Combination of bcl-2 inhibitor and FAK inhibitor, and use thereof in prevention and / or treatment of diseases

Abstract

The present invention relates to a combination of a Bcl-2 inhibitor and a FAK inhibitor, and use thereof in the prevention and / or treatment of cancer.

Description

Combination of a Bcl-2 inhibitor and a FAK inhibitor and its use in the prevention and / or treatment of a disease TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a combination product containing a Bcl-2 inhibitor and a FAK inhibitor and its use in the prevention and / or treatment of a disease (e.g., cancer). BACKGROUND

[0002] Focal adhesion kinase (FAK) high expression is associated with enhanced cell proliferation and poor prognosis in acute myeloid leukemia (AML). Once activated by integrin ligation or growth factor receptor-mediated signals, FAK cooperates with Src to activate multiple cell proliferation pathways such as MAPK and JAK-STAT3 / 5, and regulates the expression of various apoptosis-related proteins, including Mcl-1 and Bcl-xL. The B-cell lymphoma 2 (Bcl-2) protein plays an important role in apoptosis. Preclinical and clinical studies have shown that selective targeting of Bcl-2 has anti-leukemia activity against a variety of hematological malignancies, including AML, MDS and CLL. The resistance of Bcl-2 inhibitor-induced apoptosis in AML is partly mediated by pre-existing and inhibitor-induced upregulation of Mcl-1 and Bcl-xL. Considering the potential relationship between FAK and Mcl-1 / Bcl-xL, we hypothesized that inhibition of FAK could inhibit the expression of Mcl-1 or Bcl-xL, which could enhance the activity of Bcl-2 inhibitors (Bcl-2i). We have previously reported that lisaftoclax (equivalent to compound 6 in the present patent application) and compound 5-1 (equivalent to compound 5-1 in the present patent application) are a brand new Bcl-2 inhibitor and FAK inhibitor, respectively. They show unique pharmacological properties as well as clinical activity and tolerable safety in patients with hematological or solid malignancies. Considering the deficiencies of Bcl-2 inhibitors in the prior art in the treatment of AML, it is an urgent technical problem to find more effective treatment methods for AML. SUMMARY

[0003] Technical problems solved by the application

[0004] The technical problem solved by the present application is to overcome the deficiencies of the prior art in the treatment of AML with Bcl-2 inhibitors, and the subject of the present application is to provide a combination product containing a Bcl-2 inhibitor and a FAK inhibitor and its use in the treatment and / or prevention of a disease (e.g., cancer).

[0005] Technical solutions for solving the technical problems

[0006] Specifically, the first aspect of the present application relates to a combination product comprising a Bcl-2 inhibitor and a FAK inhibitor.

[0007] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A or a pharmaceutically acceptable salt thereof:

[0008] wherein:

[0009] A is

[0010] E is a C atom and is a double bond;

[0011] or E is -C(H)- and is a single bond;

[0012] or E is a N atom and is a single bond;

[0013] X 1 , X 2 , and X 3 are independently -CR 8 = and -N=;

[0014] R 1a and R 1b together with the C atom to which they are attached form a 3-, 4-, or 5- membered optionally substituted aliphatic ring;

[0015] R 1a and R 1b together with the C atom to which they are attached form a 4- or 5- membered optionally substituted heterocyclic ring;

[0016] R 2 is -NO2, -SO2CH3, -SO2CF3;

[0017] R 2a is H or X;

[0018] R 3 is H, -CN, -C≡CH, -N(R 4a )(R 4b );

[0019] R 4a is optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl;

[0020] R 4b is H and C1-4alkyl;

[0021] R 5 is optionally substituted C1-6alkyl, heterocycle, cycloalkylalkyl, and heterocycloalkyl;

[0022] R6a , R 6c , R 6e , R 6f and R 6g are independently H, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl;

[0023] R 6b and R 6d are independently H, C1-4alkyl, and halo;

[0024] R 7 is optionally substituted C1-6alkyl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkyl;

[0025] R 8 is H and halo.

[0026] In some embodiments, the Bcl-2 inhibitor is selected from the following compounds or a pharmaceutically acceptable salt or solvate thereof:

[0027] In some embodiments, the Bcl-2 inhibitor is

[0028] or a pharmaceutically acceptable salt or solvate thereof.

[0029] In some embodiments, the FAK inhibitor is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof:

[0030] wherein:

[0031] R 1a and R 1b are independently selected from hydrogen, C 1-6 alkyl, and C 3-8 cycloalkyl;

[0032] R 2a and R 2b are independently selected from hydrogen, C 1-6 alkyl, and C 3-8 cycloalkyl;

[0033] R 3 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and 4-8 membered heterocyclyl;

[0034] R 4 is selected from C 1-4 alkyl, and C 3-6 cycloalkyl;

[0035] R 5 is halogen;

[0036] R 6 is selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0037] R 7 is selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0038] provided that when R 1a , R 1b , R 2a and R 2b are each hydrogen, then R 3 is selected from C 3-6 cycloalkyl and 4-8 membered heterocyclyl.

[0039] In some embodiments, the FAK inhibitor is a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof:

[0040] wherein:

[0041] R 1a and R 1b are each independently selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0042] R 2a and R 2b are each independently selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; and

[0043] R 3 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl and 4-8 membered heterocyclyl.

[0044] In some embodiments, the FAK inhibitor is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof:

[0045] wherein:

[0046] R 1a and R 2a are each independently selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0047] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0048] In some embodiments, the FAK inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt or solvate thereof:

[0049] wherein:

[0050] R 1a and R 2a are each independently selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0051] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0052] In some embodiments, the FAK inhibitor is a compound of Formula V, or a pharmaceutically acceptable salt or solvate thereof:

[0053] wherein:

[0054] R 1a and R 2a are each independently selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0055] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0056] In some embodiments, the FAK inhibitor is a compound of Formula VI, or a pharmaceutically acceptable salt or solvate thereof:

[0057] wherein:

[0058] R 1a and R 2a are each independently selected from C 1-4alkyl and C 3-6 cycloalkyl; and

[0059] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0060] In a preferred embodiment, the combination product comprises a Bcl-2 inhibitor and a FAK inhibitor, wherein the Bcl-2 inhibitor is a compound of the following formula:

[0061] wherein the FAK inhibitor is 5-chloro-N 2 -(2-iso-propoxy-5-methyl-4-(l-(tetrahydro-2H-pyran-4-yl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl)-N 4 -(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine:

[0062] or a pharmaceutically acceptable salt or solvate thereof.

[0063] In some embodiments, the combination product is in the form of a pharmaceutical composition.

[0064] In some embodiments, the combination product is in the form of a kit.

[0065] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are each included in the kit in the form of a separate formulation.

[0066] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are administered simultaneously or sequentially.

[0067] In some embodiments, the combination product further comprises a pharmaceutically acceptable carrier, diluent, or excipient.

[0068] In some embodiments, the combination product is in the form of a tablet, capsule, granule, syrup, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream, and injection.

[0069] A second aspect of the present application relates to the use of a Bcl-2 inhibitor and a FAK inhibitor in the manufacture of a medicament for the prevention and / or treatment of a disease, which is cancer.

[0070] A third aspect of the application relates to a combination for use in the prevention and / or treatment of a disease, said combination comprising a Bcl-2 inhibitor and a FAK inhibitor, and said disease is a cancer.

[0071] A fourth aspect of the application relates to a method for the prevention and / or treatment of a disease, comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a Bcl-2 inhibitor and a FAK inhibitor, wherein said disease is a cancer.

[0072] In a preferred embodiment of the second, third and fourth aspects of the application, the combination comprises a Bcl-2 inhibitor and a FAK inhibitor, wherein the Bcl-2 inhibitor is a compound of the following formula:

[0073] wherein the FAK inhibitor is 5-chloro-N 2 -(2-iso-propoxy-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-N 4 -(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine:

[0074] or a pharmaceutically acceptable salt or solvate thereof.

[0075] In some embodiments, the cancer is selected from non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-small cell lung cancer (NSCLC).

[0076] In some embodiments, the cancer is a hematological malignancy. The hematological malignancy is selected from non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM).

[0077] In some embodiments, the Bcl-2 inhibitor or a pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 0.0025-1500 mg / day.

[0078] In some embodiments, the FAK inhibitor or a pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 0.005-5000 mg / day. BRIEF DESCRIPTION OF DRAWINGS

[0079] Figure 1 shows the anti-tumor effect of Compound 5-1 in combination with Compound 6 in a human acute myeloid leukemia MV4-11 cell xenograft model.

[0080] Figure 2 shows the effect of Compound 5-1 in combination with Compound 6 on body weight change in a human acute myeloid leukemia MV4-11 cell xenograft model.

[0081] Figure 3 shows the effect of Compound 5-1 on the growth of different human acute myeloid leukemia cells.

[0082] Figure 4 shows the effect of Compound 5-1 in combination with Compound 6 on the growth of different human acute myeloid leukemia cells

[0083] Figure 5 shows the effect of Compound 5-1 in combination with Compound 6 on the expression of apoptosis-related proteins in MV4-11 cells.

[0084] Figure 6 shows the effect of Compound 5-1 in combination with Compound 6 on the expression of apoptosis-related proteins in OCI-AML-3 cells.

[0085] Definitions

[0086] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or substitutions of techniques or replacements of equivalent techniques that would be apparent to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present application.

