Treatment of aplastic anemia (AA)

Abstract

The present invention describes a combination of a suitable prolyl hydroxylase inhibitor and a suitable thrombopoietin (TPO) receptor agonist for use in the treatment of aplastic anemia (AA). The invention also describes the preparation of such combinations and compositions thereof.

Description

Technical Field

[0001] The present invention describes a combination of a suitable prolyl hydroxylase inhibitor and a suitable thrombopoietin (TPO) receptor agonist for use in treating aplastic anemia (AA). The present invention also describes the preparation of such combination and its composition. Background Art

[0002] Aplastic anemia (AA) is a rare disease characterized by suppression of bone marrow function leading to progressive pancytopenia. 1 The most common cause of aplastic anemia is the immune system attacking stem cells in the bone marrow. Radiation and chemotherapy are other factors that can damage the bone marrow and affect blood cell production. 2 The diagnosis results showed that the hemoglobin level was less than 10 g / dl and the neutrophil level was less than 1.5 × 10 9 / L and platelet count is less than 50×10 9 / L. 3 The megakaryocyte pattern may help differentiate MDS from AA, as megakaryocytes are often reduced / absent in AA, whereas small or abnormal megakaryocytes are typical of myelodysplastic syndrome (MDS). 4 Clinical consequences are anemia, often requiring frequent red blood cell transfusions, thrombocytopenia leading to life-threatening bleeding, and neutropenia leading to infection. Bacterial and fungal infections are important causes of morbidity and mortality. 5

[0003] The standard treatment for aplastic anemia is hematopoietic stem cell transplantation in young, healthy patients with a suitable donor, followed by immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine. Thrombopoietin analogs (TPO agonists) have recently emerged as an encouraging and promising drug for the treatment of AA patients. This class of drugs has been shown to be effective in restoring trilineage hematopoiesis. Thrombopoietin (TPO) receptor agonists are the main regulator of platelet production, and their receptors (c-Mpl) are present in megakaryocytes and hematopoietic stem cells. 6 Thrombopoietin (TPO) receptor agonists include intravenous peptidomim and oral small molecules such as eltrombopag, avatrombopag, and lusutrombopag. 7

[0004] Eltrombopag bisethanolamine, chemical name 3'-(2-(l-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazole-4-methylene)hydrazino)-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid 2-hydroxy-N,N,N-trimethylethane-1-ammonium (1:1).

[0005] Eltrombopag is a small molecule, non-peptide thrombopoietin (TPO) receptor agonist that has been shown in preclinical studies and clinical trials to stimulate the proliferation and differentiation of megakaryocytes (bone marrow cells that produce platelets).

[0006] Eltrombopag bisethanolamine is a marketed drug (United States) or (EU) is an active ingredient for the treatment of chronic immune thrombocytopenia (CIT) in patients with insufficient response to corticosteroids, immunoglobulins or splenectomy. It is also suitable for the treatment of thrombocytopenia in patients with chronic hepatitis C and severe aplastic anemia. Eltrombopag is disclosed in U.S. Patent No. 7,160,870. Eltrombopag bisethanolamine salt is disclosed in U.S. Patent No. 7,547,719. Eltrombopag tromethamine salt is disclosed in International Patent Publication No. WO20170042839. International Patent Publication No. WO20190071111 and U.S. Patent No. 11,072,586 disclose crystalline forms of Eltrombopag choline.

[0007] Romiplostim is an active ingredient of the marketed drug Nplate. It is a thrombopoietin receptor agonist used to treat thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have an inadequate response to corticosteroids, immunoglobulins or splenectomy. Romiplostim is disclosed in U.S. Pat. No. 9,145,450 and WO2000 / 24770.

[0008] Desidustat (a compound of formula (Ia)), a small molecule hypoxia-inducible factor stabilizer, inhibits prolyl hydroxylases and exhibits hematogenic potential through a combined effect on endogenous erythropoietin release and effective iron utilization. It also enhances erythrocyte maturation by inhibiting the hepcidin-iron transporter axis. 8

[0009] Several other prolyl hydroxylase inhibitors are disclosed in EP661269, WO2007070359, WO2008076425, WO2011007856, WO2012106472 and WO2013043621. In particular, WO2004108681 and WO2008002576 cover prolyl hydroxylase inhibitors named Roxadustat and Vadadustat, respectively.

