Combination therapy comprising an ALK2 inhibitor and a JAK2 inhibitor

Abstract

Provided herein are compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat diseases or disorders associated with JAK2 and / or ALK2.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 939,241, filed November 22, 2019; U.S. Provisional Application No. 62 / 980,562, filed February 24, 2020; U.S. Provisional Application No. 63 / 035,194, filed June 5, 2020; and U.S. Provisional Application No. 63 / 056,768, filed July 27, 2020, the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Myeloproliferative neoplasms (MPNs) are a group of disorders that cause overproduction of blood cells (platelets, white blood cells, and red blood cells) in the bone marrow. MPNs include polycythemia vera (PV), essential or primary thrombocythemia (ET), primary or idiopathic myelofibrosis, chronic myeloid (myelocytic) leukemia (CML), chronic neutrophilic leukemia (CNL), juvenile myelomonocytic leukemia (JML), and chronic eosinophilic leukemia (CEL) / hypereosinophilic syndrome (HES). These disorders are grouped together because they share some or all of the following characteristics: involvement of pluripotent hematopoietic progenitor cells, dominance of a transformed clone over non-transformed hematopoietic progenitor cells, overproduction of one or more hematopoietic lineages in the absence of limited stimuli, colony formation independent of growth factors in vitro, myeloid hyperplasia, megakaryocytic hyperplasia and dysplasia, abnormalities mainly involving chromosomes 1, 8, 9, 13, and 20, thrombotic and hemorrhagic predispositions, extramedullary hematopoiesis of excessive proliferation, and a low rate compared to that in CML, but natural transformation to acute leukemia or development of myelofibrosis. The incidence of MPNs varies widely, from approximately 3 per 100,000 individuals over 60 years of age per year for CML to 0.13 per 100,000 children aged birth to 14 years per year for JML (Vardiman JW et al., Blood 100(7):2292-302, 2002).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

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Non-licensed literature

[0004] [Non-licensed document 1] Vardiman JW, Blood 100 (7): 2292~302 pages, 2002 [Non-licensed document 2] Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 [Non-licensed document 3] Journal of Pharmaceutical Science, 66, 2 (1977)

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Summary of the Invention

Problems to be Solved by the Invention

[0005] New treatments for MPN, as well as other cancers and related symptoms, are still needed.

Means for Solving the Problems

[0006] A combination therapy comprising an ALK2 inhibitor and a JAK2 inhibitor is provided herein. The combination therapy is useful for treating various cancers including MPN, and related symptoms such as anemia. The combination therapy is also useful for treating any number of JAK2-related and / or ALK2-related diseases.

[0007] In one aspect, a pharmaceutical combination comprising a JAK2 inhibitor or a pharmaceutically acceptable salt thereof, and an ALK2 inhibitor or a pharmaceutically acceptable salt thereof is provided herein.

[0008] In another aspect, (i) A JAK2 inhibitor having Formula I:

Chemical

Chemical

[0009] In yet another aspect, there is provided herein a pharmaceutical composition comprising an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, a JAK2 inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] In yet another aspect, an ALK2 inhibitor, a pharmaceutically acceptable carrier, and a JAK2 inhibitor having the formula I:

Chem.

[0011] In certain embodiments of the pharmaceutical composition, the ALK2 inhibitor is a compound of formula II:

Chem.

[0012] In yet another aspect, there is provided herein a method of treating cancer in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0013] In yet another aspect, a method of treating cancer in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor having the formula I:

Chem.

[0014] In certain embodiments of the method, the ALK2 inhibitor is a compound of formula II:

Chem.

[0015] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising the step of administering to the subject an ALK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments of the method of treating cancer, the ALK2 inhibitor is a compound of Formula II:

Chemical formula

[0017] In another embodiment of the method of treating cancer, the ALK2 inhibitor is administered as monotherapy. In yet another embodiment, the ALK2 inhibitor is administered in the absence of any other active pharmaceutical ingredient. In yet another embodiment, the ALK2 inhibitor is administered in the absence of a JAK2 inhibitor.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0019] Administering a combination of an ALK2 inhibitor and a JAK2 kinase inhibitor provides a surprisingly synergistic effect in the treatment of cancer, such as myeloproliferative neoplasms (MPNs), in a subject. Such approaches, i.e., the combination or co-administration of two agents, may be useful for treating individuals afflicted with cancer that are unresponsive or resistant to currently available therapies, for example.

[0020] As described herein, cancer can be treated by effectively using low doses of an ALK2 inhibitor and a JAK2 inhibitor, and thus, at least one basis is provided that there is a synergistic effect of the administration of a combination of drugs that can enable a lower dosage of each drug (relative to the currently approved recommended dosage used by clinicians) to result in an effective treatment. This provides potentially dramatic tolerability and efficacy advantages over other anti-cancer agents.

[0021] Also described herein is a method of treating cancer by using an ALK2 inhibitor as a monotherapy, for example, in the absence of a JAK2 inhibitor.

[0022] Certain terms used herein are described below. The compounds of the present disclosure are described using standard nomenclature. 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 invention belongs.

[0023] Definitions Definitions of various terms used herein are described below. Unless specifically limited individually or as part of a larger group in a particular instance, these definitions apply to the terms when used throughout this specification and the claims.

[0024] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the experimental procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly employed in the art.

[0025] As used herein, the articles "a" and "an" refer to one or more than one (i.e., at least one) of the grammatical objects of the article. By way of example, "an element" means one element or more than one element. Further, the use of the term "including" and other forms such as "include", "includes", and "included" is not limiting.

[0026] As used herein, "pharmaceutical combination" or "combination" refers to a formulation or combination product of separate compounds, with or without instructions for combined use. Thus, combination compounds may also be sold independently of each other, and it is only the instructions for their combined use that are provided in the packaging materials, such as leaflets, etc., or in other information for simultaneous or sequential use for co-activation, provided, for example, to physicians and medical staff (e.g., communication in oral communication, notes, etc.), and may be in completely separate pharmaceutical dosage forms or in a pharmaceutical composition.

[0027] As used herein, the term "monotherapy" means that the treatment treats a disease or condition using a single active pharmaceutical ingredient. Monotherapy may further include treatment with a pharmaceutically acceptable carrier or excipient. In certain embodiments of the methods provided herein, the single active pharmaceutical ingredient is a compound of formula II. In another embodiment, the compound of formula II is administered as monotherapy, rather than in combination with a Janus kinase inhibitor.

[0028] As used herein, the term "treating" or "treatment" refers to: (1) preventing a disease; e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but has not yet experienced the symptoms or overall manifestations of the disease; (2) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or showing the symptoms or overall manifestations of the disease, condition, or disorder (i.e., arresting further development of the symptoms and / or overall manifestations); and (3) alleviating a disease; e.g., alleviating a disease, condition, or disorder in an individual who is experiencing or showing the symptoms or overall manifestations of the disease, condition, or disorder (i.e., improving the symptoms and / or overall manifestations), e.g., reducing the severity of the disease, and refers to one or more of the foregoing. In some embodiments, the term "treating" or "treatment" refers to inhibiting or alleviating a disease.

[0029] As used herein, the term "prevent" or "prevention" means the absence of the onset of a disorder or disease when nothing has occurred, or the absence of the onset of a further disorder or disease when the onset of a disorder or disease has already occurred. The ability to prevent some or all of the symptoms associated with a disorder or disease is also contemplated.

[0030] As used herein, the term "patient", "individual", or "subject" refers to a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is human.

[0031] As used herein, the terms "effective amount", "pharmaceutically effective amount", and "therapeutically effective amount" refer to an amount of an agent that is non-toxic but sufficient to produce the desired biological result. The result can be a decrease or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. The appropriate therapeutically effective amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0032] As used herein, the term "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not inactivate the biological activity or properties of a compound and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of the composition in which it is contained.

[0033] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts described herein include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts contemplated herein can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two, and generally a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is used. The phrase "pharmaceutically acceptable salt" is not limited to mono- or 1:1 salts. For example, "pharmaceutically acceptable salt" also includes bis-salts such as bis-hydrochloride salts. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0034] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the composition to a patient or subject. There are numerous techniques for administering compounds in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0035] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier involved in carrying or transporting a useful compound for a patient so that it can perform its intended function, e.g., a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material. Typically, such constructs are transported or carried from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds disclosed herein, and not harmful to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0036] As used herein, "pharmaceutically acceptable carrier" includes any coating agent, antibacterial and antifungal agents, absorption delaying agents, etc. that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to the patient. Auxiliary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" can further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that can be included in the pharmaceutical composition are known in the art and are incorporated herein by reference, for example, as described in Remington's Pharmaceutical Sciences (Genaro, ed., Mack Publishing Co., 1985, Easton, PA).

[0037] As used herein, the terms "ALK2" or "ALK-2" refer to activin A receptor type I (ACVRI), also known as ACVRLK2, SKR1, ACVR1A, activin receptor type I, activin receptor-like kinase 2, serine / threonine-protein kinase receptor R1, TGF-β superfamily receptor type I, ACTRI, TSRI, activin A receptor type II-like kinase 2, activin receptor type 1, hydroxyalkyl-protein kinase, ACTR-I, TSR-I. Thus, "ALK2 inhibitor" as used herein refers to a compound that modulates the activity of ALK2.

[0038] As used herein, the term "JAK2" refers to Janus kinase-2, a member of the Janus family (JAK1, JAK2, JAK3, TYK2) of intracellular non-receptor tyrosine kinases that convert cytokine-mediated signals via the JAK-STAT pathway. Thus, "JAK2 inhibitor" as used herein refers to a compound that modulates the activity of JAK2. JAK2 inhibitors include compounds that specifically modulate JAK2 and compounds that modulate JAK2 and one or more other Janus kinases, for example, JAK1 / 2 inhibitor compounds.

[0039] As used herein, the term "single formulation" refers to a single carrier or vehicle formulated to deliver both therapeutically effective agents to a patient. The single vehicle is designed to deliver each agent in an effective amount, along with any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0040] The term "unit dose" means administering both agents together, in one dosage form, to the patient being treated at the same time. In some embodiments, the unit dose is a single formulation. In certain embodiments, the unit dose comprises one or more vehicles such that each vehicle contains at least one agent in an effective amount, along with a pharmaceutically acceptable carrier and excipient. In some embodiments, the unit dose is one or more tablets, capsules, pills, or patches administered to the patient at the same time.

[0041] The term "combination therapy" refers to the administration of two or more therapeutic compounds for treating a therapeutic condition or disorder described in the present disclosure. Such administration includes co-administration of these therapeutic compounds in a substantially simultaneous manner, for example, in a single capsule having a fixed ratio of active ingredients, or in multiple or separate containers (e.g., capsules) for each active ingredient. Additionally, such administration also includes using each type of therapeutic compound in a sequential manner, approximately simultaneously or at different times. In either case, the treatment regimen provides the beneficial effects of the drug combination in treating the condition or disorder described herein.