[0087] As used herein, the terms "comprise", "comprising", "have", "having", "include", "including", or "contain", "containing", or "involve", "involved", and other variants thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0088] As used herein, "FAK" refers to focal adhesion Kinase, and "FAK inhibitor" refers to an agent that has an inhibitory effect on FAK. In some embodiments, the FAK inhibitor also has an inhibitory effect on one or more other target(s) (e.g., ALK and / or ROS1).

[0089] The term "pharmaceutically acceptable salt" as used herein refers to salts of the free acid or free base form of the compounds, typically prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. The term can be used in reference to compounds of the application. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycol lylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methobromide, methioninate, methylnitrate, methosulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teaoclate, p-toluenesulfonate, triethiodide, trimethylamine, and valerate. When an acidic substituent is present, such as -COOH, ammonium, morpholine, sodium, potassium, barium, calcium, and the like salts can be formed for use in dosage forms. When a basic group is present (such as in limonoids or 1,1-dimethylbiguanide), such as an amino group or a basic heteroaryl group such as pyridyl, an acid salt can be formed, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, mesylate, esylate, picrate, and the like.

[0090] The term "prevent" as used herein means, when used in reference to a disease or condition (e.g., cancer), the reduction in frequency of or delay in onset of a symptom of the medical condition in a subject compared to a subject not administered the compound or drug (e.g., the combination product claimed in the present application).

[0091] The term "treatment" as used herein refers to reducing, alleviating or ameliorating a symptom of a disease or condition, ameliorating an underlying metabolic cause of a symptom, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or preventing a symptom of the disease or condition.

[0092] The term "cancer" as used herein refers to a neoplasm or tumor resulting from abnormal, uncontrolled cell growth. Non-limiting examples include those exemplary cancers described in the detailed description of the invention. The term "cancer" includes diseases involving both pre-malignant and malignant cancer cells.

[0093] The term "subject" as used herein refers to both humans (e.g., patients) and animals (e.g., mice, rats, dogs, cats, rabbits, chickens, or monkeys, etc.). When the subject is a human patient (typically weighing 60 kg), the dosages described herein can be converted using a conversion factor for experimental animals (e.g., human dose = mouse dose / 12.3) unless otherwise specified (see Kin Tam. "Estimating the "First in human" dose - a revisit with particular emphasis on oncology drugs, ADMET & DMPK 1 (4) (2013) 63-75). A person of ordinary skill in the art is capable of making reasonable adjustments to the dosages based on the specific weight of the subject, the type and severity of the disease, and other factors according to common general knowledge, and such adjustments are within the scope of the technical solutions claimed by the present application.

[0094] The term "effective amount" or "prophylactically and / or therapeutically effective amount" as used herein refers to a sufficient amount of a drug or compound being administered (e.g., a dose) to reduce to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the symptoms or conditions caused by the disease or disorder or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound or drug (e.g., the combination product claimed in the present application) to provide a significant reduction in clinical symptoms of a disease or condition, without producing significant adverse effects.

[0095] The term "dose" as used herein refers to the weight (e.g., milligrams (mg)) of active substance per kilogram (kg) of body weight of the subject.

[0096] The term "IC 50 " as used herein refers to the amount, concentration or dose of a particular test compound or drug that achieves 50% inhibition of the maximum effect measured in an assay for such an effect, e.g., inhibition of BCL-2 or FAK.

[0097] The term "room temperature" as used herein refers to 25 °C ± 1 °C. At the same time, if no specific temperature of the experiment is indicated, it is room temperature.

[0098] The term "about" as used herein refers to ± 10% of the numerical value of the term that it modifies, more preferably ± 5%, most preferably ± 2%, so that a person of ordinary skill in the art is clearly informed of the range intended for that term.

[0099] The term "alkyl" as used herein, alone or as part of another group, refers to an unbranched or branched aliphatic containing 1 to 12 carbon atoms (i.e., Ci-12alkyl) or the specified number of carbon atoms, for example, Ci alkyl such as methyl, C2alkyl such as ethyl, C3alkyl such as n-propyl or isopropyl, Ci-3alkyl such as methyl, ethyl, n-propyl, or isopropyl, and the like. In one embodiment, the alkyl group is Ci-4alkyl. Non-limiting examples of Ci-12alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of Ci-4alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, and isobutyl.

[0100] The term "cycloalkyl" as used herein, alone or as part of another group, refers to a saturated or partially unsaturated (containing one or two double bonds) cyclic aliphatic containing 1 or 2 rings having 3 to 12 carbon atoms or the number of carbon atoms is indicated (i.e., C3-12cycloalkyl). In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group is selected from C3-8cycloalkyl. In another embodiment, the cycloalkyl group is selected from C3-6cycloalkyl. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalinyl, adamantyl, cyclohexenyl, and cyclopentenyl.

[0101] The term "heterocycle" or "heterocyclyl," as used herein, alone or as part of another group, refers to a saturated or partially unsaturated (e.g., containing one or two double bonds) cyclic group containing 1, 2, or 3 rings wherein at least one of the rings is characterized by having 3 to 14 ring members (i.e., 3- to 14-membered heterocyclyl), wherein at least one carbon atom of one of the rings is replaced with a heteroatom. Each heteroatom is independently selected from an oxygen atom, a sulfur atom (including sulfoxide and sulfone), and / or a nitrogen atom (which can be oxidized or quaternized). The term "heterocyclyl" is intended to include groups in which -CH2- in a ring is replaced by -C(=O)-, such as cyclic urea groups (e.g., 2-imidazolidinone) and cyclic amide groups (e.g., β-lactam, γ-lactam, δ-lactam, ε-lactam, and piperazin-2-one). In one embodiment, a heterocyclyl group is a 3- to 8-membered cyclic group containing 1 ring and 1 or 2 oxygen and / or nitrogen atoms. In one embodiment, a heterocyclyl group is a 4-, 5-, or 6-membered cyclic group containing 1 ring and 1 or 2 oxygen and / or nitrogen atoms. In one embodiment, a heterocyclyl group is a 4- or 6-membered cyclic group containing 1 ring and 1 or 2 oxygen and / or nitrogen atoms. A heterocyclyl group can be attached to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting examples of heterocyclyl groups include dioxane, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazin-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

[0102] The term "enantiomeric excess" or "ee," as used herein, refers to a measure of how much of one enantiomer is present relative to the other enantiomer. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R-S|*100, where R and S represent the number of moles or weight fractions, respectively, in the mixture, R+S = 1. For a chiral substance of known optical rotation, the percent enantiomeric excess is defined as ([a]obs / [a]max)*100, where [a]obs represents the optical rotation of the enantiomeric mixture and [a]max represents the optical rotation of the pure enantiomer. Enantiomeric excess can be determined using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical rotation. The compounds of the present application can have an ee of about 70% or greater, such as about 80% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

[0103] The term "pharmaceutically acceptable salt," as used herein, includes both acid and base addition salts of compounds.

[0104] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclohexylsulfamate, edisylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, hexafluoro-chlorophosphate, hydrochloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate, pyrosphosphate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate salts.

[0105] Suitable base addition salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0106] For a review on suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the present application are known to those skilled in the art.

[0107] As used herein, the term "solvate" is a physical combination involving the compound of the present application with a solvent molecule, for example a disolvate, monosolvate or hemisolvate, formed by the combination, physical association and / or solvation of one or more solvent molecules with a compound of the present application in which the ratio of solvent molecules to the compound of the present application is about 2:1, about 1:1 or about 1:2, respectively. Such physical combinations involve varying degrees of ionic and co-ionic bonding (including hydrogen bonding) to varying extents. In some cases (for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid), solvates can be isolated. Thus, solvates include both solution-phase and isolatable solvates. The compounds of the present application can be in solvated forms with pharmaceutically acceptable solvents such as water, methanol and ethanol and the present application is intended to include both solvated and unsolvated forms of the compounds of the present application.

[0108] One type of solvate is a hydrate. "Hydrate" relates to a particular subset of solvates wherein the solvent molecule is water. Solvates typically act as pharmacological equivalents. The preparation of solvates is known in the art, see for example M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and water. Similar methods for preparing solvates, hemisolvates, hydrates and the like are described by van Tonder et al, AAPS Pharm. Science Tech., 5(1): Article 12 (2004) and A. L. Bingham et al, Chem. Commun. 603-604 (2001). Representative and non-limiting methods for preparing solvates include dissolving the compound of the application in the desired solvent (organic solvent, water or a mixture thereof) at a temperature above 20 °C to about 25 °C, then the solution is cooled at a rate sufficient to form crystals, and the crystals are isolated by known methods such as filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of a solvent in the solvate crystals.

[0109] In the context of the present application, "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other complication commensurate with a reasonable benefit / risk ratio, and are

[0110] Pharmaceutically acceptable carriers that can be employed in the pharmaceutical compositions or kits of the application include, but are not limited to, sterile aqueous media, such as water and isotonic saline and buffered solutions, including those of physiological pH, and parenterally acceptable oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Also among the acceptable vehicles and solvents that can be employed are physiologically saline and aqueous dextrose and glycerol solutions, especially, for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, white

[0111] The pharmaceutical compositions and components of the kits of the application can act systemically and / or locally. To this end, they can be administered by appropriate routes, for example by injection (for example intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular administration, including drip infusion) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical administration, ophthalmic preparation or inhalation.

[0112] For these administration routes, the pharmaceutical compositions and components of the kits of the application can be administered in suitable dosage forms.

