HK1240078A1 - Combination therapies for treating cancers - Google Patents

Description

Combination therapy for the treatment of cancer

Technical Field

The present invention relates generally to therapies and compositions for treating cancer, and more particularly to the use of spleen tyrosine kinase (Syk) inhibitors in combination with B-cell CLL/lymphoma 2(Bcl-2) inhibitors for the treatment of cancer.

Background

Syk inhibitors useful as anticancer agents include entospletinib, which is discussed in Phase 2Trial of Entosplitinib (GS-9973), a Selective SYK Inhibitor, in Follicullar Lymphoma (FL), Sharman et al, Blood, 124(21), Dec.6, 2014.

Various compounds that inhibit the activity of anti-apoptotic Bcl proteins are known in the art. Various Bcl-2-selective apoptosis inducing compounds are useful for treating cancer. However, some Bcl-2 inhibitors can cause thrombocytopenia and have limited use in clinical therapy (see, e.g., Zhang et al, Cell Death and Differentiation 14: 943-. Thus, there remains a need for alternative therapies to treat cancer in humans.

Disclosure of Invention

Provided herein are methods of treating cancer comprising administering a combination of a Syk inhibitor and a Bcl-2 inhibitor. In some aspects, methods of treating cancer in a human in need thereof are provided, comprising administering to the human a therapeutically effective amount of a Syk inhibitor and a therapeutically effective amount of a Bcl-2 inhibitor.

In some embodiments, the Syk inhibitor is 6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the Syk inhibitor is the mesylate salt of 6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine, or a hydrate thereof. Examples of mesylate salts and formulations thereof which may be used in the process of the invention are found in U.S.2015/0038504 (castel et al) and U.S.2015/0038505(Elford et al).

In some embodiments, the Bcl-2 inhibitor is:

(4- (4- { [2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl ] methyl } piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-yl-methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yl-oxy) benzamide);

4- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4- (dimethylamino) -1- (phenylsulfanyl) but-2-yl) amino) -3-nitrophenyl) sulfonyl) benzamide; or

4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4-morpholino-1- (phenylthio) but-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide;

or a pharmaceutically acceptable salt thereof.

Also provided herein are articles of manufacture and kits comprising a Syk inhibitor and a Bcl-2 inhibitor described herein.

Detailed Description

The following description sets forth exemplary methods, parameters, and the like. It should be understood, however, that the description is not intended to limit the scope of the invention, but is provided as a description of exemplary embodiments.

Provided herein are methods of treating cancer in a human in need thereof comprising administering to the human a therapeutically effective amount of a Syk inhibitor and a therapeutically effective amount of a Bcl-2 inhibitor. Also provided are compositions (including pharmaceutical compositions, formulations, or unit doses), articles of manufacture, and kits comprising a Syk inhibitor and a Bcl-2 inhibitor.

Compound (I)

In some embodiments, the Syk inhibitor is compound a1, or a pharmaceutically acceptable salt or hydrate thereof. Compound a1 has the following structure:

in some embodiments, the Syk inhibitor is the mesylate salt of compound a1, or a hydrate thereof. In one variation, the mesylate salt of compound a1 can be a mono-mesylate salt or a bis-mesylate salt. In another embodiment, the Syk inhibitor is the bis-mesylate, monohydrate of compound a 1. Compound a1 can be synthesized according to the methods described in U.S. patent No. 8,450,321. Compound a1 can be referred to as 6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine or entospletinib.

In a particular embodiment, compounds of formula IA are used

It is a crystalline form of the bis (mesylate) salt (MSA). In some embodiments, the bis-mesylate salt is polymorph form 3 described in u.s.2015/0038504 (castel et al) and u.s.2015/0038505(Elford et al). In some embodiments, polymorph form 3 is used, which has an X-ray diffraction (XRPD) pattern comprising the following 2 Θ -reflections (+0.2 degrees): 13.8, 16.9, 22.9 and 26.1. In some embodiments, polymorph form 3 has an X-ray diffraction (XRPD) pattern comprising at least one or more of the following 2 Θ -reflections (+0.2 degrees); at least two or more; or at least 3 or more: 13.8, 16.9, 22.9 and 26.1. In some embodiments, polymorphic form 7 described by Casteel et al and Elford et al, having an X-ray diffraction (XRPD) pattern comprising the following 2 θ -reflections (+0.2 degrees), is used: 4.9, 9.8 and 26.7. In some embodiments, polymorph form 7 has an X-ray diffraction (XRPD) pattern comprising at least one or more of the following 2 Θ -reflections (+0.2 degrees); or at least two or more of: 4.9, 9.8 and 26.7.

The term "crystalline" refers to a solid phase in which a substance has a regular ordered internal structure at the molecular level and gives a unique X-ray diffraction pattern with defined peaks. When heated sufficiently, such a substance will also exhibit the properties of a liquid, but the change from a solid to a liquid is characterized by a phase change, usually first order (melting point).

For example, in one embodiment, polymorph form 3 of the bis (mesylate) salt (IA) described herein is substantially crystalline. In another embodiment, form 7 of the bis-mesylate salt (IA) described herein is substantially crystalline. In some embodiments, the substantially crystalline compound has a composition of the compound in a crystalline form of greater than 50%; or greater than 55%; or greater than 60%; or greater than 65%; or greater than 70%; or greater than 75%; or greater than 80%; or greater than 85%; or greater than 90%; or greater than 95%, or greater than 99%. In other embodiments, the substantially crystalline compound has no more than about 20%, or no more than about 10%, or no more than about 5%, or no more than about 2% amorphous form.

In some embodiments, the Bcl-2 inhibitor is compound B1, compound B2, or compound B3, or a pharmaceutically acceptable salt thereof.

Compound B1 has the following structure:

compound B2 has the following structure:

compound B3 has the following structure:

in some embodiments, compound B1, or a pharmaceutically acceptable salt thereof, is used in combination with compound a1, or a pharmaceutically acceptable salt or hydrate thereof. In other embodiments, compound B2, or a pharmaceutically acceptable salt thereof, is used in combination with compound a1, or a pharmaceutically acceptable salt or hydrate thereof. In other embodiments, compound B3, or a pharmaceutically acceptable salt thereof, is used in combination with compound a1, or a pharmaceutically acceptable salt or hydrate thereof.

Compounds B1, B2 and B3 are commercially available and their synthesis methods are generally known in the art. For example, compounds B1, B2, and B3 can be synthesized according to U.S. patent application publication nos. 2010/0305122, 2007/0072860, or 2007/0027135.

In addition to the chemical structure, compound B1 can also be referred to or identified as (4- (4- { [2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl ] methyl } piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-yl-methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-B ] pyridin-5-yl-oxy) benzamide), 4- [4- [ [2- (4-chlorophenyl) -4, 4-dimethyl-1-cyclohexen-1-yl ] methyl ] -1-piperazinyl ] -N- [ [ 3-nitro-4- [ [2 ], [2, 4-dimethyl-1-cyclohexen-1-yl ] methyl ] -1-piperazinyl ], [2 ] (tetrahydro-2H-pyran-4-yl) methyl ] amino ] phenyl ] sulfonyl ] -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide, ABT-199, GDC0199, or Venetosalax. The crystalline form of compound B1 useful in the methods and combinations herein can be found in WO2012/071336(Catron et al).

In some embodiments herein, the form in which compound B1 is used is disclosed in WO2012/071336(Catron et al). In one embodiment, the crystalline form is compound B1 free base anhydrate characterized by when irradiated with CuKa at about 25 ℃ to form a crystalline formWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 6.3, 7.1, 9.0, 9.5, 12.5, 14.5, 14.7, 15.9, 16.9 and 18.9 degrees 2 theta (panel a in WO 2012/071336), and each peak ± 0.2 degrees 2 theta.

In another embodiment, the crystalline form is compound B1 free base anhydrate characterized by when irradiated with Cu Ka at about 25 ℃ to form a crystalline formWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 5.8, 7.7, 8.3, 9.9, 13.0, 13.3, 14.2, 15.3, 16.6, 17.9, 18.3, 19.8, 20.7, 21.2, 21.9, 22.5, 23.6 and 24.1 degrees 2 θ (WO 2.7, 23.6)012/071336, graph B), each peak ± 0.2 degrees 2 θ.

In another embodiment, the crystalline form is compound B1 free base hydrate, characterized by when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 5.8, 7.6, 7.9, 10.7, 11.7, 14.0, 15.3, 15.8, 17.4, 18.3, 19.9, 20.4, 20.7, 22.5, 24.9, 25.8 and 26.7 degrees 2 theta (panel C in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In another embodiment, the crystalline form used is the free base hydrate of compound B1 characterized by when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 3.3, 6.4, 7.1, 7.3, 10.1, 11.4, 13.2, 14.4, 14.6, 15.1, 15.8, 16.2, 17.2, 17.6, 18.0, 18.6, 19.0, 19.5, 19.8, 20.2, 20.7, 21.0, 22.5, 23.0, 26.0, 28.9 and 29.2 degrees 2 theta (panel D in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In another embodiment, the crystalline form is compound B1 free base dichloromethane solvate, characterized when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 5.9, 7.1, 9.6, 10.0, 10.7, 11.1, 13.2, 14.8 and 18.2 degrees 2 theta, peaks ± 0.2 degrees 2 theta (panel E in WO 2012/071336).

