryloxy includes, but not limited to, phenoxy.

[0035] “Arylthio” means an aryl moiety attached through a sulfur linking atom.

Arylthio includes, but not limited to, phenylthio.

[0036] “Arylsulfmyl” means an aryl moiety attached through a -S(O)- linking group. Aryl sulfmyl includes, but not limited to, phenyl sulfmyl.

[0037] “Aryl sulfonyl” means an aryl moiety attached through a -S(0)2- linking group. Aryl sulfonyl includes, but not limited to, phenyl sulfonyl.

[0038] “Amine” means H2N- and can also be used to refer to aminium group TblNk-.

[0039] The term“alkylamine” includes a mono-, a dialkylamine and can also be used to refer to aminium (bearing a positive charge). A“monoalkyl amine” means an H(alkyl)N-, a “dialkylamine” means (alkyl)(alkyl)N-, and an“aminium” means (alkyl)(alkyl)(alkyl)N⁺-₃ H(alkyl)(alkyl)N⁺-, or H2(alkyl)N⁺-, where each instance of“alkyl” independently refers to an alkyl having a specified number of atoms.

[0040] “Carbocyclyl” means a cyclic group having a specified number of atoms, wherein all ring atoms in the ring bound to the rest of the compound (also known as the “first ring”) are carbon atoms. Examples of“carbocyclyl” includes 3-18 (for example 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 12, 1, 14, 15, 16, 17, or 17 or any range therein, such as 3-12 or 3- 10) membered saturated or unsaturated aliphatic cyclic hydrocarbon rings, or 6-18 membered aryl rings. A carbocyclyl moiety can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic, or polycyclic.

[0041] A“cycloalkyl” is an example of a fully saturated carbocyclyl.

[0042] Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclic hydrocarbon rings or aromatic hydrocarbon rings having the specified number of carbon atoms, such as 3-7 carbon atoms. Monocyclic carbocyclyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, cycloalkenyl, cycloalkynyl and phenyl.

[0043] A fused bicyclic carbocyclyl has two rings which have two adjacent ring atoms in common and can be, e.g., a (6-13 membered) fused bicyclic. The first ring attached to the parent molecular group is a monocyclic carbocyclyl and the ring fused to the first ring (also known as the“second ring”) is also a monocyclic carbocyclyl.

[0044] A bridged bicyclic carbocyclyl has two rings which have three or more adjacent ring atoms in common and can be, e.g., a (4-13 membered) bridged bicyclic or (6-13 membered) bridged tricyclic such as adamantyl. The first ring attached to the parent molecular group is a monocyclic carbocyclyl and the second ring is also a monocyclic carbocyclyl.

[0045] A spiro bicyclic carbocyclyl has two rings which have only one ring atom in common and can be, e.g., a (6-13 membered) spiro bicyclic. The first ring attached to the parent molecular group is a monocyclic carbocyclyl and the second ring is also a monocyclic carbocyclyl.

[0046] Polycyclic carbocyclyls have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common. The first ring is a monocyclic carbocyclyl and the remainder of the ring structures are monocyclic carbocyclyls . Polycyclic ring systems include fused, bridged and spiro ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.

[0047] Suitable substituents for a“substituted carbocyclyls” include, but are not limited to halogen, -OH, -O-C1-C4 alkyl, C1-C4 alkyl, fluoro-substituted-Ci-C4 alkyl, C3-C18 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) phenyl, naphthalenyl, a (4-13 membered) heterocyclyl (e.g., pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran or morpholine), or -N(R^X)(R^X ), wherein R^x and R^x are as described above.

[0048] “Cycloalkoxy” means a cycloalkyl radical attached through an oxygen linking atom.“(C3-C₆)cycloalkoxy” includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

[0049] “Cycloalkene” means an aliphatic cyclic hydrocarbon ring having one or more double bonds in the ring.

[0050] “Cycloalkyne” means an aliphatic cyclic hydrocarbon ring having one or more triple bonds in the ring.

[0051] “Hetero” refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O.“Hetero” also refers to the replacement of at least one carbon atom member in an acyclic system. When one heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. -S(O)- or -S(0)2-). A hetero ring system or a hetero acyclic system may have 1, 2, 3 or 4 carbon atom members replaced by a heteroatom.

[0052] “Heterocyclyl” means a cyclic 3-18 membered, for example 3-13-membered, 3- 15, 5-18, 5-12, 3-12, 5-6 or 5-7-membered saturated or unsaturated aliphatic or aromatic ring system containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S. When one heteroatom is S, it can be optionally mono- or di-oxygenated

(i.e. -S(O)- or -S(0)2-). The heterocyclyl can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic. Non-limiting examples include (4-7 membered) monocyclic, (6-13 membered) fused bicyclic, (6-13 membered) bridged bicyclic, or (6-13 membered) spiro bicyclic.

[0053] “Saturated heterocyclyl” means an aliphatic heterocyclyl group without any degree of unsaturation (i.e., no double bond or triple bond). It can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic. [0054] Examples of monocyclic saturated heterocyclyls include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, azepane, hexahydropyrimidine,

tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, tetrahydro-2H-l,2-thiazine, tetrahydro-2H-l,2-thiazine 1,1 -dioxide, isothiazolidine, isothiazolidine 1,1 -dioxide.

[0055] One type of“heterocyclyl” is a“heteroaryl” or“heteroaromatic ring”, which refers to a 5-18 membered monovalent heteroaromatic monocyclic or bicylic ring radical.

A heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S.

[0056] A fused bicyclic heterocyclyl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycle or a monocyclic heterocyclyl. For example, the second ring is a

(C3-C₆)cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of fused bicyclic heterocyclyls include, but are not limited to,

octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline, 2,3-dihydro-lH-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, octahydrobenzo[d]oxazole, octahydro-lH-benzo[d]imidazole, octahydrobenzo[d]thiazole,

octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3. E0]hexane, and 3-azabicyclo[3.2.0]heptane.

[0057] A spiro bicyclic heterocyclyl has two rings which have only one ring atom in common. The first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycle or a monocyclic heterocyclyl. For example, the second ring is a

(C3-C₆)cycloalkyl. Examples of spiro bicyclic heterocyclyl includes, but are not limited to, azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azasprio[4.5]decane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane.

[0058] A bridged bicyclic heterocyclyl has two rings which have three or more adjacent ring atoms in common. The first ring is a monocyclic heterocyclyl and the other ring is a monocyclic carbocycle or a monocyclic heterocyclyl. Examples of bridged bicyclic heterocyclyls include, but are not limited to, azabicyclo[3.3.1]nonane,

3-azabicyclo[3.3.1]nonane, azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane,

6-azabicyclo[3.2.1]octane and azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.2]octane.