[0113] DETAILED DESCRIPTION

[0114] In a first aspect of the application relates to a combination product comprising or consisting of a Bcl-2 inhibitor and a FAK inhibitor.

[0115] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A or a pharmaceutically acceptable salt or solvate thereof:

[0116] wherein:

[0117] A is

[0118] E is a C atom and is a double bond;

[0119] or E is -C(H)- and is a single bond;

[0120] or E is a N atom and is a single bond;

[0121] X 1 , X 2 and X 3 are independently -CR 8 = and -N=;

[0122] R 1a and R 1b together with the C atom to which they are attached form a 3-, 4-, or 5- membered optionally substituted aliphatic ring;

[0123] R 1a and R 1b together with the C atom to which they are attached form a 4- or 5- membered optionally substituted heterocyclic ring;

[0124] R 2 is -NO2, -SO2CH3, -SO2CF3;

[0125] R 2a is H or X;

[0126] R 3 is H, -CN, -CºCH, -N(R 4a )(R 4b );

[0127] R 4a is optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl;

[0128] R 4b is H and C1-4alkyl;

[0129] R 5 is optionally substituted C1-6alkyl, heterocycle, cycloalkylalkyl, and heterocycloalkyl;

[0130] R 6a , R 6c , R 6e , R 6f , and R 6g are independently H, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic aryl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl;

[0131] R 6b , and R 6d are independently H, C1-4alkyl, and halogen;

[0132] R 7 is optionally substituted C1-6alkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl;

[0133] R 8 is H and halogen.

[0134] In the above compounds of Formula I-A, the variable R 2a , in the definition of "X" means halogen. Further, the above halogen means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0135] In some embodiments, the Bcl-2 inhibitor is a compound having the formula I-A, wherein: A is A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, and A-9; R 4a is optionally substituted C1-6alkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl; R 6a , R 6c , R 6e , R 6f , and R 6g are independently H, optionally substituted C1-6alkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl.

[0136] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof,

[0137] wherein:

[0138] E is a C atom and is a double bond; or E is -C(H)- and is a single bond; or E is a N atom and is a single bond;

[0139] R 1a and R 1b together with the C atom to which they are attached form a 3-, 4-, or 5- membered optionally substituted aliphatic ring;

[0140] R 1a and R 1b together with the C atom to which they are attached form a 4- or 5- membered optionally substituted heterocyclic ring;

[0141] R 2 is -NO2, -SO2CH3, -SO2CF3;

[0142] R 3 is H, -CN, -C≡CH, -N(R 4a )(R 4b );

[0143] R 4a is optionally substituted C1-6alkyl, heterocycle, cycloalkylalkyl, and heterocyclealkyl;

[0144] R 4b is H and C1-4alkyl.

[0145] In some embodiments, the Bcl-2 inhibitor is a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof,

[0146] wherein:

[0147] Y is -CH2- and -O-, R 2 and R 4a are as defined in Formula I.

[0148] In some embodiments, the Bcl-2 inhibitor is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof,

[0149] wherein:

[0150] Y is -CH2- and -O-, R 2 and R4a as defined by Formula I.

[0151] In some embodiments, the Bcl-2 inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt or solvate thereof,

[0152] wherein:

[0153] Y is -CH2- and -O-, R 2 and R 4a as defined by Formula I.

[0154] In some embodiments, the Bcl-2 inhibitor is a compound of Formula V, or a pharmaceutically acceptable salt or solvate thereof,

[0155] wherein:

[0156] Y is -CH2- and -O-, A, X 1 , X 2 and X 3 as defined by Formula I-A.

[0157] In some embodiments, the Bcl-2 inhibitor is a compound of Formula VI, or a pharmaceutically acceptable salt or solvate thereof,

[0158] wherein:

[0159] Y is -CH2- and -O-, A as defined by Formula I-A.

[0160] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-1.

[0161] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-2.

[0162] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-3.

[0163] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-4.

[0164] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-5.

[0165] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-6.

[0166] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-7.

[0167] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-8.

[0168] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-9.

[0169] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VI, or a pharmaceutically acceptable salt or solvate thereof, wherein A is A-10.

[0170] In some embodiments, the Bcl-2 inhibitor is a compound of Formula VII, or a pharmaceutically acceptable salt or solvate thereof,

[0171] wherein:

[0172] Y is -CH2- and -O-, X 1 , X 2 , X 3 , R 2 and R 4a as defined in Formula I-A.

[0173] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 , X 2 and X 3 are all -CH=.

[0174] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is -CF=, X 2 and X 3are -CH=.

[0175] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 and X 3 are -CH=, X 2 is -CF=.

[0176] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 and X 2 are -CH=, X 3 is -CF=.

[0177] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 is -N=, X 2 and X 3 are -CH=.

[0178] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 and X 3 are -CH=, X 2 is -N=.

[0179] In some embodiments, the Bcl-2 inhibitor is a compound of Formula I-A, V, or VII, or a pharmaceutically acceptable salt or solvate thereof, wherein X 1 and X 2 are -CH=, X 3 is -N=.

[0180] In some embodiments, the Bcl-2 inhibitor is a compound of any one of Formulas II-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -O-.

[0181] In some embodiments, the Bcl-2 inhibitor is a compound of any one of Formulas II-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -CH2-.

[0182] In some embodiments, the Bcl-2 inhibitor is a compound of any one of Formulas I-A or I-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -NO2.

[0183] In some embodiments, the Bcl-2 inhibitor is a compound of any one of Formulas I-VI, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is:

[0184] In some embodiments, the Bcl-2 inhibitor is a compound of any one of Formulas I-A or V-VII, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a , R 5 , R 6a , and R 7 are independently:

[0185] In some embodiments, the Bcl-2 inhibitor is a compound of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a is H or F, R 4a is as defined for Formula I-A.

[0186] In some embodiments, the Bcl-2 inhibitor is a compound of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R 4a is:

[0187] In some embodiments, the Bcl-2 inhibitor is one or more compounds of the following table, or a pharmaceutically acceptable salt or solvate thereof.

[0188] Table A

[0189] In some embodiments, the Bcl-2 inhibitor is one or more compounds of Table 1-A, or a pharmaceutically acceptable salt or solvate thereof.

[0190] Table 1-A

[0191] In some embodiments, the Bcl-2 inhibitor is a compound in Table 1-B, or a pharmaceutically acceptable salt or solvate thereof.

[0192] Table 1-B

[0193] In some embodiments, the Bcl-2 inhibitor is

[0194] or a pharmaceutically acceptable salt or solvate thereof.

[0195] Compounds of Formula I-A as Bcl-2 inhibitors, in particular Compound 6, and methods of making the same are disclosed in Chinese Patent Application No. CN201780035965.6, which is hereby incorporated by reference in its entirety.

[0196] In some embodiments, the FAK inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof:

[0197] wherein:

[0198] R 1a and R 1b are independently selected from hydrogen, C 1-6 alkyl, and C 3-8 cycloalkyl;

[0199] R 2a and R 2b are independently selected from hydrogen, C 1-6 alkyl, and C 3-8 cycloalkyl;

[0200] R 3 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and 4-8 membered heterocyclyl;

[0201] R 4 is selected from C 1-4 alkyl, and C 3-6 cycloalkyl;

[0202] R 5 is halogen;

[0203] R 6 is selected from C 1-4 alkyl, and C 3-6 cycloalkyl; and

[0204] R 7 is selected from hydrogen, C 1-4 alkyl, and C 3-6 cycloalkyl;

[0205] provided that when R 1a , R 1b , R 2a and R 2b are each hydrogen, then R 3 is selected from C 3-6 cycloalkyl and 4-8 membered heterocyclyl.

[0206] In preferred embodiments, the FAK inhibitor is a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof:

[0207] wherein:

[0208] R 1a and R 1b are each independently selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl;

[0209] R 2a and R 2b are each independently selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; and

[0210] R 3 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl and 4-8 membered heterocyclyl.

[0211] In preferred embodiments, the FAK inhibitor is a compound of Formula III, or a pharmaceutically acceptable salt or solvate thereof:

[0212] wherein:

[0213] R 1a and R 2a are each independently selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0214] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0215] In some embodiments, the FAK inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt or solvate thereof:

[0216] wherein:

[0217] R1a and R 2a each independently is selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0218] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0219] In preferred embodiments, the FAK inhibitor is a compound of Formula V, or a pharmaceutically acceptable salt or solvate thereof:

[0220] wherein:

[0221] R 1a and R 2a each independently is selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0222] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0223] In preferred embodiments, the FAK inhibitor is a compound of Formula VI, or a pharmaceutically acceptable salt or solvate thereof:

[0224] wherein:

[0225] R 1a and R 2a each independently is selected from C 1-4 alkyl and C 3-6 cycloalkyl; and

[0226] The compound has an enantiomeric excess of 90% or more. In some embodiments, the compound has an enantiomeric excess of about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0227] In preferred embodiments, the FAK inhibitor is a compound as shown in Table B below:

[0228] Table B

[0229] In preferred embodiments, the FAK inhibitor is 5-chloro-N 2 -(2-Isopropoxy-5-methyl-4-(l-(tetrahydro-2H-pyran-4-yl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl)-N 4 -(2-(Isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (Compound 5-1) or a pharmaceutically acceptable salt or solvate thereof.

[0230] The compound of Formula I, particularly Compound 5-1, as a FAK inhibitor, and methods of making the same are disclosed in Chinese Patent Application No. CN201780057518.0, which is hereby incorporated by reference in its entirety. In some embodiments, the combination product is in the form of a pharmaceutical composition.