In another embodiment, the crystalline form is compound B1 free base dichloromethane solvate, characterized by a monoclinic lattice type and a P21/n space group, having a unit cell length on three axes of about (a)(b)(c)And the three unit cell angles are about (α)90.00 °, (β)92.259 °, and (γ)90.00 °, as described in WO 2012/071336.

In a different embodiment the crystalline form is compound B1 free base ethyl acetate solvate characterized when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 5.8, 7.1, 9.5, 9.9, 10.6, 11.6, 13.1, 13.8, 14.8, 16.0, 17.9, 20.2, 21.2, 23.2, 24.4 and 26.4 degrees 2 theta (panel F in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In a different embodiment, the crystalline form is compound B1 free base ethyl acetate solvate, characterized when irradiated at about 25 ℃ with radiationWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 3.3, 6.5, 7.0, 7.3, 9.2, 9.7, 11.2, 11.4, 11.9, 12.9, 14.4, 14.9, 15.8, 16.2, 17.2, 17.4, 17.8, 18.5, 18.9, 19.4, 20.1, 20.7, 20.9, 22.0, 22.7, 23.4, 23.8, 24.7, 25.9, 27.0, and 28.9 degrees 2 θ (fig. G in WO 2012/071336), each peak ± 0.2 degrees 2 θ.

In a separate embodiment, the crystalline form is compound B1 free base acetonitrile solvate, characterized when irradiated at about 25 ℃ toThe powder X-ray diffraction pattern has at least one choice when measuredFrom peaks located below: 5.8, 7.4, 7.6, 10.2, 13.0, 13.6, 14.9, 16.4, 17.0, 17.5, 18.2, 19.4, 19.7, 20.4, 21.0, 21.2, 21.8, 22.4, 22.9, 24.2, 24.3, 26.1 and 29.2 degrees 2 theta (fig. H in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In another embodiment, the crystalline form is compound B1 free base acetonitrile solvate, characterized by a triclinic lattice type and a PI space group, having a unit cell length on three axes of about (a)(b)(c)And the three unit cell angles are about (α)92.746 °, (β)95.941 ° and (γ)113.833 °, as described in WO 2012/071336.

In another embodiment, the crystalline form is compound B1 free base acetonitrile solvate, characterized when irradiated at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 6.4, 6.9, 7.7, 8.8, 9.4, 11.1, 12.3, 12.8, 16.5, 17.0, 17.4, 18.3, 18.6, 19.0, 19.2, 20.3, 21.6, 22.3, 22.9, and 23.7 degrees 2 θ (panel I in WO 2012/071336), each peak ± 0.2 degrees 2 θ.

In a separate embodiment, the crystalline form is compound B1 free base acetone solvate, characterized when irradiated at about 25 ℃ with radiationWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 6.0, 6.8, 8.0, 9.0, 9.7, 11.2, 11.9, 12.6, 14.7, 15.0, 15.2, 15.8, 16.4, 16.6, 17.6, 17.8, 17.9,18.7, 20.2, 20.8, 21.6, 22.2, 22.6, 23.3, 23.8, 24.0, 24.4, 26.8, 27.1, 28.0 and 28.2 degrees 2 theta (graph J in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In another embodiment, the crystalline form is compound B1 hydrochloride characterized by the use of CuKa radiation when at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 5.1, 5.9, 7.7, 9.9, 10.2, 10.8, 13.6, 14.0, 15.4, 15.9, 16.2, 17.6, 18.3, 18.7,19.7, 19.9, 20.1, 20.4, 20.7, 20.9, 22.9, and 26.2 degrees 2 theta (fig. K in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In a different embodiment the crystalline form is compound B1 free base hydrochloride salt, characterized by a triclinic lattice type and a P1 space group, having a unit cell length on three axes of about (a)(b)(c)And the three unit cell angles are about (α)76.540 °, (β)87.159 ° and (γ)70.074 °, as described in WO 2012/071336.

In another embodiment, the crystalline form is compound B1 free base hydrochloride hydrate, characterized by when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 4.6, 8.7, 9.6, 9.9, 12.3, 14.9, 15.7, 17.6, 18.1, 18.4, 19.3, 19.6, 21.0, 23.3, 23.9, 24.8, 26.5, 27.2, 27.4, 29.0 and 30.1 degrees 2 theta (fig. L in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

In a different embodiment, the crystalline form is compound B1 free base sulfate, characterized by when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 4.8, 7.7, 8.3, 9.7, 10.2, 12.0, 12.6, 14.5, 15.4, 17.4, 17.9, 18.4, 19.1, 19.5, 21.0, 22.4, 23.3, 23.9, 25.1 and 26.8 degrees 2 θ (panel M in WO 2012/071336), each peak ± 0.2 degrees 2 θ.

In another embodiment, the crystalline form is compound B1 free base tetrahydrofuran, characterized by when irradiated with Cu Ka at about 25 ℃ toWhen measured, the powder X-ray diffraction pattern has at least one peak selected from the group consisting of: 4.0, 4.6, 8.0, 8.5, 9.4, 14.6, 17.1, 17.4, 17.8, 18.1, 19.2, 19.5, 20.1, 20.4, 20.5 and 21.7 degrees 2 theta (panel N in WO 2012/071336), each peak ± 0.2 degrees 2 theta.

Compound B2 can be referred to or identified as 4- (4- ((4 '-chloro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4- (dimethylamino) -1- (phenylthio) but-2-yl) amino) -3-nitrophenyl) sulfonyl) benzamide; 4- [4- [ (4 '-chloro [1,1' -biphenyl ] -2-yl) methyl ] -1-piperazinyl ] -N- [ [4- [ [ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl ] amino ] -3-nitrophenyl ] sulfonyl ] -benzamide; or ABT-737.

Compound B3 can be referred to or identified as (R) -4- (4- ((4 '-chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [1,1' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4-morpholino-1- (phenylthio) but-2-yl) amino) -3- ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide; 4- (4- { [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl ] methyl } -1-piperazinyl) -N- [ (4- { [ (2R) -4- (4-morpholinyl) -1- (phenylsulfanyl) -2-butyl ] amino } -3- [ (trifluoromethyl) sulfonyl ] phenyl) sulfonyl ] benzamide, Navitoclax, or ABT-263.

In one embodiment, compound B3 is used as ABT-263 di-HCl salt, as described in u.s.2010/0305125 (Borchardt). In other embodiments, compound B3 is used in the crystalline form taught by u.s.2011/0071151(Zhang et al). In one embodiment, compound B3 is ABT-263 free base in solid crystalline form as taught by u.s.2011/0071151(Zhang et al). In another embodiment, compound B3 is ABT-263 free base form I, characterized by at least a powder X-ray diffraction peak at any one or more of the following positions: 6.21, 6.72, 12.17, 18.03 and 20.10 ° 28, ± 0.2 ° 2 θ, as taught by u.s.2011/0071151.

In another embodiment, the crystalline form is form I ABT-263 free base, characterized by at least powder X-ray diffraction peaks at the following positions: 6.21, 6.72, 9.66, 10.92, 11.34, 12.17, 14.28, 16.40, 16.95, 17.81, 18.03, 18.47, 19.32, 20.10 and 21.87 ° 28, ± 0.2 ° 2 θ as taught by u.s.2011/0071151.

In another embodiment, the crystalline form is form II ABT-263 free base, characterized by at least a powder X-ray diffraction peak at any one or more of the following positions: 5.79, 8.60, 12.76, 15.00 and 20.56 ° 28, ± 0.2 ° 2 θ, as taught by u.s.2011/0071151.

In another embodiment, the crystalline form is form II ABT-263 free base, characterized by at least powder X-ray diffraction peaks at the following positions: 5.79, 8.60, 9.34, 10.79, 11.36, 11.59, 12.76, 13.23, 13.73, 14.01, 14.72, 15.00, 16.28, 17.07, 17.48, 18.75, 19.34, 19.71, 20.56 and 21.35 ° 28, ± 0.2 ° 2 θ, as taught in u.s.2011/0071151.

In one variation, the Bcl-2 inhibitor is (4- (4- { [2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl ] methyl } piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-4-yl-methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yl-oxy) benzamide), or a pharmaceutically acceptable salt thereof.

In another embodiment, the Bcl-2 inhibitor is 4- [4- [ (4 '-chloro [1,1' -biphenyl ] -2-yl) methyl ] -1-piperazinyl ] -N- [ [4- [ [ (1R) -3- (dimethylamino) -1- [ (phenylsulfanyl) methyl ] propyl ] amino ] -3-nitrophenyl ] sulfonyl ] benzamide, or a pharmaceutically acceptable salt thereof.

In another embodiment, the Bcl-2 inhibitor is 4- [4- [ [2- (4-chlorophenyl) -5, 5-dimethyl-1-cyclohexen-1-yl ] methyl ] -1-piperazinyl ] -N- [ [4- [ [ (1R) -3- (4-morpholinyl) -1- [ (phenylsulfanyl) methyl ] propyl ] amino ] -3[ (trifluoromethyl) sulfonyl ] phenyl ] sulfonyl ] benzamide, or a pharmaceutically acceptable salt thereof.

Other Bcl-2 inhibitors useful in the combinations, methods, and kits described herein include those selected from the group consisting of: ABT-263, Venetian de (ABT-199), ABT-737 and AT-101(Gossypol), apogossypol, TW-37, G3139(Genasense or Orimerson), obatoclax, sabutocra, HA14-1, antimycin A and S44563.