[0059] Polycyclic heterocyclyls have more than two rings, wherein the first ring can be a heterocyclyl (e.g., three rings resulting in a tricyclic ring system) and adjacent rings having at least one ring atom in common and are heterocyclyl or carbocyclyl. Polycyclic ring systems include fused, bridged and spiro ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in

common. Examples of polycyclic heterocyclyls include

[0060] “Heteroaryl” or“heteroaromatic ring” means a 5-18 membered monovalent heteroaromatic monocyclic or bicylic ring radical. A heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S. Heteroaryls include, but are not limited to furan, oxazole, thiophene, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2,5- thiadiazole 1,1-dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, and thiazole. Bicyclic heteroaryl rings include, but are not limited to, bicyclo[4.4.0] and bicyclo[4.3.0] fused ring systems such as indolizine, indole, isoindole, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.

[0061] “Halogen” and“halo” are used interchangably herein and refer to fluorine, chlorine, bromine, or iodine.

[0062] “Haloalkyl” and“halocycloalkyl” include mono, poly, and perhaloalkyl groups where each halogen is independently selected from fluorine, chlorine, and bromine.

[0063] “Fluoro” means -F.

[0064] “Chloro” means -Cl.

[0065] As used herein,“fluoro-substituted-alkyl” or“fluoroalkyl” means an alkyl having a specified number of atoms and substituted with one or more -F groups. Examples of fluoro-substituted-alkyls include, but are not limited

to, -CFs, -CH2CF3, -CH2CF2H, -CH2CH2F and -CH2CH2CF3. [0066] “Hydroxyalkyl,” as used herein, refers to an alkyl group substituted with one or more hydroxyls. Hydroxyalkyl includes mono, poly, and perhydroxyalkyl groups.

Examples of hydroxyalkyls include -CH2CH2OH and -CH2CH(0H)CH20H.

[0067] “Oxo” means substituted with =0.

[0068] As described herein, compounds of the invention may contain“optionally substituted” moieties. In general, the term“substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.

The term“stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0069] In the paragraphs below,“Ph” is phenyl.

[0070] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently

halogen; -(CH₂)o-4R°; -(CH₂)o-40R°; -0(CH₂)o-4R°,

-0-(CH₂)O-4C(0)OR°; -(CH₂)O-4CH(OR°)2; -(CH₂)O-4SR°; -(CH₂)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with

R°; -NO2; -CN; -Ns; -(CH₂)o-4N(R°)2; -(CH₂)o-4N(R⁰)C(0)R°; -N(R°)C(S)R°; -(CH₂)o-4N(R °)C(0)NR°₂; -N(R°)C(S)NR°2; -(CH₂)O-4N(R⁰)C(0)OR°; -N(R°)N(R°)C(0)R°; -N(R°)N(R °)C

(0)NR°₂; -N(R°)N(R°)C(0)OR°; -(CH₂)O-4C(0)R°; -C(S)R°; -(CH₂)O-4C(0)OR°; -(CH₂)O-4 C (0)SR°; -(CH₂)o-4C(0)0 SiR°3 ; -(CH₂)o-40C(0)R°; -OC(0)(CH₂)o-4SR-, -SC(S)SR°; -(CH₂)o-4 SC(0)R° ; -(CH₂)O-4C(0)NR°2; -C(S)NR°₂; -C(S)SR°; -SC(S)SR°, -(CH₂)O-40C(0 )NR°₂; -C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH₂C(0)R°; -C(NOR°)R⁰;-(CH2)O-4SSR°; -( CH₂)O-4S(0)2R°; -(CH₂)O-4 S(0)₂0R° ; -(CH₂)o-40S(0)2R°; -S(0)₂NR°2; -(CH₂)o-4S(0)R°; -N (R°)S(0)2NR°2; -N(R⁰)S(0)₂R°; -N(OR°)R°; -C(NH)NR°₂; -P(0)₂R°; -P(0)R°₂; -0P(0)R° 2; -OP (0)(0R°)2; SiR°3; -(Ci-4 straight or branched alkylene)0-N(R°)2; or -(Ci-4 straight or branched alkylene)C(0)0-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-₆ aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0071] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH₂)O-2R·, -(haloR*), -(CH₂)o-20H, -(CH2)o-20R*,-(CH2)o-2CH(OR*)2; -0(haloR *),

-CN, -N₃, -(CH₂)O-2C(0)R·, -(CH₂)O-2C(0)OH, -(CH₂)O-2C(0)OR·, -(CH₂)O-2SR·, -(CH₂)O-2 SH, -(CH₂)O-2NH2, -(CH₂)O-2NHR·, -(CH₂)O-2NR*2, -NO2, -SiR*₃, -OSiR*₃, -C(0)SR* -(CM straight or branched alkylene)C(0)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is

independently selected from CM aliphatic, -CfhPh, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0072] Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: =0, =S, =NNR%, =NNHC(0)R^*,

=NNHC(0)OR^*, =NNHS(0)₂R^*, =NR^*, =NOR^*, -0(C(R^* ₂))2-₃0-, or -S(C(R^* ₂))2-₃S-, wherein each independent occurrence of R^* is selected from hydrogen, Ci-₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: -0(CR^*2)2-30-, wherein each independent occurrence of R^* is selected from hydrogen, Ci-₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] Suitable substituents on the aliphatic group of R^* include

halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH₂, -NHR*

, -NR*!, or -NO2, wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently

Ci-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0074] Suitable substituents on a substitutable nitrogen of an“optionally substituted” group

include -R^†, -NR^† ₂, -C(0)R^†, -C(0)OR^†, -C(0)C(0)R^†, -C(0)CH₂C(0)R^†, -S(0)₂R^†, -S(0)₂ NR^†2, -C(S)NR^†2, -C(NH)NR^†2, or -N(R^†)S(0)2R^†; wherein each R^† is independently hydrogen, Ci-₆ aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0075] Suitable substituents on the aliphatic group of R^† are independently

halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR'), -CN, -C(0)OH, -C(0)OR*, -NH₂, -NHR*

, - R*!, or -NO2, wherein each R* is unsubstituted or where preceded by“halo” is substituted only with one or more halogens, and is independently

Ci-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0076] As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety.

Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases that are compatible with the treatment of patients.

[0077] Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable acid addition salts include adipate, alginate, ascorbate, aspartate,

benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like.

[0078] Examples of non-toxic organic or inorganic base addition salts include, but are not limited thereto, lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0079] When introducing elements disclosed herein, the articles“a,”“an,”“the,” and “said” are intended to mean that there are one or more of the elements. For example, one or more can mean 1-20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. The terms“comprising,”“having” and“including” are intended to be open-ended and mean that there may be additional elements other than the listed elements.