[0231] In some embodiments, the combination product is in the form of a kit.

[0232] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are each included in the kit in the form of separate formulations.

[0233] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are administered simultaneously or sequentially.

[0234] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are administered sequentially with a time interval of about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks.

[0235] In some embodiments, the combination product of the present application containing the Bcl-2 inhibitor and the FAK inhibitor in the form of a pharmaceutical composition, preferably each in the form of a separate dosage unit, can be administered daily as needed including but not limited to 1 time, 2 times, 3 times, 4 times, 5 times, or 6 times.

[0236] In some embodiments, the combination product of the application comprising the Bcl-2 inhibitor and the FAK inhibitor in the form of a pharmaceutical composition, preferably in the form of a dosage unit, can be administered as many times a day as needed, including but not limited to: 1, 2, 3, 4, 5, or 6 times a day.

[0237] In some embodiments, the combination product can be administered orally, buccally, by inhalation spray, sublingually, rectally, transdermally, transmucosally, topically, nasally, or enterally; by injection, such as intramuscularly, subcutaneously, intramedullary, and intrathecally, direct brain administration, in situ, subcutaneously, intraperitoneally, intravenously, intraarticular synovial, intrastemally, intrahepatically, intralesionally, intracranially, intraperitoneally, intranasally, or intraocularly, or by other means of drug delivery.

[0238] In some embodiments, the Bcl-2 inhibitor or pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 0.0025-1500 mg / day. Preferably, the Bcl-2 inhibitor is administered in an amount of 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 61 mg, 70 mg, 80 mg, 90 mg, 100 mg, 122 mg, 150 mg, 200 mg, 244 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 460 mg, 470 mg, 480 mg, 487 mg, 490 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, and ranges between each of the amounts, e.g., 1 mg-1000 mg, 30 mg-900 mg, 61 mg-800 mg, 100 mg-700 mg, 122 mg-600 mg, 122 mg-500 mg, 122 mg-487 mg, 122 mg-300 mg, 122 mg-244 mg, 30 mg-487 mg, 61 mg-487 mg, etc.

[0239] In some embodiments, the FAK inhibitor or pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 0.0025-5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 120, 150, 200, 250, 300, 350, 400, 450, 480, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 mg / day.

[0240] In some embodiments, the combination product further comprises a pharmaceutically acceptable carrier, diluent or excipient.

[0241] In some embodiments, the combination product is in the form of a tablet, capsule, granule, syrup, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream and injection.

[0242] In a second aspect of the present application relates to the use of a Bcl-2 inhibitor and a FAK inhibitor in the manufacture of a medicament for the prevention and / or treatment of a disease, which is cancer.

[0243] In some embodiments, the Bcl-2 inhibitor is those compounds (e.g., Compound I-A) or a pharmaceutically acceptable salt or solvate thereof as specifically described in the first aspect of the present application.

[0244] In some embodiments, the Bcl-2 inhibitor is

[0245] or a pharmaceutically acceptable salt or solvate thereof;

[0246] the FAK inhibitor is Compound 5-1 or a pharmaceutically acceptable salt or solvate thereof.

[0247] In some embodiments, the medicament is in the form of a pharmaceutical composition.

[0248] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are each included in a kit in the form of separate formulations.

[0249] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are administered simultaneously or sequentially.

[0250] In some embodiments, the time interval for sequential administration of the Bcl-2 inhibitor and the FAK inhibitor can be about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks.

[0251] In some embodiments, the medicament of the present application containing the Bcl-2 inhibitor and the FAK inhibitor in the form of a pharmaceutical composition (preferably, each in the form of a separate dosage unit) can be administered daily as needed including but not limited to 1, 2, 3, 4, 5 or 6 times.

[0252] In some embodiments, the medicament of the present application comprising the Bcl-2 inhibitor and the FAK inhibitor, in the form of a pharmaceutical composition, preferably in the form of a dosage unit, can be administered daily as needed, including but not limited to: 1 time, 2 times, 3 times, 4 times, 5 times, or 6 times.

[0253] In some embodiments, the medicament can be administered orally, buccally, by inhalation spray, sublingually, rectally, transdermally, transmucosally, topically, nasally, or enterally; by injection, such as intramuscularly, subcutaneously, intramedullary, and intrathecally, directly into the brain, in situ, subcutaneously, intraperitoneally, intravenously, intraarticular synovial, intrastemally, intrahepatically, intralesionally, intracranially, intraperitoneally, intranasally, or intraocularly, or by other means of drug delivery.

[0254] In some embodiments, the daily administration of the Bcl-2 inhibitor or a pharmaceutically acceptable salt or solvate thereof and the FAK inhibitor or a pharmaceutically acceptable salt or solvate thereof is as described in the first aspect of the present application in the above detailed description of the invention.

[0255] In some embodiments, the disease is cancer.

[0256] Furthermore, the cancers described in this invention include, but are not limited to, cancers selected from the following: adrenal carcinoma, lymphoepithelioma, adenoid cell carcinoma, lymphoma, acoustic neuroma, acute lymphoblastic leukemia, acral melanoma, acute myeloid leukemia, acral hidradenoma, chronic lymphocytic leukemia, acute eosinophilic leukemia, liver cancer, acute erythroblastic leukemia, small cell lung cancer, acute lymphoblastic leukemia, non-small cell lung cancer, acute megakaryoblastic leukemia, MALT lymphoma, acute monocytic leukemia, malignant fibrous histiocytoma, acute promyelocytic leukemia, malignant peripheral schwannoma, adenocarcinoma, malignant hippocampal tumor, adenoid cystic carcinoma, mantle cell lymphoma, adenoma, marginal zone B-cell lymphoma, adenoma-like odontogenic tumor, mast cell carcinoma. Leukemia, adenosquamous carcinoma, mediastinal germ cell tumor, adipose tissue tumor, medullary breast carcinoma, adrenocortical carcinoma, medullary thyroid carcinoma, adult T-cell leukemia / lymphoma, medulloblastoma, aggressive NK-cell leukemia, melanoma, AIDS-related lymphoma, meningioma, alveolar rhabdomyosarcoma, Merkel cell carcinoma, alveolar soft tissue sarcoma, mesothelioma, ameloblastoma, metastatic urothelial carcinoma, anaplastic large cell lymphoma, mixed Müllerian tumor, undifferentiated thyroid carcinoma, myxoid tumor, angioimmunoblastic T-cell lymphoma, multiple myeloma, angiomyolipoma, muscle tissue tumor, angiosarcoma, mycosis fungoides, astrocytoma, myxoid liposarcoma, atypical rhabdomyosarcoma, myxoma, B-cell Chronic lymphocytic leukemia, myxosarcoma, B-cell prolymphocytic leukemia, nasopharyngeal carcinoma, B-cell lymphoma, schwannoma, basal cell carcinoma, neuroblastoma, biliary tract cancer, neurofibroma, bladder cancer, neuroma, germ cell tumor, nodular melanoma, bone cancer, eye cancer, Brunner tumor, oligodendroma, brown tumor, oligodendroglioma, Burkitt's lymphoma, eosinophilic thyroid carcinoma, tunica vaginalis meningioma, brain cancer, optic nerve tumor carcinoma, oral carcinoma in situ, osteosarcoma, carcinosarcoma, ovarian cancer, chondroma, superior sulcus tumor, cement tumor, papillary thyroid carcinoma, myeloma, paraganglioma, chondroma, pineal blastoma, chordoma, pineal cell carcinoma, choriocarcinoma, pituitary adenoma, choroid plexus papillary adenoma, pituitary adenoma, kidney hyaline carcinoma. Cellular sarcoma, pituitary adenoma, craniopharyngioma, plasmacytoma, cutaneous T-cell lymphoma, multiple embryonal tumor, cervical cancer, precursor T-lymphoblastic lymphoma, colorectal cancer, primary central nervous system lymphoma, Degos disease, primary effusion lymphoma, proliferative small round cell tumor, primary peritoneal cancer, diffuse large B-cell lymphoma, prostate cancer, dysplastic neuroepithelial tumor, pancreatic cancer, dysgerminoma, pharyngeal cancer, embryonal carcinoma, pseudomyxoma peritonei, endocrine gland tumor, renal cell carcinoma, endodermal sinus tumor, renal medullary carcinoma, bowel-associated T-cell lymphoma, retinoblastoma, esophageal cancer, rhabdomyosarcoma, fetus-in-fetus, rhabdomyosarcoma, fibroma, Richter's transformation, fibrosarcoma, rectal cancer, follicular lymphoma, sarcomaFollicular thyroid cancer, schwannoma, gangliocytoma, seminoma, gastrointestinal cancer, Sertoli cell tumor, germ cell tumor, sex cord-gonadal stromal tumor, gestational choriocarcinoma, signet ring cell carcinoma, giant cell fibroblastoma, skin cancer, giant cell tumor of bone, small blue round cell tumor, glioma, small cell carcinoma, glioblastoma multiforme, soft tissue sarcoma, glioma, somatostatinoma, gliomatosis, somnoloma, glucagonoma, spinal tumor, gonadal blastoma, splenic marginal zone lymphoma, granular cell tumor, squamous cell carcinoma, estrogen tumor, synovial sarcoma, gallbladder cancer, Sezary disease, gastric cancer, small intestinal cancer, hairy cell leukemia, squamous cell carcinoma, hemangioblastoma. Cellular tumors, gastric cancer, head and neck cancer, T-cell lymphoma, hemangiopericytoma, testicular cancer, hematologic malignancies, sarcomas, hepatoblastoma, thyroid cancer, hepatosplenic T-cell lymphoma, transitional cell carcinoma, Hodgkin's lymphoma, laryngeal cancer, non-Hodgkin's lymphoma, urachal carcinoma, invasive lobular carcinoma, urogenital cancer, intestinal cancer, urothelial carcinoma, renal cancer, uveal melanoma, laryngeal cancer, uterine cancer, malignant lentigines, verrucous carcinoma, lethal midline carcinoma, visual pathway glioma, leukemia, vulvar cancer, testicular stromal cell tumor, vaginal cancer, liposarcoma, Waldenström's macroglobulinemia, lung cancer, adenolymphoma, lymphangioma, nephroblastoma, and lymphangiosarcoma.