[0010] WO2014102818 discloses a compound of the following general formula

[0011]

[0012] These compounds are reported to be useful in the treatment of anemia. It has now been surprisingly found that compounds of formula (Ia) given below:

[0013]

[0014] The combination of the pharmaceutically acceptable salt thereof and a suitable TPO receptor agonist can effectively treat aplastic anemia, improve two hematopoietic precursor cell lineages, and benefit patients. In addition, the combination with cyclosporin will be useful. Summary of the invention

[0015] The present invention describes a combination of a suitable prolyl hydroxylase inhibitor or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist.

[0016] The present invention describes a combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist.

[0017] In one embodiment, the present invention provides a combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist for use in treating aplastic anemia (AA).

[0018] In a further embodiment, a pharmaceutical composition is provided, comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist and at least one suitable pharmaceutically acceptable carrier, diluent, vehicle or excipient for the treatment of aplastic anemia (AA).

[0019] In another embodiment, the present invention provides a use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in combination with a suitable thrombopoietin (TPO) receptor agonist for treating aplastic anemia (AA).

[0020] In one embodiment, the present invention provides a method of treating aplastic anemia (AA) using a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment, the present invention provides a combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist and optionally a cyclosporine. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Shown are the effects of formula (Ia), romiplostim and the combination thereof on leukocytes (A) and platelets (B) in busulfan-induced aplastic anemia in Balb / c mice.

[0023] Figure 2 Shown are the effects of Formula (Ia) and its combination with romiplostim on leukocytes (A) and platelets (B) in cyclophosphamide-induced aplastic anemia in C57 mice. DETAILED DESCRIPTION

[0024] Summary of the Invention

[0025] The present invention describes a combination of a suitable prolyl hydroxylase inhibitor and a suitable thrombopoietin (TPO) receptor agonist for the treatment of aplastic anemia (AA). The present invention also describes the preparation of such combination and composition thereof.

[0026] Description of the Invention

[0027] definition:

[0028] The term "treatment" or "treat" refers to slowing, stopping or delaying the progression of a disease or clinical symptom in a patient, as evidenced by a reduction or elimination of clinical or diagnostic symptoms of a disease, disorder or condition. The term "subject" refers to humans and animals. The term "effective amount" in this context refers to the amount of drug administered sufficient to produce the desired effect. The term "pharmaceutically acceptable" is used to cover both human and veterinary use. The compound of formula (Ia) is Desidustat.

[0029] Combination of a suitable prolyl hydroxylase inhibitor and a suitable thrombopoietin (TPO) receptor agonist

[0030] In one embodiment, the present invention describes a combination of a suitable prolyl hydroxylase inhibitor and a suitable thrombopoietin (TPO) receptor agonist.

[0031] Suitable prolyl hydroxylase inhibitors are selected from Roxadustat, Vadadustat, Daprodustat, Molidustat, Enardust and a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0032] Suitable thrombopoietin (TPO) receptor agonists are romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

[0033] Combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof with a suitable thrombopoietin (TPO) receptor agonist

[0034] In one embodiment, the present invention provides a combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist, wherein formula (Ia) is represented by:

[0035]

[0036] The pharmaceutically acceptable salt of the compound of formula (Ia) may be selected from suitable inorganic metal salts or organic amine salts.

[0037] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium, and the like.

[0038] The organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tri-(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2 -Butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, daneol, hydrabamine, betaine, amantadine, L-amantadine, triphenylamine, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

[0039] Suitable thrombopoietin (TPO) receptor agonists are romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

[0040] Dosage

[0041] The above combinations may be administered by oral, rectal, topical, nasal, pulmonary, ocular, enteral or parenteral routes.

[0042] The effective amount (e.g., dosage) of the combined compound or drug can be easily determined by routine experiments, as can effective and convenient routes of administration and suitable formulations. A variety of formulations and drug delivery systems are available in the art (e.g., see Gennaro, ed. (2000) Remington's Pharmaceutical Sciences; and Hardman, Limbird, and Gilman, eds. (2001) The Pharmacological Basis of Therapeutics, supra.).