[0080] The invention also includes various isomers and mixtures thereof. Certain of the compounds of the present invention may exist in various stereoisomeric forms.

Stereoisomers are compounds which differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. “Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms “i?” and“5” represent the configuration of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, either a pure enantiomer or a mixture of both configurations is present.

[0081] “Racemate” or“racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.

[0082] The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0083] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by weight pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer that is present divided by the combined weight of the enantiomer that is present and the weight of its optical isomer.

[0084] “Cis” means on the same side.“Trans” means on opposite sides. The designation“cis” is used when two substituents have an“”up-up” or a“down-down” relationship. The designation“trans” is used when two substituents have an“up-down” or “down-up” relationship. Typically, two substituents that are“cis” to one another are arranged on the same side of a molecule.

[0085] As used herein,“subject” refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.

[0086] As used herein, the term“treating” or‘treatment” refers to obtaining desired pharmacological and/or physiological effect. The effect can include achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

[0087] As used herein,“preventing” or“prevention” refers to reducing the likelihood of the onset or development of disease, disorder or syndrome.

[0088] “Effective amount” means that amount of active compound agent that elicits the desired biological response in a subject. In one embodiment, the effective amount of a compound of the invention is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, or from about 0.5 mg/kg/day to about 50 mg/kg/day.

[0089] As used herein,“Bcl-2 inhibitor” refers to any agent that inhibits the function of the Bcl-2 protein family, such as Bax and Bak proteins. These agents include, but are not limited to venetoclax (ABT-199), navitoclax (ABT-737), obatoclax, HA14-1, AT101, sabutoclax and gambogic acid.

[0090] As used herein, the term“additive” refers to an amount of tumor growth reduction or apoptosis by a combination treatment that is the sum of the effect observed with each individual therapeutic agent alone.

[0091] As used herein, the term“synergistic” refers to an amount of tumor growth reduction or apoptosis by a combination treatment that is greater than the sum of the effect observed with each individual therapeutic agent alone.

[0092] As used herein, the terms“hematological malignancy” and“hematological cancer” are used interchangeably and refer to cancers of the blood (leukemia) or cancers of the lymph system (lymphomas). Leukemias can include acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute

granulocytic leukemia or acute nonlymphocytic leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and acute monocytic leukemia (AMoL). Lymphomas can include, Hodgkin’s lymphoma, non-Hodgkin’s lymphomas, multiple myeloma, myelodysplastic or myeloproliferative syndrome, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma/leukemia and B-cell lymphoma.

[0093] As used herein,“venetocl ax-refractory” refers to subjects that show progressive disease under venetoclax monotherapy or in combination therapy with one or more other additional therapeutic agents or who have relapsed under venetoclax monotherapy or combination therapy. In some embodiments, venetocl ax-refractory subjects have a mutation in the Bcl-2 protein, such as at GlylOl Val.

[0094] In a first embodiment, the invention relates to a method of treating

hematological cancer in a subject in need thereof, comprising the combination

administration to the subject of a first amount of venetoclax, and a second amount of a compound represented by Formula (I):

I

or a pharmaceutically acceptable salt thereof, wherein

R⁸⁰³ is a Ci-₆ alkyl, H, a Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, a C3-12 carbocyclyl-(Co- 3)alkylenyl, an amino-(Ci-C4) alkyl, a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl, or a (4- 13 member)heterocyclyl-(Co-C₃)alkylenyl, wherein the heterocyclyl portion is optionally substituted with a C1-₃ alkyl;

R⁷⁰¹ is a Ci-4 alkyloxy, H, -OH, Ci-4 alkyl, a Ci-4 haloalkyl, Ci-4 hydroxyalkyl, or Ci- 4 haloalkoxy;

R⁴⁰³ and R^403’, each independently, are H; a Ci-4 alkyl; a C1-C4 haloalkyl; a C1-C4 hydroxyalkyl; a (C1-C4 alkoxy)-(Ci-4)alkyl; an amino-(Ci-C4) alkyl; a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl; or a C₃-12 carbocyclyl-(Co-C₃)alkylenyl, wherein the carbocyclyl portion is optionally substituted with a hydroxyl group; a (Ci-4 alkyl)C(O)-, a (Ci-4 alkyl)S(0)i-2-; a (CM alkyl)C(0)NH(Ci-₄ alkylenyl)-; a (CM alkyl)S(0)i-₂NH(Ci-4 alkylenyl)-; a H0C(0)-(Ci-C₃)alkylenyl; a H2NC(0)-(Ci-C₃)alkylenyl; or a (CM

alkyloxy)C(0)-( Ci-C₃)alkylenyl; and

wherein the first and second amounts together comprise an effective amount. [0095] In a first aspect of the first embodiment, R⁴⁰³ and R^403’ are both H and the remainder of the values and variables in formula (1) are as defined above with respect to the first embodiment.

[0096] In a second aspect of the 1^st embodiment, R⁷⁰¹ is -OCH3. The remainder of the values of the variables in structural formula (I) of the first embodiment are as defined above with respect to the first embodiment or the first aspect of the first embodiment.

[0097] In the third aspect of the first embodiment, R⁸⁰³ is ethyl. The remainder of the values of the variables in structural formula (I) of the first embodiment are as defined above with respect to the first embodiment or the first or second aspects of the first embodiment.

[0098] In the fourth aspect of the first embodiment, R⁷⁰¹ is a -OCF3, and R⁸⁰³ is methyl. The remainder of the values of the variables in structural formula (I) are as defined above with respect to the first embodiment and the first aspect of the first embodiment.

[0099] In the fifth aspect of the first embodiment, the compound is represented by the following structural formula

or a pharmaceutically acceptable salt thereof. The following structural formula is referred to herein as TP-2846.

[00100] In a second embodiment of the invention, the venetoclax of the first embodiment or any one of the first, second, third, fourth or fifth aspects of the first embodiment, is administered orally once daily at a dose of from about 20 mg to about 400 mg. For example, in a specific aspect the venetoclax is administered orally once daily at a dose of about 50 mg to about 200 mg. In another specific aspect, venetoclax is administered orally once daily at a dose of 400 mg. In yet another specific aspect, a venetoclax is administered orally once daily at a dose of 200 mg. In a further specific aspect, venetoclax is

administered orally once daily at a dose of 100 mg.

[00101] In a third embodiment of the invention, compound of Formula (I) of the first embodiment or any one of the first, second, third, fourth or fifth aspects of the first embodiment or of the second embodiment, the compound of Formula (I) is administered at a dose of about 5 mg to about 40 mg per day. In a specific aspect, the compound of Formula (I) is administered at a dose of about 10 mg to about 30 mg per day. In a further specific aspect, the compound of Formula (I) is administered at a dose of 20 mg per day.