[0257] Preferably, the cancer is selected from: acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed spectrum leukemia, NUT midline carcinoma, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, and breast cancer.

[0258] Preferably, the cancer is a malignant hematological disease. The malignant hematological disease is selected from non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM).

[0259] More preferably, the cancer is selected from: non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-small cell lung cancer (NSCLC).

[0260] Most preferably, the cancer is selected from acute myeloid leukemia (AML). In particular, lisaftoclax (compound 6) in combination with compound 5-1 has a synergistic antitumor effect in preclinical AML cell and animal models.

[0261] A third aspect of the invention relates to a combination product for the prevention and / or treatment of a disease, said combination product comprising a Bcl-2 inhibitor and a FAK inhibitor, said disease being cancer. Further, said cancer includes, but is not limited to, those cancers described in the second aspect of the invention as detailed in the foregoing description.

[0262] In some embodiments, the Bcl-2 inhibitor is one of those compounds (e.g., compound IA) specifically described in the first aspect of the invention, or a pharmaceutically acceptable salt or solvation thereof.

[0263] In some embodiments, the FAK inhibitor is selected from the compounds shown in Table B.

[0264] In a preferred embodiment, the FAK inhibitor is Or its pharmaceutically acceptable salts or solvates, and

[0265] The Bcl-2 inhibitor is

[0266] Or its pharmaceutically acceptable salts or solvates.

[0267] In some embodiments, the combined product is in the form of a pharmaceutical composition.

[0268] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are each contained in the kit as separate formulations.

[0269] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are administered simultaneously or sequentially.

[0270] In some embodiments, the time interval between the sequential administration of the Bcl-2 inhibitor and the FAK inhibitor may be approximately 1 minute, approximately 5 minutes, approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 12 hours, approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 8 weeks, or approximately 12 weeks.

[0271] In some embodiments, the combination product of the present invention containing the Bcl-2 inhibitor and the FAK inhibitor, which is in the form of a pharmaceutical composition (preferably in the form of individual dosage units), may be administered daily, including but not limited to: once, twice, three times, four times, five times, or six times, as needed.

[0272] In some embodiments, the combination product of the present invention containing the Bcl-2 inhibitor and the FAK inhibitor, in the form of a pharmaceutical composition (preferably in the form of a dosage unit), may be administered daily, including but not limited to: once, twice, three times, four times, five times, or six times, as needed.

[0273] In some embodiments, the combined product can be administered via: oral, oral, inhaled spray, sublingual, rectal, transdermal, vaginal mucosa, transmucosal, local administration, nasal or intestinal administration; injection, such as intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct brain administration, in situ administration, subcutaneous, intraperitoneal, intravenous injection, intra-articular synovial, intrasternal, intrahepatic, intralesional, intracranial, intraperitoneal, nasal, or intraocular injection, or other drug delivery methods.

[0274] In some embodiments, the daily dosage of the Bcl-2 inhibitor or a pharmaceutically acceptable salt or solvation thereof, and the FAK inhibitor or a pharmaceutically acceptable salt or solvation thereof, is as described in the first aspect of the invention detailed above.

[0275] A fourth aspect of the invention relates to a method of preventing and / or treating a disease, comprising administering to a subject in need of preventative and / or therapeutically effective amounts of a Bcl-2 inhibitor and a FAK inhibitor, wherein the disease is cancer. Further, the cancer includes, but is not limited to, those cancers described in the second aspect of the invention as detailed in the foregoing description.

[0276] In some embodiments, the Bcl-2 inhibitor is one of those compounds (e.g., compound IA) specifically described in the first aspect of the invention, or a pharmaceutically acceptable salt or solvation thereof.

[0277] In some embodiments, the FAK inhibitor is selected from the compounds shown in Table B.

[0278] In a preferred embodiment, the FAK inhibitor is

[0279] Or its pharmaceutically acceptable salts or solvates, and

[0280] The Bcl-2 inhibitor is

[0281] Or its pharmaceutically acceptable salts or solvates.

[0282] lisaftoclax (compound 6) in combination with compound 5-1 has a synergistic antitumor effect in preclinical AML cell and animal models.

[0283] In some embodiments, the Bcl-2 inhibitor and FAK inhibitor are in the form of a pharmaceutical composition.

[0284] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are each contained in the kit as separate formulations.

[0285] In some embodiments, the Bcl-2 inhibitor and the FAK inhibitor are administered simultaneously or sequentially.

[0286] In some embodiments, the time interval between the sequential administration of the Bcl-2 inhibitor and the FAK inhibitor may be approximately 1 minute, approximately 5 minutes, approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 12 hours, approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 8 weeks, or approximately 12 weeks.

[0287] In some embodiments, the Bcl-2 inhibitor and FAK inhibitor, which are in the form of a pharmaceutical composition (preferably in the form of individual dosage units), may be administered daily as needed, including but not limited to: once, twice, three times, four times, five times, or six times.

[0288] In some embodiments, the Bcl-2 inhibitor and FAK inhibitor, which are in the form of a pharmaceutical composition (preferably in the form of a dose unit), may be administered daily as needed, including but not limited to: once, twice, three times, four times, five times, or six times.

[0289] In some embodiments, the Bcl-2 inhibitor and FAK inhibitor can be administered via: oral, oral, inhaled spray, sublingual, rectal, transdermal, vaginal mucosa, transmucosal, local administration, nasal or intestinal administration; injection, such as intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct brain administration, in situ administration, subcutaneous, intraperitoneal, intravenous injection, intra-articular synovial, intrasternal, intrahepatic, intralesional, intracranial, intraperitoneal, nasal, or intraocular injection, or other drug delivery methods.

[0290] In some embodiments, the daily dosage of the Bcl-2 inhibitor is 0.017 mg / kg, 0.083 mg / kg, 0.17 mg / kg, 0.33 mg / kg, 0.5 mg / kg, 0.67 mg / kg, 0.83 mg / kg, 1 mg / kg, 1.02 mg / kg, 1.16 mg / kg, 1.33 mg / kg, 1.5 mg / kg, 1.67 mg / kg, 2.03 mg / kg, 2.5 mg / kg, 3.33 mg / kg, 4.06 mg / kg, 4.17 mg / kg, 5 mg / kg, 5.83 mg / kg, 6.67 mg / kg, 7.5 mg / kg, 7.67 mg / kg, 7.83 mg / kg, 8 mg / kg, 8.12 mg / kg, 8.16 mg / kg, 8.3 mg / kg. 3 mg / kg, 9.17 mg / kg, 10 mg / kg, 10.83 mg / kg, 11.66 mg / kg, 12.5 mg / kg, 13.33 mg / kg, 14.17 mg / kg, 15 mg / kg, 15.83 mg / kg, 16.67 mg / kg, and the ranges between the stated dosages, for example, 0.017 mg-16.67 mg / kg, 0.33 mg-16.67 mg / kg, 1.02 mg-15 mg / kg, 1.02 mg-15 mg / kg, 1.02-12.5 mg, 1.02 mg-10 mg / kg, 1.02 mg-8.12 mg / kg, 1.02 mg-4.06 mg / kg, 1.02 mg-2.03 mg / kg, 2.03 mg-4.06 mg / kg, etc.

[0291] In some embodiments, the FAK inhibitor or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, for example at doses of about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, etc. kg, approximately 200 μg / kg, approximately 225 μg / kg, approximately 250 μg / kg, approximately 275 μg / kg, approximately 300 μg / kg, approximately 325 μg / kg, approximately 350 μg / kg, approximately 375 μg / kg, approximately 400 μg / kg, approximately 425 μg / kg, approximately 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg Approximately 675 μg / kg, approximately 700 μg / kg, approximately 725 μg / kg, approximately 750 μg / kg, approximately 775 μg / kg, approximately 800 μg / kg, approximately 825 μg / kg, approximately 850 μg / kg, approximately 875 μg / kg, approximately 900 μg / kg, approximately 925 μg / kg, approximately 950 μg / kg, approximately 975 μg / kg, approximately 1 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 8 mg / kg, approximately 10 mg / kg, approximately 15 mg / kg, approximately 20 mg / kg Administer in doses of approximately 25 mg / kg, approximately 30 mg / kg, approximately 35 mg / kg, approximately 40 mg / kg, approximately 45 mg / kg, approximately 50 mg / kg, approximately 60 mg / kg, approximately 70 mg / kg, approximately 80 mg / kg, approximately 90 mg / kg, approximately 100 mg / kg, approximately 125 mg / kg, approximately 150 mg / kg, approximately 175 mg / kg, or approximately 200 mg / kg, and administer one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) units daily. Detailed Implementation

[0292] The present invention will be further illustrated below with specific embodiments and comparative examples. However, it should be understood that these embodiments and comparative examples are only for more detailed and specific illustration and should not be construed as limiting the present invention in any way.