[0042] The combination of agents described herein can exhibit a synergistic effect. The term "synergistic effect" as used herein refers to an effect greater than the simple addition of the effects of each drug administered alone, for example, resulting in delaying the symptomatic progression of cancer or its symptoms, for example, the actions of two agents such as an ALK2 inhibitor (e.g., an ALK2 inhibitor of Formula II) and a JAK2 inhibitor (e.g., a JAK2 inhibitor of Formula I). The synergistic effect can be calculated using appropriate methods such as, for example, the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additivity equation (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)), and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Applying the above-mentioned equations to experimental data, creating the corresponding graphs, and using them to assist in determining the effect of the drug combination. The corresponding graphs related to the above-mentioned equations are concentration-effect curves, isobologram curves, and combination index curves, respectively.

[0043] As used herein, the term "synergistic effect" refers to the effect achieved when the active ingredients, namely the ALK2 inhibitor and the JAK2 inhibitor, are used together being greater than the sum of the effects obtained from using the compounds separately.

[0044] In one embodiment, a combination therapy comprising an effective amount of a JAK2 inhibitor and an ALK2 inhibitor is provided herein. The "effective amount" of the combination of agents (i.e., an ALK2 inhibitor (e.g., an ALK2 inhibitor of Formula II) and a JAK2 inhibitor (e.g., a JAK2 inhibitor of Formula I)) is an amount sufficient to bring about an observable improvement in the clinically observable signs and symptoms of the disorder being treated at baseline with the combination.

[0045] "Oral dosage form" includes unit dosage forms formulated for oral administration or intended for oral administration.

[0046] Combinations of therapeutic agents and administrations of combinations of agents for treating cancer and related symptoms are provided herein. As used herein, the term "cancer" includes related symptoms such as anemia. As used herein, the term "combination of agents" and similar terms refer to a combination of two agents: an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor or a pharmaceutically acceptable salt thereof. The use of racemic mixtures of the individual agents is also provided. Pharmacologically active metabolites include those that are inactive but are converted in the body to a pharmacologically active form after administration.

[0047] As used herein, the term "alkyl", by itself or as part of another substituent, unless otherwise specified, means a straight or branched chain hydrocarbon having the designated number of carbon atoms (i.e., C1-C6-alkyl means alkyl having 1 to 6 carbon atoms), including straight and branched chains. In certain embodiments, C1-C3, C1-C4, C1-C6 alkyl groups are provided herein. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl.

[0048] As used herein, the term "alkenyl", in certain embodiments, refers to a monovalent group obtained from a hydrocarbon moiety containing 2 to 4, 2 to 6, or 2 to 8 carbon atoms having at least one carbon-carbon double bond. The alkenyl group may or may not be the point of attachment to another group. The term "alkenyl" includes, but is not limited to, ethenyl, 1-propenyl, 1-butenyl, heptenyl, octenyl, and the like.

[0049] As used herein, the term "alkynyl" refers, in certain embodiments, to a monovalent group derived from a hydrocarbon moiety containing from 2 to 4, 2 to 6, or 2 to 8 carbon atoms having at least one carbon-carbon triple bond. The alkynyl group may or may not be the point of attachment to another group. The term "alkynyl" includes, but is not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0050] As used herein, the term "alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, and the like. In certain embodiments, C1-C3, C1-C4, C1-C6 alkoxy groups are provided herein.

[0051] As used herein, the term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, alone or as part of another substituent, unless otherwise specifically stated.

[0052] As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic system having 1, 2 or 3 rings, such rings may be fused. The term "fused" means that a second ring is present (i.e., attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. Cycloalkyl also includes bicyclic structures where each individual ring within the bicyclic can vary in having 3 to 10, 3 to 8, 3 to 7, 3 to 6, and 5 to 10 atoms and can be bridged or spirocyclic. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptanyl, bicyclo[2.2.2]octanyl and bicyclo[1.1.1]pentyl. In certain embodiments, 3- to 10-membered cycloalkyl groups are provided herein. In another embodiment, C8 cycloalkyl groups are provided herein. In yet another embodiment, bicyclo-C8 cycloalkyl groups are provided herein.

[0053] As used herein, the term "heterocycloalkyl" means a non-aromatic carbocyclic system containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, having 1, 2 or 3 rings, such rings may be fused, and fusion is defined above. Heterocycloalkyl includes bicyclic structures where each individual ring within the bicyclic can vary from 3 - 8, 5 - 10, 4 - 6, or 3 - 10 atoms and can be bridged or spirocyclic in nature and contain 0, 1, or 2 N, O, or S atoms. The term "heterocycloalkyl" includes, but is not limited to, cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and in particular epoxydyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl (i.e., oxanyl), pyranyl, dioxanyl, aziridinyl, azetidinyl, pyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, oxazolidinyl, thiazolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 2-aza-bicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 2-azabicyclo-[2.2.1]heptanyl, 3-aza-bicyclo[3.1.1]heptanyl, 2-azabicyclo[3.1.1]heptanyl, 3-azabicyclo-[3.1.0]hexanyl, 2-aza-bicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]-octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.5]nonanyl, 3-oxaspiro[5.3]-nonanyl, and 8-oxabicyclo-[3.2.1]octanyl. In certain embodiments, 3 - 10 membered heterocycloalkyl groups are provided herein. In another embodiment, 5 - 10 membered heterocycloalkyl groups are provided herein.In yet another embodiment, 4- to 6-membered heterocycloalkyl groups are provided herein.

[0054] As used herein, the term "heteroaryl" contains 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, has 1, 2, or 3 rings, and such rings may be fused, and means an aromatic carbocyclic system, and the fusion is defined above. The term "heteroaryl" includes, but is not limited to, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazo[1,2-a]-pyridinyl, pyrazolo[1,5-a]pyridinyl, 5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c]-pyridinyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]-pyrazolyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b]-[1,2,4]triazolyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl. In certain embodiments, 5- to 10-membered heteroaryl groups are provided herein.

[0055] When a cycloalkyl, heterocycloalkyl, or heteroaryl moiety may be attached or otherwise appended to a moiety designated by various ring atoms (i.e., shown or described without indication of a particular point of attachment), all possible points are intended, whether by a carbon atom or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, the term "thienyl" means 2- or 3-thienyl, and the like.

[0056] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0057] As used herein, the term "optionally substituted" means that the recited group may or may not be substituted. In one embodiment, the recited group is optionally substituted with 0 substituents, i.e., the recited group is unsubstituted. In another embodiment, the recited group is optionally substituted with one or more additional groups individually and independently selected from the groups described herein.

[0058] Pharmaceutical combination In one aspect, provided herein is a pharmaceutical combination comprising a JAK2 inhibitor or a pharmaceutically acceptable salt thereof, and an ALK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0059] In another aspect, an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and (i) a JAK2 inhibitor having Formula I:

Chemical formula

[0060] In certain embodiments of the pharmaceutical combination, the ALK2 inhibitor is a compound of formula II:

Chemical formula

[0061] In certain embodiments of formula II, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R2 is tetrahydropyran. In yet another embodiment, R1 is a bridged C8-cycloalkyl substituted with hydroxyl and R2 is tetrahydropyran.

[0062] In yet another aspect, (i) a JAK2 inhibitor having formula I:

Chemical formula

[0063] In certain embodiments of Formula IIa, L-R6 is

Chemical formula

[0064] In certain embodiments of the pharmaceutical combination, the ALK2 inhibitor of Formula IIa is the compound of Formula IIb:

Chemical formula

[0065] In yet another aspect, (i) a JAK2 inhibitor having Formula I:

Chemical formula

Chemical formula

[0066] In certain embodiments of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In yet another embodiment, R 4 is cyano. In certain embodiments, R 1 , R 2 and R 3 are all hydrogen and R 4 is cyano. In another embodiment, Z is cyclopentyl.

[0067] In certain embodiments of Formula II, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R1 is

Chemical formula

[0068] In yet another embodiment, R2 is tetrahydropyran. In another embodiment, R1 is a crosslinked C8-cycloalkyl substituted with hydroxyl, and R2 is tetrahydropyran.

[0069] In certain embodiments of Formula II, L-R6 is

Chemical formula

[0070] In another embodiment of the pharmaceutical combination, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile or a pharmaceutically acceptable salt thereof.

[0071] In yet another embodiment of the pharmaceutical combination, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment of the pharmaceutical combination, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile phosphate.

[0073] In yet another embodiment of the pharmaceutical combination, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0074] In certain embodiments of the pharmaceutical combination, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0075] In another embodiment of the pharmaceutical combination, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0076] In yet another embodiment of the pharmaceutical combination, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0077] In yet another embodiment of the pharmaceutical combination, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-nicotinamide or a pharmaceutically acceptable salt thereof.

[0078] In certain embodiments of the pharmaceutical combination, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0079] In another embodiment of the pharmaceutical combination, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0080] In certain embodiments, the ALK2 inhibitor is administered at a dose selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 50 mg. In another embodiment, the ALK2 inhibitor is administered at a dose of 5 mg. In yet another embodiment, the ALK2 inhibitor is administered at a dose of 10 mg. In yet another embodiment, the ALK2 inhibitor is administered at a dose of 15 mg. In certain embodiments, the ALK2 inhibitor is administered at a dose of 20 mg. In another embodiment, the ALK2 inhibitor is administered at a dose of 25 mg. In yet another embodiment, the ALK2 inhibitor is administered at a dose of 50 mg. In yet another embodiment, the ALK2 inhibitor is administered orally as a tablet. In another embodiment, the ALK2 inhibitor is administered once daily (QD).

[0081] In certain embodiments, the JAK2 inhibitor is administered at a dosage selected from the group consisting of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 50 mg, and in another embodiment, the JAK2 inhibitor is administered at a dosage of 5 mg. In yet another embodiment, the JAK2 inhibitor is administered at a dosage of 10 mg. In yet another embodiment, the JAK2 inhibitor is administered at a dosage of 15 mg. In certain embodiments, the JAK2 inhibitor is administered at a dosage of 20 mg. In another embodiment, the JAK2 inhibitor is administered at a dosage of 25 mg. In yet another embodiment, the JAK2 inhibitor is administered at a dosage of 50 mg. In yet another embodiment, the JAK2 inhibitor is administered orally as a tablet. In another embodiment, the JAK2 inhibitor is administered twice daily (BID).