[00102] In a fourth embodiment of the invention, the hematological cancer of the first embodiment or any one of the first, second, third, fourth or fifth aspects of the first embodiment or of the 2^nd embodiment, is selected form a leukemia or a lymphoma. In a particular aspect of the fourth embodiment, the hematological cancer is a leukemia selected from acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and acute monocytic leukemia (AMoL). In another particular aspect of the fourth embodiment, the hematological cancer is acute myeloid leukemia. In another particular aspect of the fourth embodiment, the hematological cancer is a lymphoma selected from Hodgkin’s lymphoma, non-Hodgkin’s lymphomas, multiple myeloma, myelodysplastic or myeloproliferative syndrome, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma/leukemia and B-cell lymphoma.

[00103] In a fifth embodiment, the invention relates to a kit for treating hematological cancers. The kit comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions for use with a Bcl-2 inhibitor (e.g., venetoclax) according to the method of the invention and optionally a device for administering the compounds of the kit. In a particular aspect, both the compound of Formula (I) and the Bcl-2 inhibitor are present in the kit in an effective amount. In another particular aspect, the compound of Formula (I) or the Bcl-2 inhibitor is present in the kit in a sub-therapeutic dose. In a further aspect, both the compound of Formula (I) and the Bcl-1 inhibitor are present in the kit in a sub-therapeutic dose.

[00104] In a sixth embodiment, the subject of the first, second, third or fourth embodiment and any aspect thereof is either venetocl ax-refractory or not refractory to venetoclax.

[00105] In a seventh embodiment, the invention further comprises administration of an additional therapeutic agent. [00106] In an eighth embodiment, the invention relates to a method of treating hematological cancer in a venetoclax-refractory subject in need thereof, comprising administering to the subject a compound represented by Formula (I)

I

or a pharmaceutically acceptable salt thereof, wherein

R⁸⁰³ is a Ci-₆ alkyl, H, a Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, a C3-12 carbocyclyl-(Co- 3)alkylenyl, an amino-(Ci-C4) alkyl, a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl, or a (4- 13 member)heterocyclyl-(Co-C₃)alkylenyl, wherein the heterocyclyl portion is optionally substituted with a C1-₃ alkyl;

R⁷⁰¹ is a Ci-4 alkyloxy, H, -OH, Ci-4 alkyl, a Ci-4 haloalkyl, Ci-4 hydroxyalkyl, or Ci- 4 haloalkoxy;

R⁴⁰³ and R^403’, each independently, are H; a Ci-4 alkyl; a C1-C4 haloalkyl; a C1-C4 hydroxyalkyl; a (C1-C4 alkoxy)-(Ci-4)alkyl; an amino-(Ci-C4) alkyl; a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl; or a C₃-12 carbocyclyl-(Co-C₃)alkylenyl, wherein the carbocyclyl portion is optionally substituted with a hydroxyl group; a (Ci-4 alkyl)C(O)-, a (Ci-4 alkyl)S(0)i-2-; a (CM alkyl)C(0)NH(Ci-₄ alkylenyl)-; a (CM alkyl)S(0)i-₂NH(Ci-4 alkylenyl)-; a HOC(0)-(Ci-C₃)alkylenyl; a H2NC(0)-(Ci-C₃)alkylenyl; or a (CM

alkyloxy)C(0)-( Ci-C₃)alkylenyl.

[00107] In a first aspect of the eighth embodiment, R⁴⁰³ and R⁴⁰³ are both H and the remainder of the values and variables in formula (1) are as defined above with respect to the eighth embodiment.

[00108] In a second aspect of the eighth embodiment, R⁷⁰¹ is -OCH_3. The remainder of the values of the variables in structural formula (I) of the seventh embodiment are as defined above with respect to the eighth embodiment or the first aspect of the eighth embodiment.

[00109] In the third aspect of the eighth embodiment, R⁸⁰³ is ethyl. The remainder of the values of the variables in structural formula (I) of the eighth embodiment are as defined above with respect to the eighth embodiment or the first or second aspects of the eighth embodiment. [00110] In the fourth aspect of the eighth embodiment, R⁷⁰¹ is a -OCF3, and R⁸⁰³ is methyl. The remainder of the values of the variables in structural formula (I) are as defined above with respect to the eighth embodiment and the first aspect of the eighth embodiment.

[00111] In the fifth aspect of the eighth embodiment, the compound is represented by the following structural formula

or a pharmaceutically acceptable salt thereof. The following structural formula is referred to herein as TP -2846. In some instances the TP -2846 compound can be depicted as follows:

[00112] In an ninth embodiment of the invention, the compound of Formula (I) of the eighth embodiment or any one of the first, second, third, fourth or fifth aspects of the seventh embodiment, the compound of Formula (I) is administered at a dose of about 5 mg to about 40 mg per day. In a specific aspect, the compound of Formula (I) is administered at a dose of about 10 mg to about 30 mg per day. In a further specific aspect, the compound of Formula (I) is administered at a dose of 20 mg per day.

[00113] In a tenth embodiment of the invention, the hematological cancer of the eighth embodiment or any one of the first, second, third, fourth or fifth aspects of the eighth embodiment or of the ninth embodiment, is selected form a leukemia or a lymphoma. In a particular aspect of the tenth embodiment, the hematological cancer is a leukemia selected from acute myeloid leukemia (AML), also known as acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia or acute nonlymphocytic leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and acute monocytic leukemia (AMoL). In another particular aspect of the ninth embodiment, the hematological cancer is acute myeloid leukemia. In another particular aspect of the ninth embodiment, the hematological cancer is a lymphoma selected from Hodgkin’s lymphoma, non-Hodgkin’s lymphomas, multiple myeloma, myelodysplastic or myeloproliferative syndrome, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma/leukemia and B-cell lymphoma.

Combination Therapy/Coadministration/Combined Administration

[00114] In certain embodiments, the combined administration of the compound of Formula (I) and the Bcl-2 inhibitor (e.g., venetoclax) can provide an enhanced therapeutic effect or can demonstrate synergy ( i.e . show a therapeutic effect that is greater than the additive effect resulting from separate administration of each component of the

combination). An advantage of a synergistic effect of the combination therapy is the ability to use less of each agent than is needed when each is administered alone. As such, undesirable side effects associated with the agents can be reduced (partially or completely). The presence of synergistic effects can be determined using suitable methods for assessing drug interaction. Suitable methods include, for example, the Sigmoid-Emax equation, the equation of Loewe additivity and the median-effect equation. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Another method for assessing synergy of the combination of a combination of Formula (I) and a Bcl-2 inhibitor (e.g., venetoclax) is SynergyFinder in combination with the Zero Interaction Potency (ZIP) model.