[0293] Example

[0294] Example 1

[0295] 1. Experimental Objective

[0296] To evaluate the antitumor effects of compound 5-1 in combination with compound 6 in the human acute myeloid leukemia cell line MV4-11.

[0297] 2. Laboratory animals

[0298] The animals used were SCID mice, 6-8 weeks old, female. The animals weighed (18-20) ± 10% of their body weight. The experimental animals were provided by Shanghai Xipu-Bikai Experimental Animal Co., Ltd. (Experiment No.: APS-EF-08-2018).

[0299] All laboratory animals were housed in the SPF-grade animal facility at the Shanghai BK Animal Laboratory Center. Dedicated personnel from the Laboratory Animal Science Team of Ascentage Pharma Co., Ltd. were responsible for daily care, while laboratory personnel from Ascentage Pharma Co., Ltd. were responsible for experimental research. All handling and management of laboratory animals strictly adhered to the laboratory animal use and management guidelines of Ascentage Pharma Co., Ltd.

[0300] Mice were housed in cages, with 6-7 mice per cage; daily temperature range: 20-26℃; daily humidity range: 40%-70%; 12-hour light cycle with alternating day and night. They were continuously provided with cobalt-60 radioactively sterilized complete pelleted feed, with unlimited access. They drank reverse osmosis water (sterilized by autoclaving) from water bottles, with uninterrupted access. The bedding consisted of autoclaved wood shavings, changed twice a week. Cage cards indicated the number of animals, sex, strain, experiment number, experiment start time, experimenters, animal origin, and group; the animals were marked with ear tags. Mice were given a minimum 3-day acclimatization period before the experiment.

[0301] 3. Test substance

[0302] 3.1 Compound 5-1

[0303] Compound 5-1 was provided by Ascentage Pharma Group Corp. Ltd. Compound 5-1 was dissolved in 20% polyethylene glycol (PG) / 80% NaH2PO4 buffer and diluted to the final concentration according to the experimental protocol, resulting in a clear final solution. The compound was administered by gavage at a dose of 100 or 50 mg / kg, in a volume of 10 ml / kg. The preparation was to be prepared every 3 days and stored at 4°C when not in use. Preparation and administration of the preparation were performed under aseptic conditions.

[0304] 3.2 Compound 6

[0305] Compound 6 was provided by Jiangsu Ascentage Pharma Group Corp. Ltd. Compound 6 was dissolved in 30% PEG400 / 60% Phosal 50PG / 10% ETOH (v / v / v) and diluted to the final concentration according to the experimental protocol, resulting in a clear final solution. The compound was administered by gavage at a dose of 50 mg / kg, with a volume of 10 ml / kg. The preparation was prepared every 3 days and stored at 4°C when not in use. Preparation and administration of the preparation were performed under aseptic conditions.

[0306] 4. Cells

[0307] Human acute myeloid leukemia cells MV4-11 were purchased from the China Center for Type Culture Collection (CCTCC). Culture conditions were as follows: IMDM (containing 10 mM HEPES buffer and 1 mM sodium pyruvate) with 10% fetal bovine serum and 1% penicillin-dextrose antibody. IMDM (Shanghai Yishan Biotechnology Co., Ltd., Cat. ES-RG001), FBS (SIGMA, Cat. F8318), penicillin-dextrose antibody (gibco, Cat. 15140-122), HEPES buffer (Shanghai Yuanpei Biotechnology Co., Ltd., Cat. B110JV), sodium pyruvate (gibco, Cat. 11360-070), PBS (Coyobio Biotechnology Co., Ltd., Cat. U10017B), trypsin (gibco, Cat. 25200-072), and Matrigel (Corning, Cat. 354234) were used. Cells were cultured in a 5% CO2 incubator at 37°C.

[0308] 5. Instruments

[0309] Biosafety cabinet (model: AC2-6S1, ESCO); CO2 cell incubator (model: CLM-170B-8-CF, ESCO); inverted microscope (model:

[0310] CKX53 (Olympus); Balance (Model: XSR205DU, Mettler Toledo); Low-speed centrifuge (Model: L600, Shanghai Luxiangyi Centrifuge Instrument Co., Ltd.); Constant temperature water bath (Model: DK-8AX, Shanghai Yiheng Scientific Instrument Co., Ltd.); Fully automatic cell counter (Model: JSY-SC-021H, Guangzhou Boda Boju Technology Co., Ltd.); Digital display vernier caliper (Model: 16EWRI4103403, Maer GmbH, Germany).

[0311] 6. Experimental Design

[0312] 6.1 Experimental Design

[0313] mice were injected subcutaneously with 5×106 MV4-11 cells were used to establish a xenograft tumor model. Mice bearing tumors with uniform tumor formation were randomly divided into different drug treatment groups according to tumor volume, with a final group of 6 mice per group. The experimental design is shown in Table 1.

[0314] Table 1. Experimental Design 1

[0315] 6.3 Experimental Methods

[0316] Under sterile conditions, a xenograft tumor model was established by subcutaneous injection of tumor cells into the right back of immunodeficient mice. When the tumor reached a suitable size (100-200 mm), the xenograft tumor was successfully established. 3 Animals were randomly assigned to groups using a randomized block design based on tumor volume. The difference in tumor volume between groups should be less than 20% of the mean. Each group consisted of 6-7 animals, and administration began on the day of grouping (day 1). The administration volume was 10 μL / g. Animal body weight and tumor size were measured twice a week during the experiment. Clinical symptoms were observed and recorded daily. The calculation of tumor-related parameters at the end of administration or the end of the experiment was based on the "Technical Guidelines for Non-Clinical Studies of Cytotoxic Antitumor Drugs" (2006) issued by the China CFDA.

[0317] The formula for calculating tumor volume (TV) is: TV = a × b 2 / 2. Where a and b represent the length and width of the tumor measurement, respectively.

[0318] The formula for calculating relative tumor volume (RTV) is: RTV = V t / V1. Where V1 is the tumor volume at the time of group administration (day 1), V t The tumor volume at the time of measurement.

[0319] The evaluation index for antitumor activity is the relative tumor proliferation rate T / C (%), calculated using the formula: Tumor proliferation rate T / C (%) = (T / C) / ... / (T / C)) RTV / C RTV )×100%, T RTV For the treatment group RTV, C RTV RTV was used as the negative control group.

[0320] Animal body weight change (%) = (measured body weight - body weight at grouping) / body weight at grouping × 100%.

[0321] The synergy score is calculated using the following formula (Clarke R, 1997):

[0322] Synergy score=((A / C)×(B / C)) / (AB / C)

[0323] A: Response to drug A; B: Response to drug B; C: Response to solvent control; AB: Effect of combined use of drugs A and B.

[0324] Efficacy evaluation criteria: According to the "Technical Guidelines for Non-Clinical Studies of Cytotoxic Antitumor Drugs" issued by the China CFDA (November 2006), a T / C (%) ≤ 40% and an RTV p < 0.05 as statistically analyzed are considered effective. If the weight loss of mice exceeds 20% or the number of drug-related deaths exceeds 20%, the drug dose is considered to be seriously toxic.

[0325] Animals that have lost more than 20% of their body weight, are in a state of disease progression, are near death, or have a tumor that is more than 10% larger than their body weight should be euthanized in accordance with animal welfare principles.

[0326] 6.4 Data Analysis

[0327] The antitumor growth curves of the test substance were plotted with treatment time (days) on the X-axis and the corresponding tumor volume (mean) on the Y-axis. One-way ANOVA was used to compare differences in tumor volume between groups. When the F-value (a ratio of treatment variance to the error variance) showed a significant difference, the Games-Howell test was used for inter-group comparisons. All data were statistically analyzed using SPSS (Statistical Product and Service Solutions) (version 18.0, IBM, Armonk, NY, US) software. Graphs were created using Prism version 6 (GraphPad Software Inc., San Diego, CA) software.

[0328] When the combined drug synergy score is <1, it indicates an antagonistic effect; =1 indicates an additive effect; and >1 indicates a synergistic effect.

[0329] 6.5 Results

[0330] Antitumor effect of compound 5-1 in combination with compound 6 in MV4-11 model

[0331] This study evaluated the combined therapeutic effect of compounds 5-1 and 6 in the MV4-11 xenograft tumor model.

[0332] The results showed that, as shown in Figure 1, the T / C value on day 22 was 67% in the compound 5-1 treatment group and 56% in the compound 6 treatment group. The T / C value on day 22 in the combination therapy group was 26%. The RTV of the combination therapy group was significantly lower than that of the solvent control group and either the compound 5-1 or compound 6 monotherapy group (P < 0.05), indicating that the combination therapy had a certain inhibitory effect on tumor growth. The synergistic factor between the two combination therapy groups was 1.43, suggesting a synergistic effect. During the treatment, no severe weight loss was observed in any group of animals, and the animals were in good condition (Figure 2).

[0333] In summary, in the MV4-11 xenograft tumor model, the combined use of compound 5-1 and compound 6 showed better antitumor effects than either compound 5-1 or compound 6 alone.

[0334] Example 2

[0335] 1. Experimental Objective

[0336] The effect of compound 5-1 on inhibiting the growth of human acute myeloid leukemia HL-60, MV4-11, MOLM-13, OCI-AML3 and ML-2 cells was evaluated.