[0082] In certain embodiments, ALK2 is administered at a dosage of 50 mg QD and the JAK2 inhibitor is administered at a dosage of 15 mg BID. In another embodiment, ALK2 is administered at a dosage of 50 mg QD and the JAK2 inhibitor is administered at a dosage of 20 mg BID. In yet another embodiment, ALK2 is administered at a dosage of 50 mg QD and the JAK2 inhibitor is administered at a dosage of 25 mg BID. In yet another embodiment, ALK2 is administered at a dosage of 50 mg QD and the JAK2 inhibitor is administered at a dosage of 10 mg BID.

[0083] Administration of the pharmaceutical combinations provided herein can provide beneficial effects, such as a synergistic therapeutic effect, e.g., alleviating symptoms, delaying the progression of symptoms or inhibiting symptoms, and can also provide further surprising beneficial effects, e.g., fewer side effects, improvement in quality of life or reduction in morbidity, compared to monotherapy applying only one of the pharmaceutically active ingredients used in the combinations of the present invention.

[0084] The JAK2 inhibitors provided herein, their synthesis, and their biological activity against JAK2 can be found in PCT / US2006 / 047369 (WO2007070514), which is hereby incorporated by reference in its entirety.

[0085] The ALK2 inhibitors provided herein, their synthesis, and their biological activities against ALK2 can be found in PCT / CN2017 / 093385 (WO2018014829), which is incorporated herein by reference in its entirety.

[0086] Pharmaceutical composition In certain embodiments, pharmaceutical compositions are provided herein that comprise a JAK2 inhibitor or a pharmaceutically acceptable salt thereof, an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0087] In another embodiment, an ALK2 inhibitor, a pharmaceutically acceptable carrier, and a JAK2 inhibitor having Formula I: [Chemical formula] (wherein R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1~4 alkyl, R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1~4 alkyl, and C 1~4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof are provided herein.

[0088] In certain embodiments of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In yet another embodiment, R 4 is cyano. In certain embodiments, R 1 , R 2 and R 3 are all hydrogen and R 4 is cyano. In another embodiment, Z is cyclopentyl.

[0089] In certain embodiments of the pharmaceutical composition, the ALK2 inhibitor is a compound of Formula II:

Chem.

[0090] In certain embodiments of Formula II, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R2 is tetrahydropyran. In yet another embodiment, R1 is a bridged C8-cycloalkyl substituted with hydroxyl and R2 is tetrahydropyran.

[0091] In another aspect, a pharmaceutically acceptable carrier, (i) a JAK2 inhibitor having Formula I:

Chem.

Chemical formula

[0092] In certain embodiments of Formula IIa, L-R6 is

Chemical formula

[0093] In certain embodiments of the pharmaceutical composition, the ALK2 inhibitor of Formula IIa is a compound of Formula IIb:

Chemical formula

[0094] In certain embodiments of Formula IIa and Formula IIb, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R2 is tetrahydropyran. In yet another embodiment, R1 is a bridged C8-cycloalkyl substituted with hydroxyl and R2 is tetrahydropyran.

[0095] In yet another aspect, a pharmaceutically acceptable carrier, (i) a JAK2 inhibitor having Formula I:

Chemical formula

[0096] In certain embodiments of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In yet another embodiment, R 4 is cyano. In one embodiment, R 1 1 R 2 and R 3 are all hydrogen and R 4 is cyano. In another embodiment, Z is cyclopentyl.

[0097] In certain embodiments of Formula II, R1 is a crosslinked C8-cycloalkyl substituted with hydroxyl. In another embodiment, R1 is [Chemical formula] .

[0098] In yet another embodiment of Formula II, R2 is tetrahydropyran. In another embodiment, R1 is a crosslinked C8-cycloalkyl substituted with hydroxyl and R2 is tetrahydropyran.

[0099] In another embodiment of the pharmaceutical composition, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0100] In yet another embodiment of the pharmaceutical composition, the JAK2 inhibitor of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile or a pharmaceutically acceptable salt thereof.

[0101] In another embodiment of the pharmaceutical composition, the JAK2 inhibitor of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile phosphate.

[0102] In yet another embodiment of the pharmaceutical composition, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment of the pharmaceutical composition, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0104] In another embodiment of the pharmaceutical composition, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0105] In yet another embodiment of the pharmaceutical composition, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0106] In yet another embodiment of the pharmaceutical composition, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)-nicotinamide or a pharmaceutically acceptable salt thereof.

[0107] In certain embodiments of the pharmaceutical composition, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0108] In another embodiment of the pharmaceutical composition, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0110] The compounds described herein also include isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number but a different atomic weight or mass number than the atomic weight or mass number typically found in nature. Examples of isotopes suitable for inclusion in the compounds described herein are 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N,15 O, 17 O, 18 O, 32 P, and 35 S, including but not limited to these. In another embodiment, the isotopically labeled compound is useful in drug or substrate tissue distribution studies. In another embodiment, substitution with a heavier isotope such as deuterium results in greater metabolic stability (e.g., an increase in in vivo half-life or a decrease in required dosage). In yet another embodiment, the compounds described herein 2 contain the

[0111] In yet another embodiment, 11 C, 18 F, 15 O and 13 substitution with a positron-emitting isotope such as N is useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. The isotopically labeled compound is prepared by any suitable method or by a process that uses a suitable isotopically labeled reagent in place of the unlabeled reagent employed in other cases.

[0112] The specific compounds described herein, and other compounds encompassed by one or more of the formulas described herein having different substituents, are synthesized as described in the techniques and materials described herein, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Edition, (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as described herein are modified using appropriate reagents and conditions for the introduction of the various moieties found in the formulas as provided herein.

[0113] In some embodiments, the JAK2 inhibitor is ruxolitinib (a JAK1 / 2 inhibitor). Ruxolitinib ((R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile) (which may be referred to as INCB018424) and its pharmaceutically acceptable salts have been previously described in U.S. Patent No. 7,598,257, which is hereby incorporated by reference in its entirety. Ruxolitinib phosphate is described in U.S. Patent No. 8,722,693, which is hereby incorporated by reference in its entirety. The present disclosure particularly describes combination methods using ruxolitinib or its pharmaceutically acceptable salts. In some embodiments, the JAK2 inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof in which one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, the JAK2 inhibitor is any of the compounds in U.S. Patent No. 9,249,149 (which is hereby incorporated by reference in its entirety) or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is CTP-543 or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound is a compound of Formula III:

Chemical formula

[0115] In some embodiments, the JAK2 inhibitor is a compound of formula III selected from the following compounds 100-130 in the table below, where R 6 , R 7 , and R 8 and each is H), or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK2 inhibitor is a compound of formula III selected from the following compounds 200-231 in the table below, 6 , R 7 , and R 8 are each D) or a pharmaceutically acceptable salt thereof.

[0116] [Table 1A]

[0117] [Table 1B]

[0118] [Table 1C]

[0119] In some embodiments, the JAK2 inhibitor is baricitinib.

[0120] In some embodiments, the JAK2 inhibitor is fedratinib.

[0121] In some embodiments, the JAK2 inhibitor is momelotinib.

[0122] In some embodiments, the JAK2 inhibitor is BMS-911543.

[0123] In some embodiments, the JAK2 inhibitor is pacritinib.

[0124] In some embodiments, the JAK2 inhibitor is NS-018.

[0125] In some embodiments, the JAK2 inhibitor is NVP-BBT594.

[0126] In some embodiments, the JAK2 inhibitor is NVP-CHZ868.

[0127] The compounds described herein are synthesized using any suitable procedure starting from compounds available from commercial sources or are prepared using the procedures described herein.

[0128] Method of treatment Also provided herein is a combination therapy comprising administering to a subject in need thereof an ALK2 inhibitor or a pharmaceutically acceptable salt thereof and a JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments of the combination therapy, the JAK2 inhibitor is a compound of Formula I:

[0130]

Chemical formula

[0131] (wherein R 1 、R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1~4 alkyl, R 4 is hydrogen, halo, cyano, nitro, hydroxy, C 1~4 alkyl, and C 1~4selected from the group consisting of alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof thereof.

[0132] In certain embodiments of Formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In yet another embodiment, R 4 is cyano. In certain embodiments, R 1 , R 2 and R 3 are all hydrogen and R 4 is cyano. In another embodiment, Z is cyclopentyl.

[0133] In another embodiment of the combination therapy, the ALK2 inhibitor is a compound of Formula II:

Chemical Formula

[0134] In certain embodiments of Formula II, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R1 is

Chemical Formula

[0135] In yet another embodiment of Formula II, R2 is tetrahydropyran. In another embodiment, R1 is a crosslinked C8-cycloalkyl substituted with hydroxyl, and R2 is tetrahydropyran.

[0136] In another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0137] In yet another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile or a pharmaceutically acceptable salt thereof.

[0138] In another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile phosphate.

[0139] In yet another embodiment of the combination therapy, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0140] In one embodiment of the combination therapy, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0141] In another embodiment of the combination therapy, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0142] In yet another embodiment of the combination therapy, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0143] In yet another embodiment of the combination therapy, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-nicotinamide or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0145] In another embodiment of the combination therapy, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0146] The combination therapy provided herein can be used in a method of treating a disease or condition in a subject, comprising administering to the subject in need thereof a combination or composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, provided herein is a method of treating anemia in a subject in need thereof, comprising administering to the subject an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0149] In another aspect, the subject is administered an ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor having the formula I: [Chemical formula] (wherein, R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1~4 alkyl, R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1~4 alkyl, and C 1~4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof A method for treating cancer in a subject in need thereof is provided herein, which comprises the step of administering.

[0150] In certain embodiments of the method, the ALK2 inhibitor is a compound of formula II: [Chemical formula] (wherein, R1 is a bridged 5- to 10-membered cycloalkyl optionally substituted 1, 2, or 3 times with hydroxyl or C1-C3 alkoxy, R 2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are optionally substituted with R 3 , R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H) or a pharmaceutically acceptable salt thereof is.