The compound names provided herein are named using ChemBioDraw Ultra 12.0. Those skilled in the art will appreciate that the compounds may be named or identified using a variety of commonly recognized naming systems and symbols. For example, the compound may be named or identified by a common name, a system or non-system name. Commonly accepted nomenclature systems and symbols in the chemical arts include, for example, Chemical Abstracts Service (CAS), chembidraw Ultra and International Union of Pure and Applied Chemistry (IUPAC).

Also provided herein are isotopically labeled forms of the compounds detailed herein. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to²H (deuterium, D),³H (tritium),¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I. providing various isotopically-labelled compounds of the invention, e.g. by incorporating radioactive isotopes such as³H、¹³C and¹⁴those of C. Such isotopically labeled compounds or salts thereof can be used in metabolic studies, reaction kinetic studies, detection, or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or for the radiotherapy of a subject (e.g., a human). Any pharmaceutically acceptable salt, or hydrate, as the case may be, is also provided for isotopically labeled compounds described herein.

In some embodiments, the compounds disclosed herein can be varied such that 1 to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds may exhibit increased metabolic resistance and, therefore, serve to increase the half-life of the compound when administered to a mammal. See, for example, Foster, "Deuterium Isotopoeffects in students of Drug Metabolism," Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.

Deuterium labeled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or improved therapeutic index.¹⁸The F-labeled compounds are useful for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is to be understood that, in this context, deuterium is considered to be a substituent of the compounds provided herein.

The concentration of such heavier isotopes, in particular deuterium, can be defined by the isotopic enrichment factor. Any atom not specifically designated with a particular isotope in the compounds of the present invention means any stable isotope of that atom. Unless otherwise mentioned, when a position is specifically designated as "H" or "hydrogen," then the position is understood to be hydrogen with a natural abundance isotopic composition. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) means deuterium.

Method of treatment

The Syk and Bcl-2 inhibitors described herein are useful in combination therapy. Accordingly, provided herein is a method of treating cancer in a human in need thereof comprising administering to the human a therapeutically effective amount of a Syk inhibitor described herein and a therapeutically effective amount of a Bcl-2 inhibitor.

In some embodiments, "treatment" or "treating" is a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results may include one or more of the following:

(i) inhibiting the disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder and/or reducing the extent of the disease or disorder);

(ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder) and/or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and/or

(iii) Alleviating a disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or disorder, enhancing the action of another drug, delaying disease progression, increasing quality of life, and/or prolonging survival).

In some embodiments, "delaying" the development of a disease or disorder refers to delaying, impeding, slowing, delaying, stabilizing, and/or delaying the development of the disease or disorder. The delay may be of varying lengths of time, depending on the history of the disease or condition, and/or the subject being treated. For example, a method of "delaying" the progression of a disease or disorder refers to a method that reduces the probability of progression of the disease or disorder at a given time period and/or reduces the severity of the disease or disorder at a given time period as compared to not using the method. Such comparisons are typically based on clinical studies, which utilize statistically significant numbers of subjects. The development of a disease or condition can be detected using standard methods, such as routine physical examination, mammography, imaging, or biopsy. Progression may also refer to the progression of a disease or disorder that may not be initially detected and includes occurrence, recurrence and onset.

Cancer treatment

In some embodiments, the cancer is a carcinoma, sarcoma, melanoma, lymphoma, or leukemia. In other embodiments, the cancer is a hematologic malignancy. In some embodiments, the cancer is leukemia (e.g., chronic lymphocytic leukemia), lymphoma (e.g., non-hodgkin's lymphoma), or multiple myeloma. In other embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is small lymphocytic lymphoma, non-hodgkin's lymphoma, indolent non-hodgkin's lymphoma (iNHL), refractory inh, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, splenic marginal zone B-cell lymphoma (+/-villous lymphocytes), nodular marginal zone lymphoma (+/-monocytic B-cells), mucosa-associated lymphoid tissue type extralymph node marginal zone B-cell lymphoma, cutaneous T-cell lymphoma, extralymph node T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, mycosis fungoides, B-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic T-cell lymphoma, cutaneous T-, Diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, small non-dividing cell lymphoma, Burkitt's lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia, T-cell acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, juvenile myelomonocytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, or Waldestrom macroglobulinemia.

In other variations, the cancer is pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular cancer, thyroid cancer, gallbladder cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult glioblastoma multiforme), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, effusion, malignant pleural effusion, mesothelioma, ms tumor, trophoblastic tumors, wilcoxoma, kaposi's sarcoma, mucoid carcinoma (myxoidcarcinoma), round cell carcinoma, squamous cell carcinoma, effusion, carcinoma, or carcinoma, Esophageal squamous cell carcinoma, oral cancer, adrenocortical carcinoma, or ACTH-producing tumors.

Test subject

The person in need thereof may be an individual having or suspected of having cancer. In some embodiments, the human is a human at risk of developing cancer (e.g., a human genetically or otherwise predisposed to developing cancer) and a human diagnosed with or not diagnosed with the cancer. As used herein, a "at-risk" subject refers to a subject at risk of developing cancer (e.g., a hematological malignancy). The subject may or may not have a detectable disease and may or may not have exhibited a detectable disease prior to the treatment methods described herein. A subject at risk may have one or more so-called risk factors, which are measurable parameters associated with the development of cancer as described herein. Subjects with one or more of these risk factors have a higher probability of developing cancer than individuals without these risk factors.

These risk factors may include, for example, age, gender, race, diet, prior medical history, presence of premonitory disease (precursor disease), genetic (e.g., genetic) causes, and environmental exposure. In some embodiments, people at risk for cancer include, for example, people whose relatives have experienced this disease, and those at risk determined by genetic or biochemical marker analysis. The history of previous cancer may also be a risk factor for, for example, recurrence of cancer.

In some embodiments, provided herein are methods of treating a human having one or more symptoms associated with cancer (e.g., a hematologic malignancy). In some embodiments, the human is in an early stage of cancer. In other embodiments, the human is in an advanced stage of cancer.

In some embodiments, provided herein is a method of treating a human undergoing one or more standard therapies, such as chemotherapy, radiation therapy, immunotherapy and/or surgery, for treating cancer (e.g., hematological malignancies). Thus, in some of the foregoing embodiments, a combination of a Syk inhibitor and a Bcl-2 inhibitor as described herein may be administered before, during, or after administration of chemotherapy, radiation therapy, immunotherapy, and/or surgery.

In another aspect, provided herein is a method of treating a human that is "refractory" to cancer treatment or "relapsed" (e.g., hematologic malignancy) following cancer treatment. A subject "refractory" to an anti-cancer treatment means that they do not respond to the particular treatment, also referred to as resistance. The cancer may be resistant to the treatment from the start or may become resistant during the course of the treatment, e.g. show some effect on the cancer after treatment but not enough to be considered remission or partial remission. By "relapsed" subject is meant that the cancer has recurred, or that signs and symptoms of the cancer recurred after a period of improvement, e.g., after treatment has shown an effective reduction in the cancer, e.g., after the subject is in remission or partial remission.

In some embodiments, the human is (i) refractory to at least one anti-cancer therapy, or (ii) relapsed after treatment with at least one anti-cancer therapy, or both (i) and (ii). In some embodiments, the human is refractory to at least two, at least three, or at least four anti-cancer therapies (including, e.g., standard or experimental chemotherapy).

In some embodiments, the subject is a human having a cancer responsive to Syk activity. In another embodiment, the subject is a human having a solid cancer tumor that expresses Syk. In some embodiments, the subject is a human having a17 p deletion, a TP53 mutation, a NOTCH1, a SF3B1 mutation, an 11q deletion, or any combination thereof. In one embodiment, the subject is a human having a17 p deletion, a TP53 mutation, or a combination thereof. In another embodiment, the subject is a human having NOTCH1, a SF3B1 mutation, a 11q deletion, or any combination thereof.

In another aspect, a method of sensitizing a human that is (i) refractory to at least one chemotherapy or (ii) relapsed after treatment with a chemotherapy or has both (i) and (ii) is provided, wherein the method comprises administering to the human a combination of a Syk inhibitor and a Bcl-2 inhibitor as described herein. Sensitized humans are humans that respond to the administration of a combination of a Syk inhibitor and a Bcl-2 inhibitor as described herein, or that are otherwise not resistant to such treatment.

In another aspect, provided herein are methods for treating a human having a comorbidity cancer, wherein the treatment is also effective in treating the comorbidity. A "co-morbidity" of cancer is a disease that occurs simultaneously with cancer.

A therapeutically effective amount

In some variations, a therapeutically effective amount refers to an amount sufficient to effect treatment as defined below when administered to a subject (e.g., a human) in need of such treatment. The therapeutically effective amount will vary depending on the subject and the disease condition being treated, the weight and age of the subject, the severity of the disease condition, the mode of administration, and the like, which can be readily determined by one skilled in the art. For example, in one variation, a therapeutically effective amount of compound a1, or a pharmaceutically acceptable salt or hydrate thereof, is an amount sufficient to modulate Syk expression, thereby treating a human with an indication, or ameliorating or alleviating a symptom of an existing indication. In one variation, a therapeutically effective amount of compound B1, compound B2, or compound B3, or a pharmaceutically acceptable salt thereof, is an amount sufficient to modulate the activity of an anti-apoptotic Bcl-2 protein, thereby treating a human having an indication, or ameliorating or alleviating a symptom of an existing indication.