[00115] As used herein,“an enhanced therapeutic effect” includes an improved therapeutic profile. Examples of enhanced therapeutic effects include the ability to use a less of one or both agents administered in the combination therapy than is needed when each is used alone, a prolonged therapeutic window of one or both compounds of the combination therapy, reduced side effects following administration of the combination therapy, reduced resistance of hemotological cancer cells to one or both compounds of the combination (e.g, reduced resistance of the hematological cancer to venetoclax) and sensitization of target cells to the action of one or both compounds of the combination therapy (e.g, increased sensitivity of hemotological cancer cells to venetoclax). [00116] As used herein, the combined administration (also referred to herein as co administration) refers to administration of a first amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and a second amount of the Bcl-2 inhibitor (e.g., venetoclax), wherein the first and second amounts together comprise an effective amount.

[00117] As used herein, an amount effective to treat a disorder, or an“effective amount” refers to an amount of the compound of Formula (I) and venetoclax that together (e.g., in combination) is effective, upon single or multiple dose administration to a subject or a cell, in curing, alleviating, relieving or improving one or more symptoms of the target disorder (e.g., hematological cancer).

[00118] In one embodiment, the compound of Formula (I) and venetoclax are each administered in a respective effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound of Formula (I) and venetoclax are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet another embodiment, the compound of Formula (I) can be administered in an effective amount, while venetoclax is administered in a sub-therapeutic dose. In still another embodiment, venetoclax can be administered in an effective amount, while the compound of Formula (I) is administered in a sub-therapeutic dose.

[00119] In some embodiments, the compound of Formula (I) is administered

simultaneously with the Bcl-2 inhibitor (e.g., venetoclax). Simultaneous administration typically means that both compounds enter the patient at essentially the same time, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. Co administration also include use of each compound of the combination therapy in a sequential manner in either order. When co-administration involves the separate administration of the first amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and the second amount of the Bcl-2 inhibitor (e.g., venetoclax) the first and second amounts are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration, which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, the compound of Formula (I) and the Bcl-2 inhibitor (e.g., venetoclax) can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, within about 30 minutes of each other, within about 15 minutes or each other or within about 5 minutes of each other.

[00120] In one example, wherein the compounds are in solution, simultaneous administration can be achieved by administering a solution containing the combination of compounds. In another example, simultaneous administration of separate solutions, one of which contains the compound of Formula (I) and the other of which contains the Bcl-2 inhibitor (e.g., venetoclax), can be employed. In one example wherein the compounds are in solid form, simultaneous administration can be achieved by administering a composition containing the combination of compounds. Alternatively, simultaneous administration can be achieved by simultaneous administration of separate solid dosage forms.

Additional Therapeutic Agents

[00121] In some embodiments, the method of treating hematological cancer can comprise administering a compound of Formula (I) and venetoclax, conjointly with one or more other additional therapeutic agent(s), for example a chemotherapeutic agent.

Likewise, the method of treating a hematological cancer in a venetoclax-refractory subject comprising administering a compound represented by structural Formula (I) or a pharmaceutically acceptable salt thereof, for example TP -2846, can also include co administration of one or more additional agents, for example a chemotherapeutic agent.

[00122] Additional chemotherapeutic agents that can be used in the inventions described herein include, but are not limited to: l-amino-4-phenylamino-9,10-di oxo-9, 10- dihydroanthracene-2-sulfonate (acid blue 25), l-amino-4-[4-hydroxyphenyl-amino]-9,10- di oxo-9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[4-aminophenylamino]-9, 10-dioxo- 9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[ 1 -naphthylamino]-9, 10-di oxo-9, 10- dihydroanthracene-2-sulfonate, l-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo- 9, 10-dihydroanthracene-2-sulfonate, l-amino-4-[2-anthracenylamino]-9, 10-dioxo-9, 10- dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, b -methyl ene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine,

dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone,

dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim,

fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA).

[00123] In other embodiments, the additional chemotherapeutic agents that can be conjointly administered in accordance with the inventions described herein include, but are not limited to: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: l-amino-4-phenylamino-9,10- dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), l-amino-4-[4-hydroxyphenyl- amino]-9, 10-di oxo-9, 10-dihydroanthracene-2-sulfonate, l-amino-4-[4-aminophenylamino]-

9.10-di oxo-9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[ 1 -naphthylamino]-9, 10-dioxo-

9.10-dihydroanthracene-2-sulfonate, l-amino-4-[4-fluoro-2-carboxyphenylamino]-9, 10- di oxo-9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4-[2-anthracenylamino]-9, 10-dioxo-

9,10-dihydroanthracene-2-sulfonate, APCP, b-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4- sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline. [00124] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds of the invention (e.g., compounds of Formula (I) either alone or in combination with venetoclax) can be conjointly administered with a combination therapy. Examples of combination therapies with which compounds of the invention (either alone or in combination with venetoclax) can be conjointly administered are included in Table 1.

Table 1 : Exemplary combinatorial therapies for the treatment of cancer

[00125] In some embodiments, the additional therapeutic agent is an adenosine receptor inhibitor. In specific embodiments, the adenosine receptor inhibitor is selected from rolofylline, tonapofylline, ATL-444, istradefylline, MSX-3, preladenant, SCH-58,261, SCH-412,348, SCH-442,416, ST-1535, VER-6623, VER-6947, VER-7835, vipadenant, and ZM-241,385. In some embodiments, the adenosine receptor inhibitor targets the A2A receptor as this subtype is predominantly expressed in most immune cells.

[00126] In other embodiments, the additional therapeutic agent is a nucleoside-based drug. In certain embodiments, the nucleoside-based drug is selected from gemcitabine, capecitabine, cytarabine, fludarabine and cladribine.

[00127] In further embodiments, the additional therapeutic agnet is an anthracycline. In other embodiments, the additional therapeutic agent is doxorubicin.

[00128] In certain embodiments, the additional therapeutic agent is an immuno- oncology agent. Cancer cells often have specific cell surface antigens that can be recognized by the immune system. Thus, immuno-oncology agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and effect cell death. Other immuno- oncology agents can suppress tumor-mediated inhibition of the native immune response or otherwise activate the immune response and thus facilitate recognition of the tumor by the immune system. Exemplary antibody immuno-oncology agents, include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immune-oncology agents are selected from anti-CD73 monoclonal antibody (mAb), anti-CD39 mAb, anti-PD- 1 mAb, and anti-CTLA4 mAb.

[00129] In some embodiments, the additional therapeutic agent is selected from an anti-PD-1 therapy and an anti-CTLA4 therapy. In certain embodiments, the additional therapeutic agent is oxaliplatin. In other embodiments, the additional therapeutic agent is doxorubicin.