[0151] In yet another aspect, the subject is (i) JAK2 inhibitors having formula I: [Chemical formula] (wherein, R 1 R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1~4 alkyl, R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1~4 alkyl, and C 1~4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof, and (ii) ALK2 inhibitors having formula IIa: [Chemical formula] (wherein, L is a bond, (CH2) n , -CH(CH3)-, -O-(CH2) n -, -C(O)-, or -C(O)-NH-(CH2) n -, n is 1, 2, or 3, R1 is a 3- to 7-membered cycloalkyl optionally substituted 1, 2, or 3 times with substituents independently selected from hydroxyl, halogen, C1-C3 alkyl; a bridged 5- to 10-membered cycloalkyl optionally substituted 1, 2, or 3 times with hydroxyl or C1-C3 alkoxy, R4 and R5 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, R6 is a 5- to 10-membered heterocycloalkyl optionally substituted 1, 2, or 3 times with R2, R2 is independently at each occurrence C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkyl, C2-C4 alkynyl, C1-C3 alkyl, (CH2) mSelected from the group consisting of -R3, wherein the alkyl and alkoxy are independently optionally substituted 1, 2, or 3 times with halo or cyano, m is 0, 1, 2, or 3, R3 is a 4- to 6-membered heterocycloalkyl independently selected from the group consisting of oxo, SO2-C1-C3 alkyl, C1-C3 alkyl, and 3- to 6-membered cycloalkyl, which is optionally substituted 1, 2, or 3 times with a substituent, and the alkyl and cycloalkyl are optionally substituted 1, 2, or 3 times with halo, or two R3 groups together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof There is provided herein a method of treating cancer in a subject in need thereof, comprising the step of administering

[0152] In certain embodiments of Formula IIa, L-R6 is

Chemical formula

[0153] In certain embodiments of the method, the ALK2 inhibitor of Formula IIa is a compound of Formula IIb:

Chemical formula

[0154] In certain embodiments of Formula IIa and Formula IIb, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R2 is tetrahydropyran. In yet another embodiment, R1 is a bridged C8-cycloalkyl substituted with hydroxyl and R2 is tetrahydropyran.

[0155] In yet another aspect, to the subject (i) a JAK2 inhibitor having Formula I: [Chemistry] (wherein, R 1 、R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1~4 alkyl, R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1~4 alkyl, and C 1~4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof, and (ii) an ALK2 inhibitor having formula II: [Chemistry] (wherein, R1 is a bridged 5- to 10-membered cycloalkyl optionally substituted 1, 2, or 3 times with hydroxyl or C1-C3 alkoxy, R 2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are optionally substituted with R 3 ; R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H) or a pharmaceutically acceptable salt thereof A method of treating cancer in a subject in need thereof is provided herein, comprising the step of administering

[0156] In certain embodiments of formula I, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In yet another embodiment, R 3 is hydrogen. In yet another embodiment, R 4 is cyano. In certain embodiments, R 1 、R 2and R 3 are all hydrogen, and R 4 is cyano. In another embodiment, Z is cyclopentyl.

[0157] In another embodiment of the method, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0158] In yet another embodiment of the method, the JAK2 inhibitor of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment of the method, the JAK2 inhibitor of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-propanenitrile phosphate.

[0160] In yet another embodiment of the method, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0161] In one embodiment of the method, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0162] In another embodiment of the method, the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0163] In yet another embodiment of the method, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0164] In yet another embodiment of the method, the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-nicotinamide or a pharmaceutically acceptable salt thereof.

[0165] In certain embodiments of the method, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0166] In another embodiment of the method, the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0167] In certain embodiments of the method, the ALK2 inhibitor and the JAK2 inhibitor are administered separately.

[0168] Provided herein is a method of treating cancer in a subject in need thereof, comprising the step of administering to the subject an ALK2 inhibitor or a pharmaceutically acceptable salt thereof.

[0169] In certain embodiments of the method of treating cancer, the ALK2 inhibitor is a compound of Formula IIa: [Chemical formula] (wherein, L is a bond, (CH2) n , -CH(CH3)-, -O-(CH2) n -, -C(O)-, or -C(O)-NH-(CH2) n -, and n is 1, 2, or 3, R1 is a 3- to 7-membered cycloalkyl optionally substituted 1, 2, or 3 times with substituents independently selected from hydroxyl, halogen, C1-C3 alkyl; a bridged 5- to 10-membered cycloalkyl optionally substituted 1, 2, or 3 times with hydroxyl or C1-C3 alkoxy, and is selected from R4 and R5 are each independently selected from the group consisting of H, halogen, C1-C3 alkyl, R6 is a 5- to 10-membered heterocycloalkyl optionally substituted 1, 2, or 3 times with R2, R2 is independently at each occurrence selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkyl, C2-C4 alkynyl, C1-C3 alkyl, (CH2) m -R3, wherein the alkyl and alkoxy are independently optionally substituted 1, 2, or 3 times with halo or cyano, m is 0, 1, 2, or 3, R3 is a substituent independently selected from the group consisting of oxo, SO2-C1-C3 alkyl, C1-C3 alkyl, and a 4- to 6-membered heterocycloalkyl optionally substituted 1, 2, or 3 times with substituents independently selected from the group consisting of C1-C3 alkyl and cycloalkyl, and the alkyl and cycloalkyl are optionally substituted 1, 2, or 3 times with halo, or two R3s together with the atoms to which they are attached form a 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof is.

[0170] In the treatment of cancer, in certain embodiments of formula IIa, L-R6 is

Chemical formula

[0171] In certain embodiments of the treatment of cancer, the ALK2 inhibitor of formula IIa is a compound of formula IIb: [Chemistry] or a pharmaceutically acceptable salt thereof.

[0172] In certain embodiments of Formula IIa and Formula IIb, R1 is a bridged C8-cycloalkyl substituted with hydroxyl. In another embodiment, R2 is tetrahydropyran. In yet another embodiment, R1 is a bridged C8-cycloalkyl substituted with hydroxyl and R2 is tetrahydropyran.

[0173] In another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula IIa is a compound of Formula II: [Chemistry] (wherein R1 is a bridged 5- to 10-membered cycloalkyl optionally substituted 1, 2, or 3 times with hydroxyl or C1-C3 alkoxy, R 2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are optionally substituted with R 3 (wherein R 3 is selected from the group consisting of hydroxyl, halo, cyano, nitro, SO2-C1-C3 alkyl, and SO3H), or a pharmaceutically acceptable salt thereof is.

[0174] In yet another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0175] In certain embodiments of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0176] In another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0177] In yet another embodiment of the method of treating cancer, the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)-nicotinamide fumarate dihydrate.

[0178] In another embodiment of the method of treating cancer, the ALK2 inhibitor is administered as monotherapy. In yet another embodiment of the method of treating cancer, the ALK2 inhibitor is administered in the absence of any other active pharmaceutical ingredient. In yet another embodiment of the method of treating cancer, the ALK2 inhibitor is administered in the absence of a Janus kinase inhibitor.

[0179] In another embodiment of the method, the cancer is a myeloproliferative neoplasm.

[0180] In another embodiment of the method, the cancer is myelodysplastic syndrome. Myelodysplastic syndrome (MDS) can include hematopoietic stem cell disorders characterized by one or more of the following: ineffective hematopoiesis, progressive cytopenia, risk of progression to acute leukemia, or cellular bone marrow with morphological and maturation disorders (myelodysplasia). Myelodysplastic syndrome can also include refractory anemia, refractory anemia with ring sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

[0181] In yet another embodiment of the method, the cancer is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, atypical chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). In yet another embodiment, the cancer is myelofibrosis (MF).

[0182] In certain embodiments of the method, the cancer is selected from the group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.

[0183] In one aspect, provided herein is a method of treating anemia in a subject in need thereof, comprising administering to the subject a JAK2 inhibitor of Formula I and an ALK2 inhibitor of Formula II.

[0184] In another embodiment of the method, the anemia is cancer-induced anemia.

[0185] In another embodiment of the method, the anemia is caused by a myeloproliferative or myelodysplastic hematologic malignancy.

[0186] In another embodiment of the method, the anemia is myelofibrosis-induced anemia.

[0187] In certain embodiments of a method of treating anemia, the JAK2 inhibitor of Formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of Formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt or hydrate thereof.

[0188] In another embodiment of the method, the subject is human.

[0189] In yet another embodiment of the method, the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor substantially simultaneously.

[0190] In yet another embodiment of the method, the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at different times.

[0191] In certain embodiments of the method, the ALK2 inhibitor is administered to the subject, followed by administration of the JAK2 inhibitor. In another embodiment, the JAK2 inhibitor is administered to the subject, followed by administration of the ALK2 inhibitor.

[0192] In another embodiment of the method, the ALK2 inhibitor and / or the JAK2 inhibitor is administered at a dosage that is ineffective when one or both of the ALK2 inhibitor and the JAK2 inhibitor are administered alone, but is effective in combination.

[0193] In yet another aspect, provided herein is a method of treating cancer, comprising the step of administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0194] In yet another aspect, provided herein is a method of treating cancer, comprising the step of administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate.

[0195] In one aspect, provided herein is a method of treating myelofibrosis (MF), comprising the step of administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0196] In another aspect, provided herein is a method for treating myelofibrosis, comprising the step of administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate.

[0197] In yet another aspect, provided herein is a method for treating polycythemia vera (PV), comprising the step of administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof, and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

[0198] In another aspect, provided herein is a method for treating polycythemia vera (PV), comprising the step of administering to a subject in need thereof 2-amino-N-(4-hydroxy-bicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide (Compound A) or a pharmaceutically acceptable salt thereof and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile phosphate.

[0199] In yet another aspect, provided herein is a method for treating polycythemia vera (PV), comprising the step of administering to a subject in need thereof a compound of Formula II:

Chemical formula

[0200] In certain embodiments of the method for treating myelofibrosis (MF), the compound of formula II is 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]-hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0201] In certain embodiments of the method for treating myelofibrosis (MF), the compound of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0202] In another embodiment of the method of treating myelofibrosis (MF), the compound of Formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0203] In one embodiment of the method of treating myelofibrosis (MF), the compound of Formula II is 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0204] In yet another aspect, provided herein is a method of treating a JAK2-related disorder comprising administering a JAK2 inhibitor and an ALK2 inhibitor to a subject in need thereof.

[0205] In one embodiment of the method, the JAK2-related disorder is selected from the group consisting of polycythemia vera, graft-versus-host disease, allograft rejection, atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis, allergic contact sensitization, pemphigus vulgaris (PV), and bullous pemphigoid (BP).

[0206] In one embodiment of the method, the method comprises administering a therapeutically effective amount of a combination or composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof to a subject (including but not limited to humans or animals) in need of treatment (including a subject identified as in need).

[0207] In another embodiment of the method, the treatment comprises co-administering an amount of an ALK2 inhibitor and an amount of a JAK2 inhibitor. In one embodiment, the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor are in a single formulation or unit dosage form. In yet other embodiments, the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor are in separate formulations or unit dosage forms.

[0208] In the foregoing method, the treatment may include administering the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor substantially simultaneously, or administering the amount of the ALK2 inhibitor and the amount of the JAK2 inhibitor at different times. In some embodiments of the foregoing method, the amount of the ALK2 inhibitor and / or the amount of the JAK2 inhibitor is administered at a dosage that is not effective when one or both of the ALK2 inhibitor and the JAK2 inhibitor are administered alone, but this amount is effective in combination.