In another variation, a therapeutically effective amount of a Syk inhibitor (e.g., compound a1), or a pharmaceutically acceptable salt or hydrate thereof, can be an amount sufficient to reduce a symptom of a disease or disorder responsive to inhibition of Syk activity. In another variation, a therapeutically effective amount of a Bcl-2 inhibitor, such as compound B1, compound B2, or compound B3, or a pharmaceutically acceptable salt thereof, may be an amount sufficient to decrease the activity of an anti-apoptotic Bcl-2 protein.

Therapeutically effective amounts of Syk and Bcl-2 inhibitors can also be determined based on data obtained from assays known in the art, including, for example, the apoptosis assay described in example 1 below. In one variation, the therapeutically effective amount of the Syk inhibitor is a dose equivalent to using 30nmol to 700nmol of the Syk inhibitor in an apoptosis assay with 10% serum. In one embodiment, the therapeutically effective amount of the Bcl-2 inhibitor is a dose equivalent to 1nmol to 200nmol of the Bcl-2 inhibitor used in an apoptosis assay with 10% serum.

In another variation, a Syk inhibitor (e.g., compound a1), or a pharmaceutically acceptable salt or hydrate thereof, is administered to a human at a dose that results in about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 99% inhibition of the Syk target. In another variation, a Bcl-2 inhibitor, e.g., compound B1, compound B2, or compound B3, or a pharmaceutically acceptable salt thereof, is administered to a human at a dose that results in about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 90%, about 95%, or about 99% Bcl-2 target inhibition.

In some variations, the Syk inhibitor, such as compound a1, or a pharmaceutically acceptable salt or hydrate thereof, is administered to a human at a dose of 100mg to 1200mg, 100mg to 800mg, 100mg to 600mg, 100mg to 400mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, or about 800 mg.

In some variations, the Bcl-2 inhibitor, such as compound B1, compound B2, or compound B3, or a pharmaceutically acceptable salt thereof, is administered to a human at a daily dose of about 20mg to 1,200mg, about 20mg to 1,000mg, about 20mg to 800mg, about 20mg to 500mg, about 100mg to 400mg, about 100mg to 200mg, about 20mg, about 40mg, about 50mg, about 75mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 1,000mg, or about 1,200 mg.

Therapeutically effective amounts of Syk and Bcl-2 inhibitors can be provided in single or multiple doses to achieve a desired therapeutic endpoint. As used herein, "dose" refers to the total amount of active ingredient taken by a human per time. Dosing, for example, the above-described orally administered doses, may be administered once daily (QD), twice daily (BID), three times daily, four times daily, or more than four times daily. In some embodiments, the Syk and/or Bcl-2 inhibitor may be administered once daily. In some embodiments, the Syk and/or Bcl-2 inhibitor may be administered twice daily.

Administration of drugs

Any suitable method known in the art may be used to administer Syk inhibitors (e.g., compound a1) and Bcl-2 inhibitors (e.g., compound B1, compound B2, and compound B3). For example, the compounds may be administered buccally, intraocularly, orally, osmotically, parenterally (intramuscularly, intraperitoneally, intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, or vaginally.

Furthermore, in certain variations, the Syk inhibitor described herein may be administered before, after, or simultaneously with the Bcl-2 inhibitor described herein.

Pharmaceutical composition

The Syk and Bcl-2 inhibitors may be administered in the form of a pharmaceutical composition. For example, in some variations, the Syk inhibitors described herein may be present in a pharmaceutical composition comprising a Syk inhibitor and at least one pharmaceutically acceptable vehicle. In some embodiments, the Bcl-2 inhibitors described herein can be present in a pharmaceutical composition comprising the Bcl-2 inhibitor and at least one pharmaceutically acceptable vehicle. The pharmaceutically acceptable vehicle may include pharmaceutically acceptable carriers, adjuvants, and/or excipients, and the other ingredients may be considered pharmaceutically acceptable, so long as they are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Accordingly, the present disclosure provides pharmaceutical compositions containing the Syk and Bcl-2 inhibitors described herein, and one or more pharmaceutically acceptable vehicles, such as excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and excipients. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the Pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, machine Publishing Co., Philadelphia, PA17th Ed. (1985); and Modern pharmaceuticals, Marcel Dekker, Inc.3rd Ed. (G.S. Bank & C.T. Rhodes, Eds.).

The pharmaceutical compositions may be administered in single or multiple doses by any acceptable mode of administration of the agents with similar uses, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via devices such as stents impregnated or coated devices, or cylindrical polymers inserted into arteries.

In some embodiments, the pharmaceutical compositions described herein are formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units of a unit dose suitable for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Each unit dosage form contains a therapeutically effective amount of the active drug of interest, including those related to unit dosage forms of compound a1, compound B1, compound B2, or compound B3, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In some variations, the pharmaceutical composition described herein is in the form of a tablet, capsule, or ampoule.

In certain embodiments, the Syk inhibitor described herein, such as compound a1, or a pharmaceutically acceptable salt or hydrate thereof, is formulated as a tablet. In some embodiments, the tablet may comprise a mesylate salt of compound a1, such as a mono-mesylate salt or a bis-mesylate salt thereof, or a hydrate thereof. Such tablets comprising compound a1 can be prepared, for example, by methods known in the art as appropriate, such as spray drying and granulation (e.g., dry granulation).

Article and kit

Compositions (including, e.g., formulations and unit doses) comprising a Syk inhibitor as described herein, as well as compositions comprising a Bcl-2 inhibitor as described herein, can be prepared and placed in a suitable container and labeled for treatment of an indicated condition. Accordingly, also provided are articles of manufacture, e.g., containers comprising a unit dosage form of a Syk inhibitor and a unit dosage form of a Bcl-2 inhibitor, as described herein, and labels containing instructions for use of the compounds. In some embodiments, the article of manufacture is a unit dosage form comprising (i) a Syk inhibitor as described herein and one or more pharmaceutically acceptable carriers, excipients, or excipients; and (ii) a Bcl-2 inhibitor as described herein and one or more pharmaceutically acceptable carriers, adjuvants, or excipients. In one embodiment, the unit dosage form of both the Syk inhibitor and the Bcl-2 inhibitor is a tablet.

Kits are also contemplated. For example, a kit can comprise a unit dosage form of a Syk inhibitor as described herein, and a composition comprising a Bcl-2 inhibitor as described herein, and a package insert comprising instructions for use of the composition to treat a medical condition. In some embodiments, a kit comprises (i) a unit dosage form of a Syk inhibitor as described herein and one or more pharmaceutically acceptable carriers, excipients, or excipients; and (ii) a Bcl-2 inhibitor as described herein and one or more pharmaceutically acceptable carriers, adjuvants, or excipients. In one embodiment, the unit dosage form of both the Syk inhibitor and the Bcl-2 inhibitor is a tablet.

The instructions for use in the kit can be for treating cancer, including, for example, hematological malignancies, as further described herein.

Combination therapy

In the present disclosure, in some aspects, the combination therapies and methods described herein involving the use of compound a1 with compound B1, compound B2, or compound B3 may be used with or further combined with other one or more agents selected from the group consisting of: a chemotherapeutic agent, an anti-cancer agent, an anti-angiogenic agent, an anti-fibrotic agent, an immunotherapeutic agent, a therapeutic antibody, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, or any combination thereof.

The combination therapies and methods described herein may be used or combined with one or more of the following other therapeutic agents: adenosine A2B receptor (A2B) inhibitors, BET-bromodomain 4(BRD4) inhibitors, isocitrate dehydrogenase 1(IDH1) inhibitors, IKK inhibitors, Protein Kinase C (PKC) activators or inhibitors, TPL2 inhibitors, serine/threonine-protein kinase 1(TBK1) inhibitors, agents that activate or reactivate latent Human Immunodeficiency Virus (HIV) such as panobinostat or romidepsin, anti-CD 20 antibodies such as Obinutuzumab (Obinuzumab), anti-PD-1 antibodies such as nivolimumab (BMS-936558, MDX1106, or MK-34775), and anti-PD-L1 antibodies such as BMS-936559, MPDL3280A, MEDI4736, 0710018 0010718C, and MDX-01.

The combination therapies and methods described herein and other therapeutic agent or agents (e.g., A2B inhibitor, apoptosis signal-regulating kinase (ASK) inhibitor, Bruton's Tyrosine Kinase (BTK) inhibitor, BRD4 inhibitor, discoidin receptor 1(DDR1) inhibitor, Histone Deacetylase (HDAC) inhibitor, Isocitrate Dehydrogenase (IDH) inhibitor, Janus kinase (JAK) inhibitor, lysyl oxidase-like protein 2(LOXL2) inhibitor, matrix metalloproteinase 9(MMP9) inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitor, PKC activator or inhibitor, spleen tyrosine kinase (SYK) inhibitor, TPL2 inhibitor, or TBK inhibitor) may further be combined with chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, radiotherapeutic agents, An antineoplastic agent, or any combination thereof, used together or in combination.

Chemotherapeutic agents

As used herein, the term "chemotherapeutic agent" or "chemotherapy" (or "chemotherapy" in the context of chemotherapeutic agent treatment) is intended to include any non-protein (i.e., non-peptide) chemical compound used to treat cancer.