[00130] In some embodiments, the additional therapeutic agent is selected from acalabrutinib, alvocidib, AMG 176, atezolizumab, avelumab, azacytidine, bendamustine, BI 836826, bisulfan, bortezomib, carfilzomib, carmustine, chlorambucil, cladribine, cobimetinib, copanlisib, CPX-351 (Vyexos), CYC065, cyclophosphamide, cytarabine, danorubicin, daratumumab, decitabine, dexamethasone, dinaciclib, duvelisib, enzalutamide, etoposide, fimepinostat, flutabarine, fulvestrant, gilteritinib, HDM201, ibrutinib, idarubicin, idasanutlin, idelalisib, ivosidenib, ixazomib, lenalidomide, Iintuzumab-Ac225, MOR00208, navitoclax, obinutuzumab (Gazyva), pevonedistat, polatuzumab vedotin, pomalidomide, ponatinib, prednisone, quizartinib, rituximab, rovalpituzumab tesirine, ruxolitnib, S 64315, sapacitabine, selinexor, TAK-659, trabectedin, ublituximab, umbralisib, vincristine, and zanubrutinib.

[00131] In some embodiments, the method of treating hematological cancer can comprise administering a compound of Formula (I) and venetoclax, conjointly with one or more other non-chemical methods of cancer treatment. Likewise, the method of treating a hematological cancer in a venetoclax refractory subject comprising administering a compound represented by structural Formula (I) or a pharmaceutically acceptable salt thereof, for example TP -2846, can also include co-administration one or more other non chemical methods of cancer treatment. In certain embodiments, the non-chemical method is radiation therapy. In other embodiments, the non-chemical method is surgery,

thermoablation, focused ultrasound therapy, cryotherapy, or any combination of these. [00132] In certain embodiments, the one or more additional therapeutic agents provide an enhanced or a synergistic effect. In other embodiments, the one or more additional therapeutic agents provides an additive effect.

Modes of Administration

[00133] Compositions of the present invention can be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, transdermally, sublingually, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and/or intraperitoneally.

[00134] The term“parenteral,” as used herein, includes subcutaneous, intracutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-arterial, intra- synovial, intrastemal, intrathecal, intralesional, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously.

[00135] The compound of Formula (I) and the Bcl-2 inhibitor (e.g., venetoclax) can each be formulated separately, in separate formulations (selected independently), or can be formulated together in a single formulation. “Composition” and“pharmaceutical composition,” used herein, include: compositions comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; compositions comprising the Bcl-2 inhibitor (e.g., venetoclax) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; and compositions comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and Bcl-2 inhibitor (e.g., venetoclax), or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.

[00136] When the compounds are formulated separately (e.g., in a composition comprising the compound and a pharmaceutically acceptable carrier), the amount of the compound of Formula (I) should be such that, when administered in combination with Bcl- 2 inhibitor (e.g., venetoclax) to treat hemotological cancer, the amount is an“effective amount.”

[00137] The compounds can also be formulated in a single dosage form (a“unit dosage form”). Thus, one embodiment is a pharmaceutical composition comprising a first amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a second amount of Bcl-2 inhibitor (e.g., venetoclax), or a pharmaceutically acceptable salt thereof, wherein the first and second amounts together comprise an effective amount. In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. The term“unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a

predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same of different for each dose.

[00138] As used herein,“pharmaceutically acceptable” includes molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards, as required by FDA Office of Biologies standards.

[00139] The phrase“pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, wool fat, cyclodextrins such as a-, b-, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- b-cyclodextrins and self- emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate.

[00140] Pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and/or emulsions are required for oral use, the active ingredient can be suspended or dissolved in an oily phase and combined with emulsifying and/or suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[00141] Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example, by an outer coating of the formulation on a tablet or capsule.

[00142] In some embodiments, an oral formulation is formulated for immediate release or sustained/delayed release.

[00143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium salts, g) wetting agents, such as acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00144] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[00145] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00146] A compound in a pharmaceutical composition of the invention can also be in micro-encapsulated form with one or more excipients, as noted above. In such solid dosage forms, the compound of the invention can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.

[00147] In another embodiment, a pharmaceutical composition can be provided as an extended (or“delayed” or“sustained”) release composition. This delayed-release composition comprises a compound in combination with a delayed-release component.

Such a composition allows targeted release of a provided compound into the lower gastrointestinal tract, for example, into the small intestine, the large intestine, the colon and/or the rectum. In certain embodiments, the delayed-release composition comprising a compound of the invention further comprises an enteric or pH-dependent coating, such as cellulose acetate phthalates and other phthalates (e.g, polyvinyl acetate phthalate, methacrylates (Eudragits)). Alternatively, the delayed-release composition provides controlled release to the small intestine and/or colon by the provision of pH sensitive methacrylate coatings, pH sensitive polymeric microspheres, or polymers which undergo degradation by hydrolysis. The delayed-release composition can be formulated with hydrophobic or gelling excipients or coatings. Colonic delivery can further be provided by coatings which are digested by bacterial enzymes such as amylose or pectin, by pH dependent polymers, by hydrogel plugs swelling with time (Pulsincap), by time-dependent hydrogel coatings and/or by acrylic acid linked to azoaromatic bonds coatings.

[00148] In certain embodiments, the delayed-release composition of the present invention comprises hypromellose, microcrystalline cellulose, and a lubricant. The mixture of a compound of the invention, hypromellose and microcrystalline cellulose can be formulated into a tablet or capsule for oral administration. In certain embodiments, the mixture is granulated and pressed into tablets.

[00149] Alternatively, pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the compound of the invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00150] Pharmaceutically acceptable compositions of this invention can also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs.

[00151] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches can also be used.

[00152] For other topical applications, the pharmaceutically acceptable compositions of the invention can be formulated in a suitable ointment containing the active components suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water and penetration enhancers. Alternatively, pharmaceutically acceptable compositions of the invention can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents. In some embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. In other embodiments, suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water and penetration enhancers.

[00153] For ophthalmic use, pharmaceutically acceptable compositions of the invention can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[00154] Pharmaceutically acceptable compositions of this invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[00155] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for oral administration.

[00156] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for intravenous administration.

[00157] In some embodiments, pharmaceutically acceptable compositions of this invention are formulated for topical administration.

[00158] The amount of the compounds that can be combined with the carrier materials to produce a composition in a single unit dosage form will vary depending upon the host treated, the particular mode of administration and the activity of the compound employed.

[00159] It should also be understood that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician and the severity of the particular disease being treated.