[0209] In some embodiments, the method or treatment reduces the hepcidin serum level in the patient relative to baseline, compared to the normal level in the patient, or compared to the level in a patient treated with the JAK2 inhibitor alone. The hepcidin serum level can be reduced by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, more than 90% or about 100%. In some embodiments, the hepcidin serum level is reduced by about 50% or more relative to baseline. In some embodiments, the hepcidin serum level is reduced to less than about 150 ng / mL, 140, 130, 120, 110, 100, 90, 80, 70, 60 or about 50 ng / mL. The hepcidin level can be assayed by standard techniques including radioimmunoassay, ELISA, ligand binding assay or mass spectrometry.

[0210] In some embodiments, the method or treatment increases the serum iron concentration in the patient relative to baseline, compared to the normal level in the patient, or compared to the level in a patient treated with the JAK2 inhibitor alone. The serum iron concentration can be increased by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, more than 90% or about 100%. The serum iron concentration can be assayed by standard techniques.

[0211] In some embodiments, the method or treatment raises the hemoglobin serum level in a patient relative to a baseline, compared to the normal level in the patient or compared to the level in a patient treated with a JAK2 inhibitor alone. The hemoglobin serum level can increase by about 5%, 10%, 15%, 20%, 25% or more than about 30%. Hemoglobin levels can be assayed by standard techniques.

[0212] In some embodiments, the method or treatment raises the transferrin saturation (TSAT) in a patient relative to a baseline, compared to the normal level in the patient or compared to the level in a patient treated with a JAK2 inhibitor alone. The TSAT can increase by about 5%, 10%, 15%, 20%, 25% or more than about 30%. TSAT can be assayed by standard techniques.

[0213] In some embodiments, the method or treatment decreases the ferritin blood level in a patient relative to a baseline, compared to the normal level in the patient or compared to the level in a patient treated with a JAK2 inhibitor alone. The ferritin blood level can decrease by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more than about 100%. Ferritin blood levels can be assayed by standard techniques.

[0214] Packaged formulation Packaged pharmaceutical formulations or pharmaceutical products are included herein. Such packaged formulations include one or more pharmaceutical formulations comprising a combination of an ALK2 inhibitor and a JAK2 inhibitor. A combination of the compounds in formulated form is contained in a container. The package typically contains instructions for using the formulation to treat an animal (typically a human patient) suffering from cancer or a JAK2-related disorder.

[0215] In certain embodiments, the packaged pharmaceutical formulation or pharmaceutical product contains a combination of the compounds described herein in a container having instructions for administering the dosage form on a fixed schedule. In some of these embodiments, the combination of compounds is provided in separate unit dosage forms.

[0216] In certain embodiments, the combination of compounds can be administered on the same schedule, either by administering a single formulation or unit dosage form containing all of the compounds of the combination, or by administering separate formulations or unit dosage forms of the compounds of the combination. However, some of the compounds used in the combination can be administered more frequently than once a day or at a frequency different from the other compounds in the combination. Thus, in one embodiment, a packaged pharmaceutical formulation comprises a formulation or unit dosage form containing all of the compounds in the combination of compounds, and an additional formulation or unit dosage form containing one of the compounds in the combination of agents, which contains no additional active compounds, in a container having instructions for administering the dosage form on a fixed schedule.

[0217] The packaged formulations provided herein include, for example, prescription information for a patient or healthcare provider, or as a label within the packaged pharmaceutical formulation. The prescription information can include, for example, efficacy, dosage, contraindications, and adverse reaction information regarding the pharmaceutical formulation.

[0218] In all of the above, the combinations of the compounds of the invention can be administered alone, as a mixture, or together with additional active agents.

[0219] Administration / Dosage / Formulation In another aspect, provided herein are pharmaceutical compositions or combinations of medicaments comprising the compounds disclosed herein together with a pharmaceutically acceptable carrier.

[0220] Administration of the combination includes administration of a combination of single formulations or unit dosage forms, simultaneous but separate administration of the individual agents of the combination, or sequential administration of the individual agents of the combination, by any suitable route. The dosage of an individual agent of the combination may require more frequent administration of one of the agents as compared to the other agents in the combination. Thus, to enable appropriate dosing, a packaged pharmaceutical product can contain one or more dosage forms containing the combination of agents, and one or more dosage forms containing one of the agents of the combination but not the other agents of the combination.

[0221] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0222] In particular, the dosage level selected will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or substances used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0223] A medical doctor, e.g., a physician or veterinarian, who is a person of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can begin administration of the pharmaceutical composition with a level of the disclosed compound lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0224] In certain embodiments, it is particularly advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unit dosages for the patients to be treated, each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. Dosage unit form is defined by and directly depends on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such disclosed compounds for the treatment of pain, depressive disorders, or drug intoxication in a patient.

[0225] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition provided herein comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0226] The drug compounds provided herein (e.g., ALK2 inhibitors and JAK2 inhibitors) are present in the combinations, dosage forms, pharmaceutical compositions, and pharmaceutical formulations disclosed herein in ratios ranging from 100:1 to 1:100. For example, the ratio of JAK2 inhibitor:ALK2 inhibitor can be in the range of 1:100 to 1:1, such as 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:2, or 1:1 JAK2 inhibitor:ALK2 inhibitor. In another example, the ratio of ALK2 inhibitor:JAK2 inhibitor can be in the range of 1:100 to 1:1, such as 1:100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:5, 1:2, or 1:1 ALK2 inhibitor:JAK2 inhibitor.

[0227] The optimal ratios, individual and total dosages, and concentrations of the drug compounds that provide efficacy without toxicity are determined using methods known to those of skill in the art based on the kinetics of the availability of the active ingredient at the target site.

[0228] Any route of administration of any of the compositions contemplated herein includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds can be formulated for administration by any suitable route, e.g., oral or parenteral, such as transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., transvaginal and perivaginal), nasal (intra), and (trans)rectal), intravesical, intratracheal, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intratracheobronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0229] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, plasters, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powders for inhalation or aerosolized formulations, compositions and formulations for intravesical administration, and the like. It should be understood that the formulations and compositions are not limited to the specific formulations and compositions described herein.

[0230] For oral application, tablets, dragees, solutions, drops, suppositories, or capsules, caplets, and gel caps are particularly suitable. Compositions for oral use can be prepared according to any method known in the art, and such compositions can contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may or may not be coated, or may be coated by known techniques for aesthetic purposes or to delay the release of the active ingredient. Formulations for oral use can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0231] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in bolus doses or by continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles, optionally containing other formulation agents such as suspending agents, stabilizers, or dispersing agents, can be used.

[0232] One of ordinary skill in the art can recognize or confirm numerous equivalents of the specific procedures, embodiments, claims, and examples described herein using only routine experimentation. Such equivalents are considered to be within the scope of this disclosure and are encompassed by the claims appended hereto. For example, modifications in reaction conditions, including but not limited to reaction time, reaction size / volume, and experimental reagents such as solvents, catalysts, pressure, atmospheric conditions such as nitrogen atmosphere, and reducing / oxidizing agents, using alternatives recognized in the art and only routine experimentation, are to be understood as being within the scope of this application.

[0233] Wherever values and ranges are provided herein, it is to be understood that all values and ranges encompassed by these values and ranges are intended to be included within the scope of this disclosure. Further, all values falling within these ranges, as well as the upper or lower limits of ranges of values, are also contemplated by this application.

[0234] The following examples further illustrate aspects of the present disclosure. However, they are in no way intended to limit the teachings of the present disclosure as described.

Example

[0235] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limitations. The practice of the present disclosure employs conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art unless otherwise indicated.

[0236] Processes for preparing the compounds disclosed herein can be found at least in WO2018 / 014829 and WO2010 / 083283, the contents of which are incorporated in their entirety.

[0237] (Example 1) Terpentine-induced anemia C57Bl / 6 mice (7 - 8 weeks old, female) were purchased from Charles River Laboratories, Wilmington, MA and placed on a low - iron diet (Test diet #AIN - 76A 5TJK) two weeks prior to the start of the study. The mice continued on this diet throughout the course of the study. In the intrascapular region of the back of the recipient mice, 100 μl volumes of sterile - filtered terpentin (Aldrich, catalog number 24245) or sterile saline were subcutaneously injected into the mice weekly for three weeks. The therapeutic agent was orally administered at a total volume of 10 mL / kg body weight. Mice were administered vehicle (0.5% DMAC:95% methylcellulose) or compound (n = 10 per treatment group), which was initiated immediately after the first terpentin injection (day 0) and continued daily until the end of the study. Blood was collected once a week from the orbital venous plexus and complete blood count values (CBC) were determined using a blood analyzer (Abaxis model HM5). Statistical analysis was performed using Graphpad Prism software. Mice were handled in accordance with Incyte's IACUC protocol.

[0238] In each of the experiments conducted, the ALK2 inhibitor (Compound A, 2 - amino - N-(4 - hydroxybicyclo[2.2.2]octan - 1 - yl)-5-(4-(3-(tetrahydro - 2H - pyran - 4 - yl)-3 - azabicyclo[3.1.0] - hexan - 1 - yl)phenyl)nicotinamide) (100 mg / kg QD) cured the anemia induced by terpentin. In Figure 1, Compound A improved the red blood cell count, hemoglobin, and hematocrit to levels similar to those of the saline (no terpentin - induced anemia) control 28 days after the first terpentin injection. In Figure 2, using Compound A administered at 30 mg / kg BID, the same trend was demonstrated by day 21 after the first terpentin injection and the changes were statistically significant (determined by unpaired t - test * p < 0.05, ** p < 0.01, *** p < 0.001, ****p < 0.0001). Also, the JAK2 inhibitor (ruxolitinib, 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile) (90 mg / kg BID) worsened the anemia caused by terpentin injection in each experiment, which was most likely due to the pancytopenic effect of JAK2 inhibition in mice. Compound A improved the blood parameters of mice also administered ruxolitinib, with a significant increase in RBC, hemoglobin, and hematocrit levels in Figure 2. Overall, these experiments show that ALK2 inhibition reversed the decrease in RBC count, hemoglobin, and hematocrit caused by inflammation-induced anemia brought about by terpentin, and this anti-anemic effect derived from ALK2 inhibition is possible in the presence of ruxolitinib.

[0239] (Example 2) Clinical protocol A study of an ALK2 inhibitor administered as monotherapy or in combination with a JAK2 inhibitor is conducted in adult participants with anemia due to myeloproliferative or myelodysplastic blood malignancies.

[0240] Overall study design. An open-label, multi-site, dose-escalating and expansion, safety and preliminary efficacy study of Compound A administered as monotherapy or in combination with ruxolitinib in subjects with anemia due to myeloproliferative or myelodysplastic blood malignancies (defined as Hgb < 10 g / dL). For both the monotherapy and combination parts, each participant is observed for at least one treatment cycle (28 days).