Chemotherapeutic agents can be classified by their mechanism of action, for example, into the following groups:

antimetabolite/anticancer agents such as the pyrimidine analogs floxuridine, capecitabine, and cytarabine;

purine analogs, folic acid antagonists and related inhibitors;

antiproliferative/antimitotic agents comprising natural products such as vinca alkaloids (vinblastine, vincristine) and tubulin inhibitors such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones (epothilones), vinorelbineAnd epipodophyllotoxins (etoposide, teniposide);

DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamideActinomycin D, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, paclitaxel, taxotere, teniposide, etoposide, and triethylenethiophosphoramide;

antibiotics such as actinomycin D, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin;

enzymes such as L-asparaginase, which systemically metabolizes L-asparagine and eliminates cells that are unable to synthesize their own asparagine;

anti-platelet agents;

antiproliferative/antimitotic alkylating agents such as nitrogen mustards, cyclophosphamide and the like (melphalan, chlorambucil, hexamethylmelamine and thiotepa), alkyl nitrosoureas (carmustine) and the like, streptozocin, and triazenes (dacarbazine);

antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate);

platinum coordination complexes (cisplatin, oxaliplatin (oxilplatinim) and carboplatin), procarbazine, hydroxyurea, mitotane and aminoglutethimide;

hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide and nilutamide), and aromatase inhibitors (letrozole and anastrozole);

anticoagulants such as heparin, synthetic heparin salts, and other inhibitors of thrombin;

fibrinolytic agents such as tissue plasminogen activators, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel;

an anti-transfer agent;

antisecretory agents (breveldin);

immunosuppressants tacrolimus, sirolimus, azathioprine and mycophenolate mofetil;

compound (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitor and fibroblast growth factor inhibitor);

angiotensin receptor blockers, nitric oxide donors;

an antisense oligonucleotide;

antibodies such as trastuzumab and rituximab;

cell cycle inhibitors and differentiation inducers such as tretinoin;

inhibitors, topoisomerase inhibitors (doxorubicin, daunorubicin, actinomycin D, teniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan and irinotecan) and corticosteroids (cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone and prednisolone);

growth factor signal transduction kinase inhibitors;

a dysfunction-inducing agent;

toxins such as cholera toxin, ricin, pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin (Bordetella pertussis adenylate cyclase toxin), diphtheria toxin, and caspase activators;

and chromatin.

Other examples of chemotherapeutic agents include:

alkylating agents such as thiotepa and cyclophosphamide

Alkyl sulfonates such as busulfan, improsulfan, and piposulfan;

aziridines such as benzodopa, carboquone, meturedopa and uredopa;

ethyleneimine (ethylenimine) and methylaminoacridine (methyamelamine), including hexamethylmelamine, triimizine (triethyleneemimine), triethylenephosphoramide (triethylenephosphoramide), triethylenephosphoramide (triethylenethiophosphamide), and trimethymelamine;

annonaceous acetogenins, especially bullatacin (bullatacin) and bullatacin (bullatacinone);

camptothecin, including the synthetic analog topotecan (topotecan);

bryostatin;

callystatin；

CC-1065, including its adozelesin (adozelesin), carvelesin (carzelesin), and bizelesin (bizelesin) synthetic analogs;

cryptophycins, in particular cryptophycin 1 and cryptophycin 8;

dolastatin (dolastatin);

duocarmycin, including the synthetic analogs KW-2189 and CB1-TM 1;

eiscosahol (eleutherobin);

pancratistatin；

sarcodictyin；

spongistatin；

nitrogen mustards such as chlorambucil, chlorophosphamide (chlorophosphamide), cyclophosphamide, estramustine, ifosfamide, mechlorethamine (mechlorethamine), mechlorethamine hydrochloride (mechlorethamine oxydehydrochloride), melphalan, neomustard (novembichin), benzene mustard (phenesterine), prednimustine (prednimustine), trofosfamide (trofosfamide), uracil mustard (uracilmustard);

nitroureas such as carmustine, chlorozotocin (chlorozotocin), fotemustine, lomustine, nimustine and ranimustine;

antibiotics such as enediyne (endidiyne) antibiotics (e.g., calicheamicin, especially calicheamicin γ 1I, calicheamicin phiI 1); anthracyclines (kinemicin), including kinemicin a; bisphosphonates (bisphosphatates) such as clodronate (clodronate); esperamicin (esperamicin); and the neooncostatin chromophore (neocarzinostatin chromophore) and related chromoprotein enediyne antibiotics chromophore (endineentibic chromophore), aclacinomycin, actinomycin (actinomycin), aurramycin, azaserine (azaserine), bleomycin, actinomycin C (cactinomycin), carabicin, nordaunorubicin (carminomycin), carcinophilin (carzinophilin), chromomycin (chromomycin), actinomycin D (dactinomycin), daunorubicin (daunorubicin), desobicin (detritucin), 6-diazo-5-oxo-L-norleucine (6-diazo-5-oxo-L-norleucin), doxorubicin (including morpholino-doxorubicin, cyanomycin, 2-pyrroline and doxorubicin), doxorubicin (epirubicin), mitomycin (epirubicin, mitomycin, doxorubicin (epirubicin), doxorubicin (epirubicin, and doxorubicin (epirubicin), doxorubicin (epirubicin, mitomycin, doxorubicin, and doxorubicin (mitomycin, and doxorubicin (mitomycin, and doxorubicin, and, Mycophenolic acid (mycophenolic acid), noramycin (nogalamycin), olivomycin (olivomycin), pelomycin (peplomycin), pofiomycin (porfiromycin), puromycin (puromycin), triiron doxorubicin (quelamycin), rodobicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), tubercidin (tubercidin), ubenimex (ubenimex), neat stastatin (zinostatin), zorubicin;

antimetabolites such as methotrexate and 5-fluorouracil (5-FU);

folic acid analogs such as denopterin, methotrexate, pteropterin (pteropterin), trimetrexate (trimetrexate);

purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine (thiamiprine), thioguanine (thioguanine);

pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azaguanosine (6-azauridine), carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine (floxuridine);

androgens such as carposterone (calusterone), methyl androsterone propionate (dromostanolone propionate), epitioandrostanol (epitiostanol), mepiquane (mepiquitane), testolactone (testolactone);

anti-adrenaline (anti-adrenaline) such as aminoglutethimide, mitotane, trilostane;

folic acid replenisher (folic acid replenisher) such as folinic acid (frilic acid);

trichothecenes (trichothecene) (especially T-2 toxin, veracurin A, bacillocin A and anguidine);

taxanes, e.g. paclitaxelAnd docetaxel

Platinum analogs, such as cisplatin and carboplatin;

acetoglucurolactone (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); bestrabuucil(ii) a Bisantrene; idazot (edatraxate); desphosphamide (defofamine); colchicine (demecolcine); diazaquinone (diaziqutone); elfornitine; ammonium etiolate (ellitiniumacetate); epothilone (epothilone); etoglut (etoglucid); gallium nitrate (gallium nitrate); hydroxyurea (hydroxyurea); lentinan (lentinan); leucovorin; lonidamine (lonidainine); maytansinol (maytansinoids) such as maytansinoids (maytansine) and ansamitocins (ansamitocins); mitoguazone (mitoguzone); mitoxantrone (mitoxantrone); mopidanmol; rhizobia (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); fluoropyrimidines; folinic acid; podophyllinic acid (podophyllic acid); 2-ethyl hydrazine; procarbazine (procarbazine); polysaccharide K (PSK); razoxane (rizoxane); rhizomycin (rhizoxin); sizofuran (sizofiran); germanium spiroamines (spirogyranium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2,2' -trichlorotriethylamine; uratan; vindesine; dacarbazine (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (vancristine); vinorelbineNorfloxacin (novantrone); teniposide (teniposide); idazocide (edatrexate); daunorubicin; aminopterin; (xioloda); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid (retinoid); capecitabine (capecitabine); FOLFIRI (fluorouracil, leucovorin and erib)Tikang);

and a pharmaceutically acceptable salt, acid or derivative of any of the above.

Anti-hormonal agents

Also included in the definition of "chemotherapeutic agents" are anti-hormonal agents such as antiestrogens and Selective Estrogen Receptor Modulators (SERMs), enzyme aromatase inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing for modulating or inhibiting the hormonal effects on tumors.

Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX)^TM) Raloxifene, droloxifene, 4-hydroxyttamoxifen, troloxifene, raloxifene, LY117018, onapristone and toremifene

Enzyme aromatase inhibitors modulate the production of estrogen in the adrenal glands. Examples include 4(5) -imidazole, aminoglutethimide, megestrol acetateExemestane, formestane, fadrozole and vorozoleLetrozoleAnd anastrozole

Examples of antiandrogens include flutamide, nilutamide, bicalutamide, leuprorelin and goserelin.