[0043] Suitable routes of administration can include, for example, oral, rectal, topical, nasal, pulmonary, eye, intestinal and parenteral administration. The main routes of parenteral administration include intravenous administration, intramuscular administration and subcutaneous administration. Minor routes of administration include intraperitoneal, intraarterial, intraarticular, intracardiac, intracisternal, intradermal, intralesional, intraocular, intrapleural, intrathecal, intrauterine and intraventricular administration. The physical, chemical and biological properties of the indication to be treated and the medicine determine the type of preparation to be used and the route of administration, and whether to give priority to topical administration or systemic administration.

[0044] In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose in the range of 1 mg to 500 mg, or in the range of 50 mg to 450 mg, or in the range of 100 mg to 400 mg, or in the range of 150 mg to 350 mg, or in the range of 200 mg to 300 mg, or in the range of 1 mg to 50 mg, or in the range of 1 mg to 25 mg. In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject, providing the compound of formula (Ia) or a pharmaceutically acceptable salt thereof at a dose of 1 mg to 150 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose of 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 7.5 mg, or 7.5 mg to 10 mg, or 10 mg to 12.5 mg, or 12.5 mg to 15 mg, or 15 mg to 17.5 mg, or 17.5 mg to 20 mg, or 20 mg to 22.5 mg, or 22.5 mg to 25 mg, or 25 mg to 30 mg, or 30 mg to 35 mg, or 35 mg to 40 mg, or 40 mg to 45 mg, or 45 mg to 50 mg, or 50 mg to 55 mg, or 55 mg to 60 mg, or 60 mg to 65 mg, or 65 mg to 70 mg, or 70 mg to 75 mg, or 75 mg to 80 mg, or 80 mg to 85 mg, or 85 mg to 90 mg, or 90 mg to 95 mg, or 95 mg to 100 mg.

[0045] In a further embodiment, eltrombopag is orally administered to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment, avatrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, rutrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg.

[0046] In further embodiments, eltrombopag is orally administered to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg, and 100 mg. In further embodiments, avatrombopag is orally administered to a subject in an amount of about 20 mg. In further embodiments, rutrombopag is orally administered to a subject in an amount of about 3 mg.

[0047] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is parenterally administered to a subject at a dose ranging from 1 mg to 50 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

[0048] In further embodiments, romiplostim is administered parenterally to a subject at a dose of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg, about 150 μg to about 350 μg, about 200 μg to about 300 μg.

[0049] In a certain embodiment, romiplostim is administered parenterally to a subject at a dose of about 125 μg, 250 μg, and 500 μg. In a further embodiment.

[0050] In certain embodiments, the combination of a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist can be further characterized by the dose of the compound administered to a subject, wherein the subject is an animal or a human.

[0051] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered as a composition. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered continuously. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.

[0052] A method for treating aplastic anemia (AA) by combining a compound of formula (Ia) or a pharmaceutically acceptable salt thereof with a suitable thrombopoietin (TPO) receptor agonist

[0053] In one embodiment, the present invention provides a method of treating aplastic anemia (AA) in a subject, comprising administering a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in combination with a suitable thrombopoietin (TPO) receptor agonist.

[0054] The pharmaceutically acceptable salt of the compound of formula (Ia) may be selected from suitable inorganic metal salts or organic amine salts.

[0055] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium, and the like.

[0056] The organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tri-(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2 -Butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, daneol, hydrabamine, betaine, amantadine, L-amantadine, triphenylamine, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

[0057] Suitable thrombopoietin (TPO) receptor agonists are romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

[0058] The above combinations may be administered by oral, rectal, topical, nasal, pulmonary, ocular, enteral or parenteral routes.