[0241] Part 1: Monotherapy portion, including both dose escalation and expansion phases, in which Compound A is administered alone to subjects with anemia due to low-risk myelodysplastic syndrome (MDS). A combination portion, including a dose escalation phase, in which Compound A is administered in combination with ruxolitinib to subjects with primary myelofibrosis (PMF), post-polycythemia vera (PV), or post-essential thrombocythemia (ET) myelofibrosis, collectively referred to as "MF" subjects, who have anemia.

[0242] Part 2: Combination portion, including only the expansion phase, in which Compound A is administered in combination with ruxolitinib to MF subjects.

[0243] Both the monotherapy and combination portions are divided into two stages. The dose escalation stage determines the maximum tolerated dose (MTD), the recommended expanded phase dose (REPD) that can be advanced in the corresponding expansion portion, and the biologically active dose (BAD) defined as the tolerated dose that provides evidence of the biological effect of the investigated dose / regimen. The expansion stage evaluates the safety, efficacy, PK, and PD of the REPD selected in the dose escalation stage (monotherapy and combination portions) of the corresponding treatment group.

[0244] Three different treatment groups are prepared. For the monotherapy portion, only one treatment group is prepared: Treatment Group A (TGA) including subjects with anemia due to low-risk myelodysplastic syndrome (MDS). For the combination portion, two different treatment groups are defined in subjects with anemia due to MF: Treatment Group B (TGB) including MF subjects with anemia who take a stable dose of ruxolitinib for at least 8 weeks (the acceptable starting doses are 10 mg twice a day [BID], 15 mg BID, 20 mg BID, and 25 mg BID), and Treatment Group C (TGC) including treatment-naive MF subjects with anemia. The treatment can continue as long as the subject is benefiting from the study treatment and does not meet any criteria for permanent treatment discontinuation.

[0245] The primary objective of each part of the study is, for Part 1 (dose escalation phase of monotherapy and combination parts (all treatment groups) and expansion phase of monotherapy part), to evaluate the safety and tolerability of Compound A administered alone or in combination with ruxolitinib. For Part 2 (expansion phase of combination part - only TGB and TGC), to evaluate the efficacy of Compound A administered in combination with ruxolitinib. The secondary objectives applicable to all treatment groups include evaluation of PD parameters (including hepcidin blood levels), PK parameters of Compound A and, where applicable, ruxolitinib, and efficacy based on response criteria applicable to MDS patients for the expansion phases of monotherapy and combination parts.

[0246] The overall design of the study includes a screening part of up to 28 days to confirm eligibility of subjects, a treatment part as long as the subjects benefit from the study drug therapy and do not show any study drug treatment discontinuation criteria, and a follow-up part for survival / long-term outcome from the time of permanent discontinuation of the study drug until the end of the study.

[0247] Compound A is administered orally as tablets / capsules. The starting dose can vary from approximately 10 to approximately 50 mg, which is an approximate daily dose including a starting dose of approximately 25 mg QD or approximately 30 mg QD. Dose escalation is based on the type and severity of toxicity and the observed PK / PD results. The dosing can range from approximately 10 to approximately 150 mg per day, including approximately 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125 and approximately 150 mg.

[0248] For the TGB and TGC groups, ruxolitinib is administered orally as tablets twice daily (BID) continuously. For TGC, when the subject's platelet value is 100 - 200×10 9 / L, the starting dose is approximately 15 mg BID. When the subject's platelet value is 200×10 9If it exceeds / L, the starting dose is about 20 mg BID. During treatment with ruxolitinib, additional doses include 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg BID, according to the disease response and hematological toxicity experienced by the subject. Dose escalation is based on the type and severity of toxicity and the observed PK / PD results.

[0249] The following clinical tests are performed on the subject samples. Iron metabolism (centrally measured) is examined in a chemistry panel that includes serum hepcidin, serum iron, serum ferritin and ferritin index [FTI], ferritin saturation, serum transferrin, transferrin saturation, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), serum non-transferrin-bound iron (NTBI), available serum transferrin receptor (sTFR), and growth differentiation factor 15 (GDF-15)=bone morphogenetic protein (BMP) receptor. Hematological parameters are examined as part of a hematology panel that includes reticulocytes, nucleated red blood cells, erythrocyte hemoglobin, erythropoietin (EPO), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and bone marrow blast cells in peripheral blood. Additional markers of inflammation are examined as part of a biochemistry panel that includes C-reactive protein (CRP), and a cytokine panel that includes interleukin (IL)-1, IL-2 and IL-2 receptor (IL-2R), IL-6, IL-8, and IL-22.

[0250] Inclusion criteria: The inclusion criteria for treatment groups A, B, and C include the following: Ability to understand and willingness to sign the written informed consent form (ICF) for the study, 18 years of age or older at the time of signing the informed consent, Histologically confirmed disease, Participants with anemia due to MDS or MF, defined as follows: a. Hemoglobin [Hgb] value < 10 g / dL without the influence of red blood cell (RBC) transfusion; record at three separate opportunities with a measurement interval of at least 7 days, considering that a 2-week washout period must be demonstrated during screening, or b. Participants who received at least 4 units of RBC transfusion in the 28 days immediately preceding Day 1 of Cycle 1 or an average of at least 4 units of RBC transfusion in the 8 weeks immediately preceding Day 1 of Cycle 1 for hemoglobin levels < 8.5 g / dL in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must not have occurred in the 28 days prior to Day 1 of Cycle 1. Note: The latter option corresponds to the definition of baseline transfusion-dependent participants. Eastern Cooperative Oncology Group (ECOG) Performance Status Score: a. 0 or 1 for the dose escalation part (monotherapy and combination parts), b. 0, 1, or 2 for the expansion part (monotherapy and combination parts), Life expectancy of more than 6 months, Willingness to undergo pretreatment and regular bone marrow biopsies and / or aspirations (depending on the disease) during the study. If biopsies and aspirations are not possible or are contraindicated, or if tissue requirements cannot be met, this requirement may be waived by approval from the sponsor's medical monitor. Willingness to avoid pregnancy or having children based on the following criteria: (i) Postmenopausal women (i.e., surgical infertility due to hysterectomy and / or bilateral oophorectomy or amenorrhea of ≥ 12 months and at least 50 years old). (ii) Reproductive women who have a negative serum pregnancy test at screening and before the first dose on Day 1 and agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening to safety follow-up. Approved methods that are at least 99% effective in preventing pregnancy should be communicated to and their understanding confirmed. (iii) Males who agree to take appropriate preventive measures (with at least 99% certainty) to avoid creating children from screening to safety follow-up. It should be communicated to and the understanding of approved methods that are at least 99% effective in preventing pregnancy should be confirmed.

[0251] Inclusion criteria defining the characteristics of the disease: Subjects with < 10% peripheral blood blasts. Subjects who do not require cytoreductive therapy or therapeutic intervention.

[0252] For Treatment Group A (TGA) Additional inclusion criteria for Treatment Group A include a confirmed diagnosis of myelodysplastic syndrome (MDS) according to the 2016 World Health Organization (WHO) criteria (Swerdlow et al., 2017 and Arber et al., Blood, 2016).

[0253] For subjects with myelodysplastic syndrome (MDS): Excluding subjects showing myelodysplastic syndrome with ring sideroblasts (MDS-RS), very low-risk, low-risk or intermediate-risk MDS as defined by the IPSS-R criteria (Greenberg et al., Blood, 2012), or

[0254] For subjects with MDS / MPN overlap syndrome: i. Low-risk or intermediate-risk chronic myelomonocytic leukemia (CMML) according to Patnaik et al., 2013, or ii. Well- or intermediate-risk unclassifiable MDS / MPN overlap syndrome (MDS / MPN, unclassifiable) as per the criteria of Liu et al., 2012, iii. Excluding participants showing atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML) or MDS / MPN with ring sideroblasts and thrombocytosis (MDS / MPN-RS-T).

[0255] For Treatment Groups B and C (TGB and TGC): Additional inclusion criteria for Treatment Groups B and C (TGB and TGC) include histologically confirmed diagnosis and previous treatment of primary myelofibrosis (PMF), post-polycythemia vera (PV), or post-essential thrombocythemia (ET) myelofibrosis according to the 2016 World Health Organization criteria (for PMF, see Swerdlow et al., 2017 and Passamonti et al., ASH publications, 2016; for post-ET and post-PV myelofibrosis, see Barosi et al., Leukemia, 2008).

[0256] For TGB, each subject must have received a therapeutic and stable regimen of ruxolitinib (10 mg, 15 mg, 20 mg, or 25 mg BID) for at least 8 consecutive weeks immediately prior to the first treatment dose in the study, and the dose and dosing regimen of ruxolitinib for treating MF in each subject must not have been modified at any time during the 8 weeks immediately prior to the first treatment dose in the study.

[0257] For TGC, each subject must be treatment-naïve to any JAK inhibitor.

[0258] Exclusion criteria: Exclusion criteria for Treatment Groups A, B, and C include the following: Subjects with screening test values as defined in Table 1 (Table 2).

[0259]