Anti-angiogenic agents

Anti-angiogenic agents include, but are not limited to, retinoids and derivatives thereofThe compound, 2-methoxyestradiol,Suramin, squalamine, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage derived inhibitors, paclitaxel (protein bound paclitaxel), platelet factor 4, protamine sulfate (menhaden protamine), sulfated chitin derivatives (prepared from the shell of Macaca fascicularis), sulfated polysaccharide peptide polysaccharide complex (sp-387), staurosporine, modulators of matrix metabolism, including, for example, the proline analogue ((1-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d, I-3, 4-dehydroproline, thioheteroproline (thiaproline), α' -bipyridine, β -aminopropionitrile fumaric acid, 4-propyl-5- (4-pyridine) -2(3h) -oxazolone, methotrexate, mitoxantrone, heparin, interferons, 2-macroglobulin, inhibitors of gallinaceous protease-3 (Anan-3), chymotrypsin inhibitors of chymotrypsin, benzathine β -29-tetracycline, antimycosin, antimycotic acid, VEGF-2-growth inhibitors, monoclonal anti-carboxykinase inhibitors such as VEGF-2-carboxykinase inhibitors, VEGF-2-carboxypeptidase, VEGF-2-aminopeptidase inhibitors, preferably VEGF-2-carboxypeptidase-2, and other monoclonal antibodies, particularly monoclonal antibodies against the carboxypeptidase-2-CGF-5, VEGF-2, and other monoclonal antibodies.

Anti-fibrotic agents

Anti-fibrotic agents include, but are not limited to, compounds such as β -aminopropionitrile (BAPN), and the compounds disclosed below: US 4965288, which relates to lysyl oxidase inhibitors and their use in the treatment of diseases and disorders associated with abnormal deposition of collagen, and US 4997854, which relates to compounds that inhibit LOX to treat various pathological fibrotic states, are incorporated herein by reference. Other exemplary inhibitors are described in US 4943593 (which relates to compounds such as 2-isobutyl-3-fluoro-, chloro-or bromo-allylamine), US 5021456, US5059714, US 5120764, US 5182297, US 5252608 (which relates to 2- (1-naphthyloxymethyl) -3-fluoroallylamine, and US 2004-0248871, which are incorporated herein by reference.

Exemplary anti-fibrotic agents also include primary amines that react with the carbonyl group of the active site of lysyl oxidase, and more particularly those that upon binding to the carbonyl group yield a resonance-stabilized product, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazides, and urea derivatives, aminonitriles, such as BAPN, or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamine, and seleno-homocysteine lactone.

Other anti-fibrotic agents are copper chelators, either penetrating or impermeable to cells. Exemplary compounds include indirect inhibitors, such as compounds that block aldehyde derivatives (derived from the oxidative deamination of lysyl and hydroxyllysyl residues by lysyl oxidase). Examples include thiolamines, in particular D-penicillamine, and analogues thereof such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3- ((2-acetamidoethyl) dithio) butyric acid, p-2-amino-3-methyl-3- ((2-aminoethyl) dithio) butyric acid, 4- ((p-1-dimethyl-2-amino-2-carboxyethyl) dithio) butanesodium sulfide (sodium-4- ((p-1-dimethyl-2-amino-2-carboxyethyl) dithio) butane sulfate, 2-acetamido-2-acetamidoethane mercaptan sulfonate (sulfosalt), sodium 4-mercaptobutanesulfinate trihydrate.

Immunotherapeutic agent

Immunotherapeutics include, without limitation, therapeutic antibodies suitable for treating patients. Some examples of therapeutic antibodies include immituzumab, abamectin (abagomab), adalimumab (adelimumab), atropizumab (afutuzumab), alemtuzumab (alemtuzumab), alelimumab (amatuximab), anatumumab, alemtuzumab (arcitumomab), baviximab (bavituximab), betuzumab (bectuzumab), betuzumab (bevacizumab), bivatuzumab, civil brevumguzumab (blinatumomab), berentuzumab (brentuximab), cantuzumab (brentuzumab), castuzumab (castuzumab), castitumomab (cattuzumab), cetuximab (cetuximab), cetuximab (cituzumab), bevacizumab (brazizumab), bevacizumab), castitumomab (castitumomab), cetuximab (netuzumab), bevacizumab (castitumomab), castitumomab (castitumomab), castitumomab (cetuximab (geitumomab), castitumomab (deguzumab), castitumomab (cetitumomab), castitumomab (castitumomab), castitumomab (cetitumomab (castitumomab), castitumomab (castitumomab, Rituzumab (elotuzumab), enzitumumab (ensituximab), estemeimab (ertumaxomab), edazumab (etaracizumab), farezumab (farletuzumab), felitumumab (fitlatuzumab), non-gemumab (figitumumab), flantezumab (flantuzumab), pumicitumab (futuximab), ganitumumab (ganitumab), gemtuzumab (gemtuzumab), gleba (glemobamumumab), ibritumomab (ibritumomab), govituzumab (igoolimumab), imazezumab (indtuzumab), ibritumomab (ibritumomab), golimumab (igomozumab), imazezumab (igovamtuzumab), imazezumab (ibritumomab), rituzumab), gemtuzumab (ibritumomab), rituzumab (irtuzumab), rituximab (indatuzumab), rituzumab (intuzumab), yamtuzumab (rituzumab), yamtuzumab), yamazumab (rituzumab), yamazumab (indtuzumab (ritukumae (ritukumakumakumakumakumakumakumakumakumakumakumakumaku, Milatuzumab (matuzumab), gmuimomab (minretumumab), mituzumab (mitumomab), moxidermumab (moxetumumab), nauteruzumab (narnatuzumab), namomuzumab (nauteruzumab), nimotuzumab (necitumumab), nimotuzumab (nimotuzumab), norvastuzumab (nofetumabn), ocaprasuzumab (ocaratuzumab), ofatumumab (ofatumumab), olaratuzumab (olab), olaratuzumab (onartuzumab), ostruthitumumab (oportuzumab), agovacizumab (opoutuzumab), ostritumumab (orezumab), pangolimab (oregozumab), panitumumab (orezumab), panitumumab (rituximab), rituximab (rituximab), rituximab (or (rituximab), and so-for example, Situximab (siltuximab), solituzumab (solitomab), tacatuzumab (tacatuzumab), tacrolimus (tapritumomab), tylumumab (tallitumomab), tenatemumab (tenatemomab), tipolizumab (tigtuzumab), tositumomab (tositumomab), trastuzumab (trastuzumab), tuzumab (tuzumab), ulibituzumab (ubtuzumab), vituzumab (veltuzumab), voretuzumab (vortuzumab), zalumumab (zetuzumab), CC49, and 3F 8. Rituximab is useful in the treatment of indolent B-cell cancers, including marginal zone lymphoma, WM, CLL and small lymphocytic lymphomas. Combinations of rituximab and chemotherapeutic agents are particularly effective.

Exemplary therapeutic antibodies may be further labeled or combined with radioisotope particles such as indium-111, yttrium-90, or iodine-131.

In a certain embodiment, the other therapeutic agent is a nitrogen mustard alkylating agent. Non-limiting examples of nitrogen mustard alkylating agents include chlorambucil.

Lymphoma or leukemia combination therapy

These agents include aldesleukin, alvocidib, antineodone AS2-1, antineodone A10, antithymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, β alethine, Bcl-2 family protein inhibitor ABT-263, ABT-199, ABT-737, BMS-345541, bortezomibBryostatin 1, busulfan, carboplatin, campath-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, cladribine, chlorambucil, curcumin, cyclosporin,Cyclophosphamide, cytarabine, dinil, dexamethasone, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide), docetaxel, dolastatin 10, doxorubicin hydrochloride, enzastaurin, alfacitinib, etoposide, everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, fraparin, fludarabine, geldanamycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide: (A) (D/D), and pharmaceutically acceptable salts thereofCC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motesafen gadolinium, mycophenolate mofetil, nelarabine, orlistat, obatoclax (GX15-070), orlistat, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated liposomal doxorubicin HCl, pefilgrastim, pentostatin, perifosine, prednisolone, prednisone, R-roscovitine (seliciclib, CYC202), recombinant interferon α, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, sargrastim, sildenafil citrate, simvastatin, sirolimus, styryl sulfone, tacrolimus, temsirolimus (CCl-779), sarduldomide, therapeutic lymphoblastic, bortezomib, allogeneic piroxicam, picrolimus, and picrolimusPS-341), vincristine sulfate, vinorelbine ditartrate, SAHA suberanilohydroxamic acid, or suberoylanilide and hydroxamic acid), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatinAnd etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP).

An improved method is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as indium-111, yttrium-90 and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomabYttrium-90 ibritumomab tiuxetanAndand HOP.

The above treatments may be supplemented or combined with stem cell transplantation or therapy. Methods of treatment include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, systemic irradiation, stem cell infusion, stem cell-supported bone marrow eradication, ex vivo-treated peripheral blood stem cell transplantation, cord blood transplantation, immunoenzymatic techniques, low LET cobalt-60 gamma ray therapy, bleomycin, routine surgery, radiation therapy, and allogeneic hematopoietic stem cell transplantation without bone marrow eradication.

Non-hodgkin lymphoma combination therapy

Treatment of non-hodgkin's lymphoma (NHL), especially B cell-derived tumors, includes the use of monoclonal antibodies, standard chemotherapeutic methods (e.g., CHOP, CVP, FCM, MCP, etc.), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies for use in treating NHL/B-cell cancers include rituximab, alemtuzumab, human or humanized anti-CD 20 antibodies, rozezumab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD 74.

Examples of experimental antibody reagents for treating NHL/B-cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, luuximab, aprezumab, milnacizumab, and bevacizumab.