[00160] The pharmaceutical compositions of this invention comprising the compound of Formula (I), the Bcl-2 inhibitor (e.g., venetoclax), or a combination of the compound of Formula (I) and the Bcl-2 inhibitor (e.g., venetoclax) are preferably administered by oral administration or by injection. The pharmaceutical compositions of this invention can contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.

[00161] The pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.

[00162] In some embodiments, the Bcl-2 inhibitor (e.g., venetoclax) is administered orally once daily at a dose of about 20 mg to about 400mg. In some embodiments, venetoclax is administered orally once daily at a dose of about 50 mg to about 200 mg. In some embodiments, venetoclax is administered orally once daily at a dose of about 400 mg. In some embodiments, venetoclax is administered orally once daily at a dose of 200 mg. In some embodiments, venetoclax is administered orally once daily at a dose of lOOmg.

[00163] In some embodiments, the compound of Formula (I) is administered at a dose of about 5 mg to about 100 mg per day. In some embodiments, compound of Formula (I) is administered at a dose of about 5 mg to about 40 mg per day. In some embodiments, compound of Formula (I) is administered at a dose of aboutlO mg to about 30 mg per day. In some embodiments, the compound of Formula (I) is administered at a dose of about 20 mg.

[00164] Doses lower or higher than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[00165] Upon improvement of a patient’s condition, a maintenance dose of a

composition of this invention can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon recurrence of disease symptoms.

EXEMPLIFICATION

Example 1. Antiproliferative activity of TP-2846 against a venetoclax-sensitive and a venetoclax resistant cell line

[00166] The antiproliferative activity of TP-2846 was compared to that of venetoclax (CAS 1257044-40-8, also called ABT-199) against the OCI-AML-2 (venetoclax sensitive) and OCI-AML-3 (venetoclax resistant) cell lines. Cell proliferation assays were performed at test concentrations up to 10 uM using Promega Cell-Titer-Glo (#G7572) assay kits according to manufacturer instructions. Cells were plated in white-walled clear flat-bottom cell-culture treated assay plates (Coming #3903) targeting approximately l-2xl0⁵ cells per mL in a total 50pL volume at the time of compound addition. Compound dilutions were prepared at a 2X concentration and 50 pL added to appropriate wells. Treatment plates were incubated for 72 hours. At each time point, cells were removed from the incubator and allowed to come to room temperature. Cell-Titer-Glo reagent was prepared according to manufacturer instructions and 100 pL added to assay plates. Plates were briefly shaken on a plate shaker then allowed to incubate at room temperature for 10 minutes prior to read out. Plates were read on a LumiStar Optima luminometer. Relative luminescence values were used to calculate growth percentages relative to no treatment control wells, activity was plotted in Graph Pad Prism and inhibition values derived from best fit curves for each plot. Treatment groups were plotted as a percentage of no treatment using a minimum of two replicates per plate and presented as an average of multiple assays where data are available.

[00167] The results are outlined in FIG. 1 A and FIG. IB. Against the OCI-AML-2 cell line (FIG. 1A), venetoclax shows potent activity (ICso between 0.01 and 0.1 uM). TP -2846 also demonstrated significant activity in the assay, with an ICso between 0.1 and 1 uM. Against the OCI-AML-3 cell line (FIG. IB), TP-2846 demonstrated significant activity in the assay, with an ICso between 0.1 and 1 uM, but venetoclax showed less activity, with an IC50 around 10 uM, which is more than 100-fold less potenct compared with the OCI- AML2 cell line. In summary, TP-2846 demonstrated the ability to inhibit AML cell lines regardless of their venetoclax resistance status. Example 2. Antiproliferative activity of TP-2846 in combination with venetoclax against the OCI-AML-3 cell line

[00168] TP-2846 and venetoclax were combined to evaluate a potential synergy (i.e., more-than-additive effects) between the two agents against the OCI-AML-3 cell line (venetoclax resistant). The antiproliferative assays was run under conditions similar to Example 1, except that a set of concentrations of each agent was used in a checkerboard combination. TP-2846 concentrations up to 1 uM and venetoclax concentrations up to 20 uM were used with 4X compound stocks each overlaid in 25 pL volumes. Synergy and antagonism scores were calculated using the SynergyFinder server

(https://synergyfmder.fimm.fi/, model published in Bioinformatics, 33(15), 2017, 2413- 2415, Ianevski et al.) and analyzed by the zero interaction potency (ZIP) model. Results are outlined in FIG 2 A and FIG. 2B. Across a wide range of concentrations, TP-2846 and venetoclax demonstrate a positive ZIP score which is indicative of synergy. This assays demonstrates the potential for combination of venetoclax and TP -2846 in AML treatment to achieve significant tumor control and prolonged anticancer activity.

Example 3: Antiproliferative activity of TP-2846 in combination with venetoclax against the OCI-AML-2 cell line

[00169] TP-2846 and venetoclax were combined to evaluate a potential synergy (i.e., more-than-additive effects) between the two agents against the venetoclax-sensitive OCI- AML-2 cell line. The antiproliferative assays was run under conditions similar to Example 2, except that TP-2846 concentrations ranged from 0 to 500 nM and venetoclax

concentrations ranged from 0 to 50 nM. Results are outlined in FIG. 3 A and FIG. 3B. Across a wide range of concentrations, TP-2846 and venetoclax demonstrate a positive ZIP score which is indicative of synergy. This effect is observed on both venetoclax-resistant lines (Example 2) or venetoclax-sensitive lines (Example 3).

Claims

CLAIMS What is claimed is:

1. A method of treating hematological cancer in a subject in need thereof, comprising the combination administration to the subject of a first amount of venetoclax, and a second amount of a compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R⁸⁰³ is a Ci-₆ alkyl, H, a Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, a C3-12 carbocyclyl-(Co- 3)alkylenyl, an amino-(Ci-C4) alkyl, a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl, or a (4- 13 member)heterocyclyl-(Co-C₃)alkylenyl, wherein the heterocyclyl portion is optionally substituted with a C1-₃ alkyl;

R⁷⁰¹ is a Ci-4 alkyloxy, H, -OH, Ci-4 alkyl, a Ci-4 haloalkyl, Ci-4 hydroxyalkyl, or Ci- 4 haloalkoxy;

R⁴⁰³ and R^403’, each independently, are H; a Ci-4 alkyl; a C1-C4 haloalkyl; a C1-C4 hydroxyalkyl; a (C1-C4 alkoxy)-(Ci-4)alkyl; an amino-(Ci-C4) alkyl; a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl; or a C₃-12 carbocyclyl-(Co-C₃)alkylenyl, wherein the carbocyclyl portion is optionally substituted with a hydroxyl group; a (Ci-4 alkyl)C(O)-, a (Ci-4 alkyl)S(0)i-2-; a (CM alkyl)C(0)NH(Ci-₄ alkylenyl)-; a (CM alkyl)S(0)i-₂NH(Ci-4 alkylenyl)-; a H0C(0)-(Ci-C₃)alkylenyl; a H2NC(0)-(Ci-C₃)alkylenyl; or a (CM

alkyloxy)C(0)-( Ci-C₃)alkylenyl; and

wherein, the first and second amounts together comprise an effective amount.