Table 2

[0260] Subjects with any major surgery within 28 days prior to the first study treatment. Any prior chemotherapy, immunomodulatory drug therapy, immunosuppressive therapy, biologic therapy, endocrine therapy, targeted chemotherapy, antibody, erythropoietin-stimulating agent (ESA), methylation inhibitor, or granulocyte colony-stimulating factor [G-CSF], granulocyte / macrophage colony-stimulating factor [GM-CSF], romiplostim, eltrombopag, folic acid (folate), or vitamin B12 (cobalamin) for the treatment of the subject's disease within 5 half-lives or within 28 days prior to the first study treatment (whichever is shorter), except for luksolitinib in TGB. Subjects who have received treatment with another investigational drug or were treated with an investigational drug within 28 days prior to screening, Subjects who have received treatment with a strong / moderate inhibitor or inducer of CYP3A4 / 5 within 28 days or 5 half-lives (whichever is longer) from the first study treatment, or who are expected to receive such treatment during the study. Any prior radiotherapy within 28 days or 5 half-lives (whichever is longer) from the first study treatment. Palliative radiotherapy to a single site or small area was permitted with a washout of at least 1 week prior to the first study treatment. Any prior allogeneic or autologous transplantation, or subjects who are candidates for allogeneic or autologous transplantation, History of leukocytosis (WBC > 25×10 9 / L history), Presence of any hematologic malignancy other than MDS or MF, Active invasive malignancies over the past 5 years, except for subjects with early basal cell or cutaneous squamous cell carcinoma, or completely resected cervical intraepithelial neoplasia, or completely resected papillary thyroid carcinoma and follicular thyroid carcinoma who may be eligible for participation at the discretion of the study physician. Subjects with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery may be enrolled as long as they have a reasonable expectation of cure with the treatment received. Known active diseases involving the central nervous system (CNS), such as brain metastases or spinal cord compression, except for primary CNS lymphoma. History of clinically significant or uncontrolled heart disease, including unstable angina or acute myocardial infarction within the last 12 months, or New York Heart Association class III or IV congestive heart failure, or clinically significant arrhythmia not controlled by medications. Subjects with a rhythm that has been well controlled for at least 1 month prior to the first dose of the pacemaker and study drug are allowed. History or presence of clinically significant abnormal ECG, in the opinion of the principal investigator of the clinical trial. Screening QTc interval > 450 milliseconds is excluded. For subjects with intraventricular conduction delay (QRS interval 120 ms), with the approval of the sponsor, the JTc interval may be used instead of the QTc. Subjects with left bundle branch block are excluded. Subjects with QTc prolongation due to a pacemaker may be enrolled with prior approval from the sponsor's medical monitor. Presence of chronic or current active infectious disease requiring systemic antibiotics, antifungals, or antiviral treatment. Subjects with acute bacterial infection requiring antibiotic use should delay screening / enrollment until the course of antibiotic therapy is completed and the infection is no longer active. Subjects with a diagnosis of chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis). Subjects with known active hepatitis A, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection or who are HIV positive. Absence of the intention to receive blood components transfusions, including red blood cell packs and platelet transfusions. Subjects who, in the opinion of the principal investigator of the clinical trial, cannot or are unlikely to comply with the dosing schedule and study evaluations. Any condition that, in the judgment of the principal investigator of the clinical trial, precludes full participation in the study, including administration of the study drug and attendance at the required study visits, poses a significant risk to the subject, or interferes with the interpretation of study data. Active alcohol or drug intoxication that interferes with the ability to comply with study requirements. Gastroesophageal reflux disease not controlled by medications within 28 days prior to the initial study drug dose (i.e., current symptoms of esophagitis or endoscopic evidence), Any non-resolving toxicity ≥ Grade 2 from prior therapy, excluding stable chronic toxicity (≤ Grade 2) such as stable Grade 2 peripheral neuropathy that is not expected to resolve, Subjects with a known hypersensitivity or severe reaction to any active substance or excipient in the use of Compound A or ruxolitinib or a similar compound appropriate for the related treatment group, or any known contraindication, Women who are pregnant or currently breastfeeding, Unable to swallow and retain oral medications, and Unable to understand or unwilling to sign the informed consent form (ICF).

[0261] Additional exclusion criteria for Treatment Groups B and C (TGB and TGC) are platelet count < 50 × 10 9 / L or ANC < 0.5 × 10 9 / L in any subject with a history, and any subject who has received treatment with a hematopoietic growth factor receptor agonist (i.e., erythropoietin [EPO]), granulocyte colony-stimulating factor (G-CSF), romiplostim, eltrombopag at any time within 4 weeks prior to screening, and any subject who has received or is expected to receive treatment with a strong / moderate inhibitor or inducer of CYP3A4 within 14 days or 5 half-lives (whichever is longer) from the first study drug dose, and any subject who is unwilling or unable to undergo an MRI or CT scan as required by the study protocol.

[0262] Primary analysis: Part 1: Safety analysis for TGA - dose escalation and expansion, TGB - dose escalation, TGC - dose escalation: The safety of Compound A administered alone or in combination with ruxolitinib was descriptively analyzed using the following parameters for each dose level in each part, treatment group, and safety analysis population: - Frequency, duration, and severity of adverse events (AE), serious adverse events (SAE), and dose-limiting toxicity (DLT), - Changes in clinical evaluations including vital signs and electrocardiogram (ECG), - Clinical laboratory blood and urine sample evaluations, - The DLT rate is summarized for each cohort in the dose escalation part.

[0263] Part 2: Efficacy analysis for TGB-dose expansion, TGC-dose expansion: The proportion of participants with an anemia response defined as an increase in Hgb of ≥ 1.5 g / dL for ≥ 12 weeks during treatment is estimated with its 95% confidence interval (CI) if not transfusion-dependent or, if applicable, achieving transfusion independence for ≥ 12 weeks if transfusion-dependent at baseline. The proportion is tested against 20% using a test of the population proportion in the full analysis set (FAS) population with a one-sided alpha of 5%.

[0264] Participants with missing judgments that impede the evaluation of the primary endpoint are considered non-responders for their treatment group. Data imputation is not applied.

[0265] Secondary analysis: Analysis of the dose escalation phase (all treatment groups) of the monotherapy and combination parts and the expansion phase of the monotherapy part includes the efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound A administered in the defined patient population, either alone or in combination with ruxolitinib. The expansion phase of the combination part (TGB and TGC only) includes the safety of Compound A administered in combination with ruxolitinib in anemic MF subjects. Safety assessments are PK of Compound A in plasma: C max 、t max 、AUC 0-t 、AUC 0-∞ 、t 1 / 2 、Cl / F, Vz / F, and λz, PK of compound A in urine: Ae96h and CLr, PK of compound A in saliva: C max , t max , AUC 0-t , AUC 0-∞ and CL, and PK of the metabolite of compound A in plasma (C max , t max , AUC 0-t , AUC 0-∞ ), and urine (Ae, CLr, Fe (excretion %)) are included.

[0266]

Table 3

[0267] The following PD parameters are descriptively summarized for each part, stage, treatment group, and dose level in the PD - evaluable population at each visit. - Plasma hepcidin level - PD parameters for determining iron homeostasis: total serum iron (TSI), ferritin, transferrin, transferrin saturation (TSAT), total iron - binding capacity (TIBC), unsaturated iron - binding capacity (UIBC), non - transferrin - bound serum iron (NTBI), - PD parameters for determining erythropoiesis: reticulocyte count (RC), nucleated red blood cell (NRBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), - Other PD parameters: erythropoietin (EPO).

[0268] Efficacy analysis for part 1 TGA dose escalation: - The percentage of participants with hematological improvement in the erythroid series (HI - E), hematological improvement in platelets (HI - P), and hematological improvement in neutrophils (HI - N) as defined by Cheson et al., 2006 is estimated with 95% CI. - The mean change from baseline in Hgb values over the 4-week treatment period is descriptively summarized. - The percentage of participants with a ≥50% reduction in transfusion burden compared to baseline in any 8-week window during the treatment period is estimated. - The percentage of participants with complete response (CR) or partial response (PR) as defined for myelodysplastic syndromes by Cheson et al., 2006 or, where applicable, for MDS / MPN overlap syndromes by Savona et al., 2015 is estimated with 95% CI. - The progression-free survival (PFS) defined as the interval from the first dose of Compound A to the first documentation of definitive disease progression (as defined for myelodysplastic syndromes by Cheson et al., 2006 or for MDS / MPN overlap syndromes by Savona et al., 2015) or death from any cause is estimated using the Kaplan-Meier method. - The leukemia-free survival (LFS) defined as the interval from the first dose of Compound A to the first documented leukemic transformation (≥20% blasts percentage in bone marrow or peripheral blood at any point during the study) or death from any cause is estimated using the Kaplan-Meier method. - For transfused-dependent (TD) participants at screening: ○ The percentage of participants with a decrease in the absolute number of ≥4 RBC transfusions / 8-week RBC transfusion units compared to pre-treatment transfusions in the previous 8 (eight) weeks as per Cheson et al., 2006 and, where applicable, is estimated. ○ The percentage of participants with red blood cell transfusion independence (RBC-TI) defined as no RBC transfusions for at least consecutive 8 weeks during the treatment period is estimated.

[0269] Safety analysis for Part 2 TGB and TGC dose escalation: The safety of Compound A administered in combination with ruxolitinib is descriptively analyzed using the following parameters for each treatment group and dose level in the safety analysis population: - Frequency, duration, and severity of AE and SAE - Changes in vital signs, ECG, and physical examinations, - Changes in clinical blood and urine test parameters.

[0270] Part 2 Efficacy analysis for TGB and TGC dose escalation: - Anemia response ○ Duration of anemia response defined as follows · For baseline TI participants, the earliest date of disappearance of anemia response lasting at least 4 (four) weeks from the first onset of Hgb increase ≥ 1.5 g / dL for ≥ 12 weeks, or the interval until death from any cause, or · For baseline TD participants, the transfusion independence period is defined as the interval from the date of the first onset of transfusion independence to the date of the earliest onset of transfusion dependence or death from any cause is estimated at 95% CI separately for baseline transfusion-dependent (TD) and transfusion-independent (TI) participants using the Kaplan-Meier method. - The mean change from baseline in Hgb values over the 12-week treatment period is descriptively summarized. - RBC transfusion rate at weeks 24 to 48 defined as the mean number of RBC units per month for participants during treatment. The proportion of participants receiving RBC transfusions is estimated for each month after the baseline period, and the total number of RBC units received per participant is calculated for each month after the baseline period. - The 24-week spleen response rate (SSR24) defined as the proportion of participants achieving a ≥ 35% decrease in spleen volume at week 24 relative to baseline, measured by MRI or CT scan, is estimated at 95% CI. - The spleen length response defined as the proportion of participants achieving a ≥ 50% decrease in spleen length at any visit relative to baseline, measured by palpation, is estimated. - The percentage of participants achieving a ≥50% decrease in total symptom score (TSS) at week 24 relative to baseline, as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 form (Gwaltney et al., 2017), is estimated, defined as the symptom response rate at week 24. - The percentage of participants with CR or PR according to the definition of Tefferi et al., 2013 is estimated with 95% CI. - The morphological effects of the combination of Compound A and ruxolitinib on the bone marrow are summarized descriptively. - The progression-free survival (PFS), defined as the interval from the first dose of the study treatment to the first documentation of definitive disease progression or death from any cause, as per the definition of Tefferi et al., 2013, is estimated by the Kaplan-Meier method. - The leukemia-free survival (LFS), defined as the interval from the first dose of Compound A to the first documented leukemic transformation or death from any cause, is estimated by the Kaplan-Meier method.

[0271] For PFS, the earliest time at which any event was observed is as follows: - For splenomegaly, the date of progression is the date of the first MRI showing an increase in spleen volume of 25% or more compared to the lowest value during the study (the mid-study period includes the baseline assessment). - For splenic irradiation, splenectomy, or death, the date of progression is the actual date of the event. - For leukemic transformation: ○ Determined by a myeloblast count of 20% or more, and the date of progression is the date of the bone marrow aspiration or biopsy, if applicable. ○ Determined by the peripheral blast count, and the date of progression is the date of the first peripheral blast count of 20% or more confirmed by bone marrow aspiration / biopsy after a sustained high blast count [i.e., no number <20% in between] lasting 8 (8) weeks.

[0272] Safety analysis for Part 2 TGB and TGC dose escalation: The safety assessment is the same as that in the dose-escalation part.