[0337] 2. Test substance

[0338] 2.1 Compound 5-1

[0339] Compound 5-1 was provided by Jiangsu Ascentage Pharma Group Corp. Ltd. Compound 5-1 was dissolved in DMSO to a stock solution concentration of 10 mM, and then diluted to the final concentration according to the experimental protocol. The final solution was a clear solution. Preparation and use were performed under aseptic conditions.

[0340] 3. Cells

[0341] Human acute myeloid leukemia (AML) cells HL-60 and ML-2 were donated by the Wang Shaomeng laboratory at the University of Michigan. Human AML cells MV-4-11, MOLM-13, and OCI-AML-3 were purchased from Nanjing Kebai Biotechnology Co., Ltd. HL-60, MOLM-13, and OCI-AML-3 were cultured using RPMI-1640 with 20% fetal bovine serum and 1% penicillin-dextrose antibody. ML-2 was cultured using RPMI-1640 with 10% fetal bovine serum and 1% penicillin-dextrose antibody. MV-4-11 was cultured using IMDM with 20% fetal bovine serum and 1% penicillin-dextrose antibody. RPMI-1640 (gibco, Cat. C11875500BT), IMDM (KGI Biotech, Cat. KGM12200N-500), FBS (SIGMA, Cat. F8318), penicillin antibody (gibco, Cat. 15140-122), PBS (Kyobo Biotechnology Co., Ltd., Cat. U10017B), trypsin (gibco, Cat. 25200-072), and cells were cultured in a 5% CO2 incubator at 37°C.

[0342] 4. Instruments

[0343] Biosafety cabinet (model: AC2-6S1, ESCO); CO2 cell incubator (model: CLM-170B-8-CF, ESCO); inverted microscope (model: CKX53, Olympus); balance (model: XSR205DU, Mettler Toledo); low-speed centrifuge (model: L600, Shanghai Luxiangyi Centrifuge Instrument Co., Ltd.); constant temperature water bath (model: DK-8AX, Shanghai Yiheng Scientific Instrument Co., Ltd.); fully automated cell counter (model: JSY-SC-021H, Guangzhou Boda Boju Technology Co., Ltd.). Microplate reader (SpectraMax Plus 384, Molecular Devices, LLC., US).

[0344] 5. Experimental Design

[0345] Cell Plating: The antiproliferative effect of the compound was detected using a Cell Titter Glo (Cell Titter Glo kit, Promega) assay. Cells were seeded in 96-well plates. Each negative control group received 50 μL of complete culture medium, and each test well received 50 μL of complete culture medium containing cell suspension. The cell density was (5-10) x 10^4 cells / well. Drug Addition (Proceed in the Dark): In the 96-well plates, based on the sensitivity of different cells to different drugs, the appropriate highest concentration was selected and serially diluted at a ratio of 1:2 or 1:3 to obtain 6 or 9 concentrations. 50 μL of culture medium containing the compound was added to each well, with 2-3 replicates for each concentration. After adding the compound, the 96-well plates were incubated in a 5% CO2 incubator at 37°C. The combined effect of the compound (I-1) and doxorubicin hydrochloride was tested by treating different concentrations of doxorubicin hydrochloride with three fixed doses of the compound shown in formula (I-1) for 72 hours.

[0346] Reading: At the end of the culture, add the reaction substrate from the Cell titer glo kit and detect the chemiluminescence value using a microplate reader. Calculate the cell viability percentage using the average OD value of the replicates using the following formula: (Test wells - Blank control wells) / (Cell control wells - Blank control wells) × 100%. Calculate the IC50 using the nonlinear regression data analysis method in Graphpad Prism 9 software. 50 .

[0347] 6. Experimental Results

[0348] The results are shown in Figure 3. Compound 5-1 inhibited the growth of different AML cells, with an IC50 concentration of 100 mg / kg / dL. 50 The range is between 0.5 and 7 μM.

[0349] Example 3

[0350] 1. Experimental Objective

[0351] The effects of compound 5-1 in combination with compound 6 on inhibiting the growth of human acute myeloid leukemia cells MOLM-13, MV4-11, ML-2 and OCI-AML-3 were evaluated.

[0352] 2. Test substance

[0353] 2.1 Compound 5-1

[0354] Compound 5-1 was provided by Jiangsu Ascentage Pharma Group Corp. Ltd. Compound 5-1 was dissolved in DMSO to a stock solution concentration of 10 mM, and then diluted to the final concentration according to the experimental protocol. The final solution was a clear solution. Preparation and use were performed under aseptic conditions.

[0355] 2.1 Compound 6

[0356] Compound 6 was provided by Jiangsu Ascentage Pharma Group Corp. Ltd. Compound 6 was dissolved in DMSO to a stock solution concentration of 10 mM, and then diluted to the final concentration according to the experimental protocol. The final solution was a clear solution. Preparation and use were performed under aseptic conditions.

[0357] 3. Cells

[0358] Human acute myeloid leukemia cells MV-4-11, MOLM-13, and OCI-AML-3 were purchased from Nanjing Kebai Biotechnology Co., Ltd. MOLM-13 and OCI-AML-3 were cultured using RPMI-1640 with 20% fetal bovine serum and 1% penicillin-dextrose antibody. MV-4-11 was cultured using IMDM with 20% fetal bovine serum and 1% penicillin-dextrose antibody. RPMI-1640 (gibco, Cat. C11875500BT), IMDM (KGI Biotechnology, Cat. KGM12200N-500), FBS (SIGMA, Cat. F8318), penicillin-dextrose antibody (gibco, Cat. 15140-122), PBS (Keyoubo Biotechnology Co., Ltd., Cat. U10017B), and trypsin (gibco, Cat. 25200-072) were added. Cells were cultured at 37°C in a 5% CO2 incubator.

[0359] 4. Instruments

[0360] Biosafety cabinet (model: AC2-6S1, ESCO); CO2 cell incubator (model: CLM-170B-8-CF, ESCO); inverted microscope (model: CKX53, Olympus); balance (model: XSR205DU, Mettler Toledo); low-speed centrifuge (model: L600, Shanghai Luxiangyi Centrifuge Instrument Co., Ltd.); constant temperature water bath (model: DK-8AX, Shanghai Yiheng Scientific Instrument Co., Ltd.); fully automated cell counter (model: JSY-SC-021H, Guangzhou Boda Boju Technology Co., Ltd.). Microplate reader (SpectraMax Plus 384, Molecular Devices, LLC., US).

[0361] 5. Experimental Design

[0362] Cell Plating: The antiproliferative effect of the compound was detected using a Cell Titter Glo (Cell Titter Glo kit, Promega) assay. Cells were seeded in 96-well plates. Each negative control group received 50 μL of complete culture medium, and each test well received 50 μL of complete culture medium containing cell suspension. The cell density was (5-10) x 10^4 cells / well. Drug Addition (Proceed in the Dark): In the 96-well plates, based on the sensitivity of different cells to different drugs, the appropriate highest concentration was selected and serially diluted at a ratio of 1:2 or 1:3 to obtain 6 or 9 concentrations. 50 μL of culture medium containing the compound was added to each well, with 2-3 replicates for each concentration. After adding the compound, the 96-well plates were incubated in a 5% CO2 incubator at 37°C. The combined effect of the compound (I-1) and doxorubicin hydrochloride was tested by treating different concentrations of doxorubicin hydrochloride with three fixed doses of the compound shown in formula (I-1) for 72 hours.

[0363] Reading: At the end of the culture, add the reaction substrate from the Cell titer glo kit and detect the chemiluminescence value using a microplate reader. Calculate the cell viability percentage using the average OD value of the replicates using the following formula: (Test wells - Blank control wells) / (Cell control wells - Blank control wells) × 100%. Calculate the IC50 using the nonlinear regression data analysis method in Graphpad Prism 9 software. 50 For combined experiments, cell viability was calculated after normalizing the average OD values ​​of the three replicates from the single-drug control. The IC50 was obtained from the curves of combined administration versus single administration. 50 The comparison showed that the two compounds achieved a synergistic effect (the curve shifted to the left for combined administration).

[0364] 6. Experimental Results

[0365] As shown in Figure 4, compounds 5-1 and 6 inhibited cell growth in both Bcl-2 inhibitor-sensitive cell lines (MV4-11, MOLM13, and ML-2) and Bcl-2 inhibitor-insensitive cell line (OCI-AML-3). The curve of the combination group shifted to the left compared to the single-drug group, indicating that compound 5-1 and compound 6 had a synergistic effect.

[0366] Example 4

[0367] 1. Experimental Objective

[0368] To evaluate the effects of compound 5-1 in combination with compound 6 on the expression of apoptosis-related pathway proteins in human acute myeloid leukemia cell lines MV4-11 and OCI-AML-3.

[0369] 2. Test substance

[0370] 2.1 Compound 5-1

[0371] Compound 5-1 was provided by Jiangsu Ascentage Pharma Group Corp. Ltd. Compound 5-1 was dissolved in DMSO to a stock solution concentration of 10 mM, and then diluted to the final concentration according to the experimental protocol. The final solution was a clear solution. Preparation and use were performed under aseptic conditions.

[0372] 2.1 Compound 6

[0373] Compound 6 was provided by Jiangsu Ascentage Pharma Group Corp. Ltd. Compound 6 was dissolved in DMSO to a stock solution concentration of 10 mM, and then diluted to the final concentration according to the experimental protocol. The final solution was a clear solution. Preparation and use were performed under aseptic conditions.