Examples of standard chemotherapeutic regimens for NHL/B-cell cancers include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90 ibritumomab tiuxetanAnd iodine-131 tositumomab

Combined treatment of mantle cell lymphoma

The treatment regimen for Mantle Cell Lymphoma (MCL) includes combination chemotherapy such as CHOP, hyperCVAD and FCM. These protocols may also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R and R-FCM. Any of the above treatments can be combined with stem cell transplantation or ICE to treat MCL.

Another method of treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies, such as rituximab. Another uses cancer vaccines based on the genetic makeup of individual patient tumors, such as GTOP-99.

An improved method of treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-133 tositumomabAnd yttrium-90 ibritumomab tiuxetanIn another example of the above-described method,used in a continuous process with CHOP.

Other methods of treating MCL include autologous stem cell transplantation in combination with high dose chemotherapy, administration of proteasome inhibitors such as bortezomib (r) ((r))Or PS-341), or administering an anti-angiogenic agent such as thalidomide, particularly in combination with rituximab.

Another therapeutic approach is the administration of drugs that cause degradation of the Bcl-2 protein and increase the sensitivity of cancer cells to chemotherapy, such as Orimerson in combination with other chemotherapeutic agents.

Further methods of treatment include administration of mTOR inhibitors, which can result in inhibition of cell growth and even cell death. A non-limiting example is temsirolimus (CCI-779) and temsirolimus withOr combinations of other chemotherapeutic agents.

Recent other therapies for MCL have been disclosed. Examples include fusiformity, PD0332991, R-roscovitine (seliciclib, CYC202), styryl sulfone, obaticla (GX15-070), TRAIL, anti-TRAIL death receptors DR4 and DR5 antibodies, temsirolimus (Tacrolimus: (A) (B))CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (R) ((R)CC-5013) and geldanamycin (17-AAG).

Combination therapy for Waldenstrom macroglobulinemia

Therapeutic agents for Waldenstrom Macroglobulinemia (WM) include perifosine, bortezomibRituximab, sildenafil citrateCC-5103, thalidomide, epratuzumab (hLL 2-anti-CD 22 humanized antibody), simvastatin, enzastaurin, campath-1H, dexamethasone, DT-PACE, orlistatin, anti-oncone A10, anti-oncone AS2-1, alemtuzumab, β alethine, cyclophosphamide, doxorubicin hydrochloride, prednisone, vincristine sulfate, fludarabine, filgrastim, melphalan, recombinant interferon α, carmustine, cisplatin, cyclophosphamide, cytarabine, etoposide, melphalan, dola 10, indium-111 monoclonal antibody MN-14, yttrium-90 humanized epuzumab, anti-thymocyte globulin, busulfan, cyclosporine, methotrexate, mycophenolate mofetil, therapeutic allolymphocyte, yttrium-90 ibrinomakins, sirolimus, tacrolimus, platinum, tacrine, paclitaxel, interleukin-2-L-arginine, paclitaxel-arginine, paclitaxel-arginine- α, paclitaxel-arginine- α -arginine-acetate, paclitaxel-arginine-acetate, paclitaxel-arginine- α -arginine-acetate, cysteine-arginine- α -arginine- α, cysteine-arginine- α -arginine-2, cysteine-arginine-lysine- α -lysine, cysteine-arginine-lysine, cysteine-lysine-arginine-lysine, cysteine-arginine-lysine-arginine-lysine, cysteine-lysine-arginine-lysine-arginine-lysineTolanthraquinone, octreotide acetate, tositumomab, iodine-131 tositumomab, motexafine gadolinium, arsenic trioxide, tipifarnib, autologous human tumor-derived HSPPC-96, vetuzumab, bryostatin 1, pegylated liposomal doxorubicin hydrochloride, and any combination thereof.

Examples of therapeutic methods for treating WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, systemic irradiation, stem cell infusion, stem cell-supported bone marrow eradication, ex vivo-treated peripheral blood stem cell transplantation, cord blood transplantation, immunoenzymatic techniques, low LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and allogeneic hematopoietic stem cell transplantation other than bone marrow eradication.

Diffuse large B-cell lymphoma combination therapy

Therapeutic agents useful for the treatment of diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, an anti-CD 20 monoclonal antibody, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and R-ICE.

Chronic lymphocytic leukemia combination therapy

Examples of therapeutic agents for the treatment of Chronic Lymphocytic Leukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM, as well as combination chemotherapy and chemoimmunotherapy, including the following general combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

Myelofibrosis combination therapy

Inhibitors of myelofibrosis include, but are not limited to, hedgehog inhibitors, Histone Deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. A non-limiting example of a hedgehog inhibitor is saridegib.

Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.

A non-limiting example of a tyrosine kinase inhibitor is lestaurtinib.

Kinase inhibitors

In one embodiment, the compounds described herein may be used or combined with one or more other therapeutic agents. The one or more therapeutic agents include, but are not limited to, Abl inhibitors, Activated CDC Kinase (ACK), adenosine A2B receptor (A2B), apoptosis signal-regulating kinase (ASK), Auroa kinase, Bruton's Tyrosine Kinase (BTK), BET-Bromodomains (BRD) such as BRD4, c-Kit, c-Met, CDK-activated kinase (CAK), calmodulin-dependent protein kinase (CaMK), cyclin-dependent kinase (CDK), Casein Kinase (CK), Discoid Domain Receptor (DDR), Epidermal Growth Factor Receptor (EGFR), Focal Adhesion Kinase (FAK), Flt-3, FYN, Glycogen Synthase Kinase (GSK), HCK, Histone Deacetylase (HDAC), IKK such as IKK β, Isocitrate Dehydrogenase (IDH) such as IDH1, JAK kinase (JAK), kdnus, lymphocyte-specific protein tyrosine kinase (LCK), and the like, Lysyl oxidase protein, lysyl oxidase-like protein (LOXL), LYN, Matrix Metalloproteinase (MMP), MEK, mitogen-activated protein kinase (MAPK), NEK9, NPM-ALK, p38 kinase, Platelet Derived Growth Factor (PDGF), Phosphorylase Kinase (PK), POLO-like kinase (PLK), phosphatidylinositol 3-kinase (PI3K), Protein Kinases (PK) such as protein kinase A, B and/or C, PYK, spleen tyrosine kinase (SYK), serine/threonine kinase TPL2, serine/threonine kinase STK, signal transduction and transcription (STAT), SRC, serine/threonine-protein kinase (TBK) such as TBK1, TIE, Tyrosine Kinase (TK), Vascular Endothelial Growth Factor Receptor (VEGFR), YES, or any combination thereof.

Apoptosis signal-regulating kinase (ASK) inhibitors

ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011/008709(Gilead Sciences) and WO 2013/112741(Gilead Sciences).

Bruton's Tyrosine Kinase (BTK) inhibitors

Examples of BTK inhibitors include, but are not limited to, ibrutinib (ibrutinib), HM71224, GS-4059(ONO-4059), and CC-292.

Discotic Domain Receptor (DDR) inhibitors

DDR inhibitors include inhibitors of DDR1 and/or DDR 2. Examples of DDR inhibitors include, but are not limited to, those described in WO2014/047624(Gilead Sciences), US 2009-0142345(Takeda Pharmaceuticals), US 2011-0287011(Oncomed Pharmaceuticals), WO 2013/027802(Chugai Pharmaceuticals) and WO2013/034933(Imperial Innovations).

Histone Deacetylase (HDAC) inhibitors

Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.

Janus kinase (JAK) inhibitors

JAK inhibitors inhibit JAK1, JAK2, and/or JAK 3. Examples of JAK inhibitors include, but are not limited to, compound a, luzotinib, fedratinib, tofacitinib, barretinib (baricitinib), lestaurtinib, pacritinib, XL019, AZD1480, INCB039110, LY2784544, BMS911543, and NS 018.

Inhibitors of lysyl oxidase-like protein (LOXL)

LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL 5. Examples of LOXL inhibitors include, but are not limited to, antibodies described in WO 2009/017833(Arresto Biosciences).

Examples of LOXL2 inhibitors include, but are not limited to, antibodies described in WO 2009/017833(Arresto Biosciences), WO2009/035791(Arresto Biosciences), and WO 2011/097513(Gilead Biologics).

Matrix Metalloproteinase (MMP) inhibitors

MMP inhibitors include inhibitors of MMPs 1 through 10. Examples of MMP9 inhibitors include, but are not limited to, those described in marimastat (BB-2516), cimastat (Ro 32-3555), and WO 2012/027721(Gilead Biologics).

Phosphatidylinositol 3-kinase (PI3K) inhibitors

PI3K inhibitors include inhibitors of PI3K γ, PI3K, PI3K β, PI3K α, and/or pan-PI 3K. Examples of PI3K inhibitors include, but are not limited to, wortmannin, BKM120, CH5132799, XL756, and GDC-0980.

Examples of PI3K γ inhibitors include, but are not limited to, ZSTK474, AS252424, LY294002, and TG 100115.

Examples of PI3K inhibitors include, but are not limited to, compounds B, C, D, E, PI3KII, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443 and the compounds described in WO 2005/113556(ICOS), WO 2013/052699(Gilead Calistoga), WO 2013/116562(Gilead Calistoga), WO 2014/100765(Gilead Calistoga), WO 2014/100767(Gilead Calistoga) and WO 2014/201409(Gilead Sciences).

Examples of PI3K β inhibitors include, but are not limited to, GSK2636771, BAY 10824391, and TGX 221.

Examples of PI3K α inhibitors include, but are not limited to, buparlisib, BAY 80-6946, BYL719, PX-866, RG7604, MLN1117, WX-037, AEZA-129, and PA 799.