[0273] (Example 3) Additional clinical protocol for MF-induced anemia This study is a phase 1 / 2, open-label, multi-center, dose-escalation and expansion study to evaluate compound A alone (treatment group A [TGA]) or in combination with ruxolitinib (treatment group B [TGB]) in patients with MF who are transfusion-dependent or have symptomatic anemia. For TGA, patients must have been intolerant, resistant, refractory, or lost response to previous therapy with a Janus kinase inhibitor (≥ 12 weeks) and have an intermediate-2 or high risk classification according to the Dynamic International Prognostic Scoring System (DIPSS). For TGB, patients must have received a therapeutic and stable regimen of ruxolitinib for ≥ 12 consecutive weeks prior to the first dose of the study treatment and have an intermediate-1 or -2, or high DIPSS risk classification. To be eligible, patients must be ≥ 18 years old, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 during the dose-escalation phase or 0-2 during the dose-expansion phase, have a life expectancy > 6 months, and have histologically confirmed primary or secondary (post-polycythemia vera, post-essential thrombocythemia) MF.

[0274] Patients are ineligible if they have any other hematologic malignancy, have received any previous allogeneic or autologous stem cell transplantation, have undergone major surgery within 28 days of the first dose of the study drug, or have received previous chemotherapy, immunomodulatory drugs, immunosuppression, biologic, endocrine, or targeted chemotherapy, or antibody / methylation inhibitors within 5 half-lives or within 28 days prior to the first dose of the study drug.

[0275] In Part 1 (dose escalation) of the study, patients are enrolled in TGA or TGB. Monotherapy with Compound A is orally administered at a starting dose of 50 mg / day in TGA (28-day cycle). The dose escalation phase uses a Bayesian optimal interval design to determine the maximum tolerated dose (MTD), with dose increases not exceeding 100% (doubling) until treatment-related toxicity grade ≥2 is observed. Dose escalation in TGB starts 2 dose levels below the maximum evaluated dose (recommended dose for expansion [RDE]) determined to be safe and tolerable in TGA, and patients in TGB receive Compound A in combination with ruxolitinib. In each treatment group in Part 1, ≤24 patients are treated in the dose escalation phase. In Part 2 (dose expansion), the RDE in TGB is evaluated in approximately 25 patients in combination with ruxolitinib. Patients receive treatment for up to 12 months, and treatment may continue if the patient is deriving clinical benefit and has no evidence of progressive disease.

[0276] The primary study objective is to determine the safety and tolerability of monotherapy with Compound A or in combination with ruxolitinib (as determined by the frequency and severity of adverse events [AE], physical examinations, and monitoring of vital signs and laboratory values, as well as identification of dose-limiting toxicity, MTD, and RDE for TGB). The secondary objectives are to determine the efficacy of monotherapy with Compound A or in combination with ruxolitinib (as determined by anemia response, duration of anemia response, mean change from baseline in hemoglobin, and RBC transfusion rate at weeks 24 to 48), to evaluate the pharmacokinetics of Compound A, and to evaluate the effect of Compound A as monotherapy or in combination with ruxolitinib on hepcidin levels, iron homeostasis, and erythropoiesis.

[0277] The disclosed subject matter should not be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure will become apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0278] All references (e.g., publications or patents or patent applications) cited in this specification are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) were specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. An ALK2 inhibitor or a pharmaceutically acceptable salt thereof, and a JAK2 inhibitor having the formula I, for use in the treatment of cancer in a subject in need thereof: 【Chemical 1】 (wherein, R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1～4 alkyl R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1～4 alkyl, and C 1～4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof A combination therapy composition comprising: The ALK2 inhibitor is a compound of formula II: [Chemical 2] (wherein, R 1 is an unsubstituted, or monosubstituted, disubstituted or trisubstituted by hydroxyl or C 1 to C 3 alkoxy bridged 5- to 10-membered cycloalkyl, R 2 is selected from the group consisting of C 1 to C 3 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, C 1 to C 3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are unsubstituted or substituted with R 3 and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 to C 3 alkyl, and SO 3 H) or a pharmaceutically acceptable salt thereof A combination therapy composition as described above.)

2. R in formula I 1 , R 2 and R 3 are all hydrogen, and R 4 in formula I is cyano, the combination therapy composition according to claim 1.

3. The combination therapy composition according to claim 1 or 2, wherein the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

4. The combination therapy composition according to any one of claims 1 to 3, wherein the JAK2 inhibitor of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

5. R in formula II 1 is a crosslinked C 8 -cycloalkyl substituted with hydroxy, the combination therapy composition according to any one of claims 1 to 4.

6. R in formula II 2 The combination therapy composition according to any one of claims 1 to 5, wherein 2 is tetrahydropyranyl.

7. The combination therapy composition according to any one of claims 1 to 6, wherein the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

8. The combination therapy composition according to claim 7, wherein the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

9. The combination therapy composition according to claim 7, wherein the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

10. The combination therapy composition according to any one of claims 1 to 9, wherein the ALK2 inhibitor and the JAK2 inhibitor are administered in a single formulation.

11. The combined therapy composition according to claim 10, further comprising a pharmaceutically acceptable carrier.

12. The combined therapy composition according to any one of claims 1 to 9, wherein the ALK2 inhibitor and the JAK2 inhibitor are administered separately.

13. The combined therapy composition according to any one of claims 1 to 12, wherein the cancer is a myeloproliferative neoplasm or myelodysplastic syndrome.

14. The combined therapy composition according to claim 13, wherein the cancer is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, atypical chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).

15. The combined therapy composition according to claim 13 or 14, wherein the cancer is myelofibrosis (MF).

16. The combined therapy composition according to any one of claims 13 to 15, wherein the cancer is selected from the group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.

17. The combined therapy composition according to any one of claims 1 to 16, wherein the subject is human.

18. The combined therapy composition according to any one of claims 1 to 17, wherein the treatment comprises simultaneously administering an ALK2 inhibitor and a JAK2 inhibitor.

19. The combined therapy composition according to any one of claims 1 to 9 and 12 to 17, wherein the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at different times.

20. The combined therapy composition according to claim 19, wherein the ALK2 inhibitor is administered to the subject, followed by the administration of the JAK2 inhibitor.

21. The combined therapy composition according to claim 19, wherein the JAK2 inhibitor is administered to the subject, followed by the administration of the ALK2 inhibitor.

22. The combined therapy composition according to any one of claims 1 to 21, wherein the ALK2 inhibitor and / or the JAK2 inhibitor is administered at a dose that is ineffective when one or both of the ALK2 inhibitor and the JAK2 inhibitor are administered alone, but is effective in the combination.

23. A combination therapy composition for use in the treatment of cancer in a subject in need thereof, comprising 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

24. (i) A JAK2 inhibitor having the formula I: [Chemical Formula 3] (wherein, R 1 , R 2 and R 3 are independently selected from the group consisting of hydrogen, halo, and C 1～4 alkyl, R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1～4 alkyl, and C 1～4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof, and (ii) An ALK2 inhibitor having the formula II: [Chemical Formula 4] (wherein, R 1 is an unsubstituted, or 1, 2, or 3 - substituted by hydroxyl or C 1 -C 3 alkoxy cross - linked 5 - to 10 - membered cycloalkyl, R 2 is selected from the group consisting of C 1 to C 3 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, C 1 to C 3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are unsubstituted or substituted with R 3 and is R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 to C 3 alkyl, and SO 3 H) or a pharmaceutically acceptable salt thereof A pharmaceutical combination composition comprising.

25. The pharmaceutical combination composition according to claim 24, wherein the JAK2 inhibitor is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical combination composition according to claim 24 or 25, wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

27. The pharmaceutical combination composition according to any one of claims 24 to 26, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical combination composition according to any one of claims 24 to 27, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical combination composition according to any one of claims 24 to 27, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

30. An ALK2 inhibitor, a pharmaceutically acceptable carrier, and a JAK2 inhibitor having the formula I: [Chemical Formula 5] (In the formula, R 1 、 R 2 and R 3 and R 1～4 are independently selected from the group consisting of hydrogen, halo, and C R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1～4 alkyl, and C 1～4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof comprising a pharmaceutical composition, wherein the ALK2 inhibitor is a compound of formula II: 【Chemical Formula 6】 (In the formula, R 1 is an unsubstituted, or 1, 2, or 3 times substituted by hydroxyl or C 1 -C 3 alkoxy crosslinked 5- to 10-membered cycloalkyl, R 2 is selected from the group consisting of C 1 to C 3 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, C 1 to C 3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are unsubstituted or substituted with R 3 and R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 to C 3 alkyl, and SO 3 H) or a pharmaceutically acceptable salt thereof which is a pharmaceutical composition.

31. R in formula I 1 , R 2 and R 3 are all hydrogen, and R 4 in formula I is cyano, the pharmaceutical composition according to claim 30.

32. The pharmaceutical composition according to claim 30 or 31, wherein the JAK2 inhibitor is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

33. The pharmaceutical composition according to any one of claims 30 to 32, wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof.

34. R in formula II 1 is a crosslinked C 8 -cycloalkyl substituted with hydroxyl, the pharmaceutical composition according to any one of claims 30 to 33.

35. R in formula II 2 The pharmaceutical composition according to any one of claims 30 to 34, wherein 2 is tetrahydropyranyl.

36. The pharmaceutical composition according to any one of claims 30 to 35, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

37. The pharmaceutical composition according to any one of claims 30 to 36, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition according to any one of claims 30 to 36, wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

39. A JAK2 inhibitor having the formula I: 【Chemical Formula 7】 (wherein, R 1 、 R 2 and R 3 、 are independently selected from the group consisting of hydrogen, halo, and C 1～4 alkyl, R 4 is selected from the group consisting of hydrogen, halo, cyano, nitro, hydroxy, C 1～4 alkyl, and C 1～4 alkoxy, Z is 3- to 6-membered cycloalkyl) or a pharmaceutically acceptable salt thereof, and a compound of formula II: [Chemical Formula 8] (wherein, R 1 is an unsubstituted, or 1, 2, or 3 times substituted by hydroxyl or C 1 to C 3 alkoxy crosslinked 5- to 10-membered cycloalkyl, R 2 is selected from the group consisting of C 1 to C 3 alkyl, C 2 to C 4 alkenyl, C 2 to C 4 alkynyl, C 1 to C 3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are unsubstituted or substituted with R 3 and, R 3 is selected from the group consisting of hydroxy, halo, cyano, nitro, SO 2 -C 1 to C 3 alkyl, and SO 3 H) or a pharmaceutically acceptable salt thereof A composition for use in a method of treating myelofibrosis (MF)-induced anemia, comprising an ALK2 inhibitor which is as defined above.

40. The composition according to claim 39, wherein the JAK2 inhibitor of formula I is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor of formula II is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt or hydrate thereof.

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