[0374] 3. Cells

[0375] Human acute myeloid leukemia cells MV-4-11 and OCI-AML-3 were purchased from Nanjing Kebai Biotechnology Co., Ltd. OCI-AML-3 was cultured using RPMI-1640 with 20% fetal bovine serum and 1% penicillin-dextrose antibody. MV-4-11 was cultured using IMDM with 20% fetal bovine serum and 1% penicillin-dextrose antibody. RPMI-1640 (gibco, Cat. C11875500BT), IMDM (KGI Biotechnology, Cat. KGM12200N-500), FBS (SIGMA, Cat. F8318), penicillin-dextrose antibody (gibco, Cat. 15140-122), PBS (Keyoubo Biotechnology Co., Ltd., Cat. U10017B), and trypsin (gibco, Cat. 25200-072) were used. Cells were cultured at 37°C in a 5% CO2 incubator.

[0376] 4. Instruments

[0377] Biosafety cabinet (model: AC2-6S1, ESCO); CO2 cell incubator (model: CLM-170B-8-CF, ESCO); inverted microscope (model: CKX53, Olympus); balance (model: XSR205DU, Mettler Toledo); low-speed centrifuge (model: L600, Shanghai Luxiangyi Centrifuge Instrument Co., Ltd.); constant temperature water bath (model: DK-8AX, Shanghai Yiheng Scientific Instrument Co., Ltd.); fully automated cell counter (model: JSY-SC-021H, Guangzhou Boda Boju Technology Co., Ltd.). Microplate reader (SpectraMax Plus 384, Molecular Devices, LLC., US).

[0378] 5. Experimental Design

[0379] Cell Plating: The effect of compounds on protein expression levels was detected by Western blot. Cells were seeded in 6-well plates, with DMSO added as a solvent control in each negative control group. The cell density was (5-10) x 10^6 cells / well. Drug Addition (Proceed in the Dark): Appropriate concentrations of compounds were added to the 6-well plates according to the sensitivity of different cell types to different drugs. After adding the compounds, the 6-well plates were incubated in a 5% CO2 incubator at 37°C. Cells were treated with different concentrations of compound 5-1 and one fixed concentration of compound 6 for 36 hours, and the expression level of the target protein was detected. The expression level of the corresponding protein was detected by Western blot. Specific information on the antibodies used is as follows:

[0380] 6. Experimental Results

[0381] As shown in Figure 5 or Figure 6, compound 5-1, in combination with compound 6, synergistically induced apoptosis in the Bcl-2 inhibitor-sensitive cell line MV4-11 and the insensitive cell line OCI-AML-3, enhancing the expression levels of apoptosis-related proteins cleaved-PARP and cleaved-caspase 3. At the same time, it antagonized the upregulation of Mcl-1 or Bcl-xL caused by Bcl-2 inhibitors. This may be because the combination therapy can reduce the expression of FAK and the activation of downstream signaling such as STAT5, STAT3 and AKT.

[0382] These and other modifications and variations to the invention can be made by those skilled in the art without departing from the spirit and scope of the invention, which is more precisely set forth in the appended claims. Furthermore, it should be understood that aspects of the various embodiments can be interchanged, in whole or in part. Moreover, those skilled in the art should understand that the foregoing description is merely exemplary and is not intended to limit the invention further described in the appended claims.

Claims

1. A combination comprising a Bcl-2 inhibitor and a FAK inhibitor.

2. The combination of claim 1, wherein the Bcl-2 inhibitor has the compound of Formula I-A or a pharmaceutically acceptable salt thereof or solvate thereof: wherein: A is E is a C atom and is a double bond; or E is -C(H)- and is a single bond; or E is an N atom and is a single bond; X 1 , X 2 , and X 3 are independently -CR 8 = and -N=; R 1a and R 1b together with the C atom to which they are attached form a 3-, 4-, or 5-membered optionally substituted aliphatic ring; R 1a and R 1b together with the C atom to which they are attached form a 4- or 5-membered optionally substituted heterocyclic ring; R 2 is -NO2, -SO2CH3, -SO2CF3; R 2a is H or X; R 3 is H, -CN, -CºCH, -N(R 4a )(R 4b ); R 4a is optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl; R 4b is H and C1-4alkyl; R 5 is optionally substituted C1-6alkyl, heterocycle, cycloalkylalkyl and heterocyclealkyl; R 6a , R 6c , R 6e , R 6f , and R 6g are independently H, optionally substituted C1-6alkyl, optionally substituted C3-6cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl; R 6b and R 6d independently H, C1-4alkyl and halo; R 7 is optionally substituted C1-6alkyl, heterocycle, heteroalkyl, cycloalkylalkyl, and heterocycloalkyl; R 8 is H and halogen.

3. The combination of claim 2, wherein the Bcl-2 inhibitor is selected from the following compounds or a pharmaceutically acceptable salt thereof or solvate thereof:

4. The combination of claim 1, wherein the FAK inhibitor is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1a and R 1b are independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; R 2a and R 2b are independently selected from hydrogen, C 1-6 alkyl and C 3-8 cycloalkyl; R 3 selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl and 4-8 membered heterocyclyl; R 4 selected from C 1-4 alkyl and C 3-6 cycloalkyl; R 5 is halogen; R 6 selected from C 1-4 alkyl and C 3-6 cycloalkyl; and R 7 selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; provided that when R 1a , R 1b , R 2a and R 2b are each hydrogen, then R 3 is selected from C 3-6 cycloalkyl and 4-8 membered heterocyclyl.

5. The combination of claim 4, wherein the FAK inhibitor is a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1a and R 1b are independently selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; R 2a and R 2b are independently selected from hydrogen, C 1-4 alkyl and C 3-6 cycloalkyl; and R 3 selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl and 4-8 membered heterocyclyl.

6. The combination of claim 4, wherein the FAK inhibitor is a compound of Formula III: ###00016### III or a pharmaceutically acceptable salt or solvate thereof. wherein: R 1a and R 2a are each independently selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl; and said compound has an enantiomeric excess of 90% or more.

7. The combination of claim 4, wherein the FAK inhibitor is a compound of Formula IV: ###00007### IV or a pharmaceutically acceptable salt or solvate thereof. wherein: R 1a and R 2a are each independently selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl; and said compound has an enantiomeric excess of 90% or more.

8. The combination of claim 4, wherein the FAK inhibitor is a compound of Formula V: ###00010### or a pharmaceutically acceptable salt or solvate thereof. wherein: R 1a and R 2a are each independently selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl; and said compound has an enantiomeric excess of 90% or more.

9. The combination of claim 4, wherein the FAK inhibitor is a compound of Formula VI: ###00006### VI or a pharmaceutically acceptable salt or solvate thereof. wherein: R 1a and R 2a each independently is selected from C 1-4 alkyl and C 3-6 cycloalkyl; and said compound has an enantiomeric excess of 90% or more.

10. The combination of any one of claims 1-9 wherein the Bcl-2 inhibitor is the compound or a pharmaceutically acceptable salt or solvate thereof.

11. The combination of claim 10, wherein the FAK inhibitor is 5-chloro-N 2 - (2-isopropoxy-5-methyl-4-(l-(tetrahydro-2H-pyran-4-yl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl)-N 4 - (2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine: or a pharmaceutically acceptable salt or solvate thereof.

12. The combination according to any one of claims 1-11, wherein the Bcl-2 inhibitor and the FAK inhibitor are in the form of a pharmaceutical composition or in the form of a kit.

13. The combination according to any one of claims 1-11, wherein the Bcl-2 inhibitor and the FAK inhibitor are administered simultaneously or sequentially.

14. The combination according to any one of claims 1-11, further comprising a pharmaceutically acceptable carrier, diluent or excipient.

15. The combination according to any one of claims 1-11, wherein the combination is in the form of a tablet, capsule, granule, syrup, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream and injection.

16. The combination according to any one of claims 1-11, for use in the prevention and / or treatment of cancer, wherein the cancer is a hematological malignancy selected from the group consisting of non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM).

17. Use of a combination according to any one of claims 1-11, for the manufacture of a medicament for the prevention and / or treatment of cancer.

18. A method of prevention and / or treatment of cancer, comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a combination according to any one of claims 1-11.

19. A method of preventing and / or treating cancer comprising administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of a combination of a Bcl-2 inhibitor and a FAK inhibitor, wherein the Bcl-2 inhibitor is the compound ###0009### or a pharmaceutically acceptable salt or solvate thereof. wherein the FAK inhibitor is 5-chloro-N 2 -(2-Isopropoxy-5-methyl-4-(l-(tetrahydro-2H-pyran-4-yl)-l,2,3,6-tetrahydropyridin-4- yl)phenyl)-N 4 -(2-(Isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine: or a pharmaceutically acceptable salt or solvate thereof.

20. The use according to claim 17 or the method according to claim 18 or 19, wherein the cancer is a hematological malignancy selected from the group consisting of non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM).

21. The use according to claim 17 or the method according to claim 18 or 19, wherein the Bcl-2 inhibitor or a pharmaceutically acceptable salt or solvate thereof is administered in an amount of about 0.0025-1500 mg per day.

22. The use according to claim 17 or the method according to claim 18 or 19, wherein the FAK inhibitor, or pharmaceutically acceptable salt or solvate thereof, is administered in an amount of about 0.005-5000 mg per day.

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