Examples of pan-PI3K inhibitors include, but are not limited to, LY294002, BEZ235, XL147(SAR 2454408), and GDC-0941.

Spleen tyrosine kinase (SYK) inhibitors

Examples of SYK inhibitors include, but are not limited to, those described in tamatinib (R406), fostamatinib (R788), PRT062607, BAY-61-3606, NVP-QAB 205AA, R112, R343, and US 8450321(Gilead Connecticut).

Tyrosine-kinase inhibitors (TKIs)

TKIs can target receptors for Epidermal Growth Factor Receptors (EGFRs) and Fibroblast Growth Factors (FGFs), platelet-derived growth factors (PDGFs) and Vascular Endothelial Growth Factors (VEGF). Examples of TKIs targeting EGFR include, but are not limited to, gefitinib and erlotinib. Sunitinib is a non-limiting example of a TKI that targets receptors for FGF, PDGF, and VEGF.

Examples

The following examples are provided to further aid in the understanding of the embodiments disclosed herein and are provided in light of the understanding of conventional methods well known to those of ordinary skill in the art to which the examples pertain. The specific materials and conditions described below are intended to be illustrative of particular aspects of the embodiments disclosed herein and should not be construed as limiting the reasonable scope thereof.

Example 1: human CLL apoptosis assay

Peripheral Blood Mononuclear Cells (PBMC) were isolated from primary Chronic Lymphocytic Leukemia (CLL) patients and cultured in lymphocyte growth medium (LGM, RPMI 1640,1mM sodium pyruvate, 10mM HEPES, pH 7.4,100U/mL penicillin/100. mu.g/mL streptomycin, 55. mu.M β mercaptoethanol, 2mM GlutaMAX and 10% FBS) with 5% CO at 37 ℃₂Culturing for 3-5 hr. The cells were then centrifuged at room temperature for 10 minutes and resuspended in an appropriate volume of LGM for plating (maximum cell density 3.12X 10 ═⁶3 × 10 in 100. mu.l plates with HS-5 co-culture (before assay, at 37 ℃ C.)⁴HS-5 cells were plated overnight) or final assay wells were set in U-bottom 96-well tissue culture plates without co-culture.

Cell suspension (80. mu.L, 2.5 × 10)⁵–9.4×10⁴) Add to plate and incubate for 1 hour, then stimulate with α IgM/α IgG (7.8. mu.g/well) and α CD40 (4. mu.g/well). Cells were incubated with compound at 37 ℃ for about 66 hours. After incubation, cells were transferred to deeper plates and 500. mu.L of 1 XPBS^+/+And washing once. Cells were resuspended in aqua Live/Dead reagent from Invitrogen according to the manufacturer's instructions and incubated on ice for 30 minutes. With an equal volume of PBS containing 4% FBS (FACS buffer)^+/+Quenching Aqua Live/dead the cells were centrifuged and labeled with α CD5-PE, &lttt transfer = α "&gtt α &ltt/t &gtt CD19-BV421 and annexin V-APC in a total volume of 85 μ L and incubated on ice for 30 minutes after labeling, the cells were rinsed twice in FACS buffer and then fixed on ice for 30 minutes with BD fixation buffer.

For apoptosis analysis, a total of 5000-. Identification of CD5⁺/CD19⁺Cells, followed by annexin V⁺/LiveDead and annexin V⁺/LiveDead⁺The population was gated.

The flow cytometry data is extracted into a flow cytometry standard (fcs) file. Determination of annexin V for Positive controls and negative wells (no compound)⁺Average percentage of cells. Annexin V⁺The percentage of cells represents the percentage or level of apoptosis. The results for CLL cells without HS-5 co-culture are summarized in table 1. Similar results were obtained for CLL cells with HS-5 co-culture.

TABLE 1 annexin V from CLL patients treated with Compound A1 and Compound B1⁺Percentage of cells

Sample (I)	1	1	1	1	2	2	2	2	3	3	3	3
													Compound A1(nM)	0	300	100	30	0	300	100	30	0	300	100	30
200nM Compound B1	46	76	58	52	97	98	98	98	100	100	100	100
													100nM Compound B1	36	54	30	36	95	98	97	97	99	100	100	100
50nM Compound B1	31	42	31	30	93	97	96	96	97	99	99	98
													25nM Compound B1	24	34	24	22	89	94	92	91	89	96	94	90
12.5nM Compound B1	19	28	20	17	76	89	85	85	69	80	74	68
													6.3nM Compound B1	16	23	16	16	55	79	72	66	50	63	57	48
3.1nM Compound B1	15	19	14	14	35	66	56	43	33	46	39	32
													1.6nM Compound B1	15	18	14	12	18	51	37	27	21	32	28	20
0.8nM Compound B1	13	16	13	13	10	38	21	15	16	26	20	16
													0nM Compound B1	NA	16	12	12	NA	20	12	9	NA	18	15	13
Of stimulation	13	13	13	13	6	6	6	6	12	12	12	12
													Non-irritating	67	67	67	67	25	25	25	25	13	13	13	13

Claims (21)

1. A method of treating cancer in a human in need thereof comprising administering to the human a therapeutically effective amount of a Syk inhibitor and a therapeutically effective amount of a Bcl-2 inhibitor, wherein:

the Syk inhibitor is a compound of formula a 1:

or a pharmaceutically acceptable salt or hydrate thereof; and is

The Bcl-2 inhibitor is selected from the group consisting of a compound of formula B1, a compound of formula B2, and a compound of formula B3:

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the pharmaceutically acceptable salt of the Syk inhibitor is a mesylate salt, or a hydrate of the mesylate salt.

3. The method of claim 2, wherein the mesylate salt is a mono-mesylate salt or a bis-mesylate salt, or a combination thereof.

4. The method of any one of claims 1 to 3, wherein the Bcl-2 inhibitor is a compound of formula B1:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the compound of formula B1 is in a form selected from the group consisting of: free base anhydrate, free base dichloromethane solvate, free base ethyl acetate solvate, free base acetonitrile solvate, free base acetone solvate, hydrochloride salt hydrate, free base sulfate salt, and free base tetrahydrofuran.

6. The method of any one of claims 1 to 3, wherein the Bcl-2 inhibitor is a compound of formula B2:

or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 3, wherein the Bcl-2 inhibitor is a compound of formula B3:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the Bcl-2 inhibitor is the di-HCl salt of the compound of formula B3.

9. The method of any one of claims 1-8, wherein the Syk inhibitor is administered intravenously, intramuscularly, parenterally, nasally, or orally.

10. The method of any one of claims 1 to 9, wherein the Bcl-2 inhibitor is administered intravenously, intramuscularly, parenterally, nasally, or orally.

11. The method of any one of claims 1 to 10, wherein the Syk inhibitor is administered before, after, or simultaneously with the Bcl-2 inhibitor.

12. The method of any one of claims 1 to 11, wherein the cancer is a hematologic malignancy.

13. The method of any one of claims 1 to 12, wherein the cancer is leukemia, lymphoma or multiple myeloma.

14. The method of any one of claims 1 to 11, wherein the cancer is small lymphocytic lymphoma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, refractory iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, splenic marginal zone B-cell lymphoma (+/-villous lymphocytes), nodular marginal zone lymphoma (+/-monocytic B-cells), mucosa-associated lymphoid tissue type extralymph node marginal zone B-cell lymphoma, cutaneous T-cell lymphoma, extralymph node T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, mycosis fungoides, b-cell lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, small non-dividing cell lymphoma, Burkitt's lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia, T-cell acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, juvenile myelomonocytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorders, or Waldestrom macroglobulinemia.

15. The method of any one of claims 1 to 14, wherein the cancer is chronic lymphocytic leukemia.

16. The method of any one of claims 1 to 14, wherein the cancer is acute lymphocytic leukemia.

17. The method of any one of claims 1 to 14, wherein the cancer is non-hodgkin's lymphoma.

18. The method of any one of claims 1-17, wherein the human is (i) refractory to at least one anti-cancer therapy, or (ii) relapsed after treatment with at least one anti-cancer therapy, or both refractory to at least one anti-cancer therapy and relapsed after treatment with at least one anti-cancer therapy.

19. An article of manufacture, comprising:

(i) a unit dosage form comprising a therapeutically effective amount of a Syk inhibitor, wherein the Syk inhibitor is a compound of formula a 1:

or a pharmaceutically acceptable salt thereof; and

(ii) a unit dosage form comprising a therapeutically effective amount of a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is selected from the group consisting of a compound of formula B1, a compound of formula B2, and a compound of formula B3:

or a pharmaceutically acceptable salt thereof, and

(iii) a label comprising instructions for treating cancer using a unit dosage form comprising a Syk inhibitor and a Bcl-2 inhibitor.

20. A kit, comprising:

(i) a pharmaceutical composition comprising a therapeutically effective amount of a Syk inhibitor, wherein the Syk inhibitor is a compound of formula a 1:

or a pharmaceutically acceptable salt or hydrate thereof;

(ii) a pharmaceutical composition comprising a therapeutically effective amount of a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is selected from the group consisting of a compound of formula B1, a compound of formula B2, and a compound of formula B3:

or a pharmaceutically acceptable salt thereof.

21. The kit of claim 12, further comprising a package insert comprising instructions for using the pharmaceutical composition to treat cancer.