2. A method of treating hematological cancer in a venetocl ax-refractory subject in need thereof, comprising administering to the subject a compound represented by Formula

(I) or a pharmaceutically acceptable salt thereof, wherein

R⁸⁰³ isa Ci-6 alkyl, H, a Ci-6 haloalkyl, Ci-6 hydroxyalkyl, a C3-12 carbocyclyl-(Co- 3)alkylenyl, an amino-(Ci-C4) alkyl, a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl, or a (4- 13 member)heterocyclyl-(Co-C3)alkylenyl, wherein the heterocyclyl portion is optionally substituted with a C1-3 alkyl;

R⁷⁰¹ is a Ci-4 alkyloxy, H, -OH, Ci-4 alkyl, a Ci-4 haloalkyl, Ci-4 hydroxyalkyl, or Ci-4 haloalkoxy;

R⁴⁰³ and R^403’, each independently, are H; a Ci-4 alkyl; a C1-C4 haloalkyl; a C1-C4 hydroxyalkyl; a (C1-C4 alkoxy)-(Ci-4)alkyl; an amino-(Ci-C4) alkyl; a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl; or a C₃-12 carbocyclyl-(Co-C3)alkylenyl, wherein the carbocyclyl portion is optionally substituted with a hydroxyl group; a (Ci-4 alkyl)C(O)-, a (Ci-4 alkyl)S(0)i-2-; a (CM alkyl)C(0)NH(Ci-₄ alkylenyl)-; a (CM alkyl)S(0)i-₂NH(Ci-4 alkylenyl)-; a H0C(0)-(Ci-C3)alkylenyl; a H2NC(0)-(Ci-C3)alkylenyl; or a (CM

alkyloxy)C(0)-( Ci-C3)alkylenyl.

3. The method of claim 1 or 2, wherein R⁴⁰³ and R⁴⁰³ are both H.

4. The method of any one of claims 1-3, wherein R⁷⁰¹ is -OCH_3.

5. The method of any one of claims 1-4, wherein R⁸⁰³ is ethyl.

6. The method of any one of claims 1-3, wherein R⁷⁰¹ is a -OCF₃, and R⁸⁰³ is methyl.

7. The method of any one of claims 1-3, wherein R⁷⁰¹ is -CF3, and R⁸⁰³ is a CM alkyl or a (C3-C6)carbocyclyl-(Co-C3)alkylenyl.

8. The method of any one of claims 1 and 3-7, wherein venetoclax is administered once daily at a dose of 20mg to 400mg.

9. The method of any one of claims 1 and 3-8, wherein venetoclax is administered once daily at a dose of 50 mg to 200mg.

10. The method of any one of claims 1 and 3-8, wherein venetoclax is administered once daily at a dose of 400 mg.

11. The method of any one of claims 1 and 3-9, wherein venetoclax is administered once daily at a dose of 200mg.

12. The method of any one of claims 1 and 3-9, wherein venetoclax is administered once daily at a dose of lOOmg.

13. The method of any one of claims 1-12, wherein the compound of Formula (I) is administered once daily at a dose of 5 mg to 40 mg.

14. The method of any one of claims 1-13, wherein the compound of Formula (I) is administered once daily at a dose of 10 mg to 30 mg.

15. The method of any one of claims 1-14, wherein the compound of Formula (I) is administered once daily at a dose of 20 mg.

16. The method of any one of claims 1 and 3-15, wherein the venetoclax is administered orally.

17. The method of any one of claims 1-16, wherein the compound of Formula (I) is administered parenterally.

18. The method of any one of claims 1-17, wherein the hematological cancer is selected from a leukemia, a lymphoma or a myeloma.

19. The method of claim 18, wherein the leukemia is selected from acute myeloid

leukemia (AML), acute myeloblastic leukemia, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), and acute monocytic leukemia (AMoL).

20. The method of claim 18, wherein the lymphoma is non-Hodgkin’s lymphoma.

21. The method of claim 18, wherein the myeloma is multiple myeloma.

22. The method of any one of claims 1-17, wherein the hematological cancer is selected from myelodysplastic syndrome or myeloproliferative syndrome.

23. The method of claim 18, wherein the lymphoma is selected form mantle cell

lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma/leukemia and B-cell lymphoma.

24. The method of any one of claims 1-17, wherein the hematological cancer is acute myeloid leukemia.

25. The method of any one of claim 1-24, wherein the compound of Formula (I) is represented by the following structural formula:

26. The method of any one of claims 1-25, further comprising administration of one or more additional therapeutic agents.

27. A pharmaceutical composition comprising a compound represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R⁸⁰³ is a Ci-6 alkyl, H, a Ci-6 haloalkyl, Ci-6 hydroxyalkyl, a C3-12 carbocyclyl-(Co-3)alkylenyl, an amino-(Ci-C4) alkyl, a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl, or a (4-13 member)heterocyclyl-(Co-C3)alkylenyl, wherein the heterocyclyl portion is optionally substituted with a C1-₃ alkyl;

R⁷⁰¹ is a Ci-4 alkyloxy, H, -OH, Ci-4 alkyl, a Ci-4 haloalkyl, Ci-4 hydroxyalkyl, or Ci-4 haloalkoxy;

R⁴⁰³ and R^403’, each independently, are H; a Ci-4 alkyl; a C1-C4 haloalkyl; a C1-C4 hydroxyalkyl; a (C1-C4 alkoxy)-(Ci-4)alkyl; an amino-(Ci-C4) alkyl; a mono- or di- (C1-C4 alkyl)amino-(Ci-4)alkyl; or a C₃-12 carbocyclyl-(Co-C3)alkylenyl, wherein the carbocyclyl portion is optionally substituted with a hydroxyl group; a (Ci -4 alkyl)C(O)-, a (CM alkyl)S(0)i-₂-; a (CM alkyl)C(0)NH(Ci-₄ alkylenyl)-; a (CM alkyl)S(0)i-2NH(Ci-4 alkylenyl)-; a HOC(0)-(Ci-C₃)alkylenyl; a H₂NC(0)- (Ci-C3)alkylenyl; or a (Ci-4 alkyloxy)C(0)-( Ci-C3)alkylenyl;

venetoclax; and

a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27, wherein the compound of Formula (I) is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition of claim 27 or claim 28, further comprising one or more additional therapeutic agents.