[0059] In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose in the range of 1 mg to 500 mg, or in the range of 50 mg to 450 mg, or in the range of 100 mg to 400 mg, or in the range of 150 mg to 350 mg, or in the range of 200 mg to 300 mg, or in the range of 1 mg to 50 mg, or in the range of 1 mg to 25 mg. In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject, providing the compound of formula (Ia) or a pharmaceutically acceptable salt thereof at a dose of 1 mg to 150 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose of 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 7.5 mg, or 7.5 mg to 10 mg, or 10 mg to 12.5 mg, or 12.5 mg to 15 mg, or 15 mg to 17.5 mg, or 17.5 mg to 20 mg, or 20 mg to 22.5 mg, or 22.5 mg to 25 mg, or 25 mg to 30 mg, or 30 mg to 35 mg, or 35 mg to 40 mg, or 40 mg to 45 mg, or 45 mg to 50 mg, or 50 mg to 55 mg, or 55 mg to 60 mg, or 60 mg to 65 mg, or 65 mg to 70 mg, or 70 mg to 75 mg, or 75 mg to 80 mg, or 80 mg to 85 mg, or 85 mg to 90 mg, or 90 mg to 95 mg, or 95 mg to 100 mg.

[0060] In a further embodiment, eltrombopag is orally administered to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment, avatrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, rutrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg.

[0061] In further embodiments, eltrombopag is orally administered to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg, and 100 mg. In further embodiments, avatrombopag is orally administered to a subject in an amount of about 20 mg. In further embodiments, rutrombopag is orally administered to a subject in an amount of about 3 mg.

[0062] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is parenterally administered to a subject at a dose ranging from 1 mg to 50 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

[0063] In further embodiments, romiplostim is administered parenterally to a subject at a dose of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg, about 150 μg to about 350 μg, about 200 μg to about 300 μg.

[0064] In a certain embodiment, romiplostim is administered parenterally to a subject at a dose of about 125 μg, 250 μg, and 500 μg. In a further embodiment.

[0065] In certain embodiments, the combination of a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist can be further characterized by the dose of the compound administered to a subject, wherein the subject is an animal or a human.

[0066] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered as a composition. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered continuously. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.

[0067] A compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist for use in treating aplastic anemia (AA)

[0068] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist, optionally with one or more pharmaceutically acceptable excipients, for the treatment of aplastic anemia (AA).

[0069] The pharmaceutically acceptable salt of the compound of formula (Ia) may be selected from suitable inorganic metal salts or organic amine salts.

[0070] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium, and the like.

[0071] The organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tri-(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2 -Butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, daneol, hydrabamine, betaine, amantadine, L-amantadine, triphenylamine, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

[0072] Suitable thrombopoietin (TPO) receptor agonists are romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

[0073] The pharmaceutical compositions mentioned in the above embodiments may be in oral, rectal, topical, nasal, pulmonary, ocular, enteral or parenteral form.

[0074] Oral dosage form:

[0075] The pharmaceutical composition is in oral form.

[0076] The pharmaceutical oral compositions as described above or anywhere else in this specification may be in the form of tablets, capsules and oral liquids.

[0077] The pharmaceutically acceptable excipient is selected from at least one of a diluent, a binder, a disintegrant, a lubricant, a glidant, a sweetener, a pH adjuster, a suspending agent or a viscosity adjuster, a flavoring agent, and an optional premix coating agent.

[0078] Diluents include, but are not limited to, lactose monohydrate, lactose, microcrystalline cellulose, polymethacrylates selected from Eudragit, potassium chloride, sulfobutyl ether b-cyclodextrin, sodium chloride, spray-dried lactose, and preferably sulfobutyl ether b-cyclodextrin, and combinations thereof and other such materials known to those of ordinary skill in the art.

[0079] Binders include, but are not limited to, hypromellose 3Cps, carbomer selected from Carbopol, gellan gum, gum arabic, hydrogenated vegetable oils, polymethacrylate selected from Eudragit, xanthan gum, a combination of lactose and zein, and other such materials known to those of ordinary skill in the art.

[0080] Disintegrants include, but are not limited to, croscarmellose sodium, bicarbonate, chitin, gellan gum, polacrilin potassium, and docusate sodium, and combinations thereof, and other such materials known to those of ordinary skill in the art.

[0081] Glidants include, but are not limited to, colloidal silicon dioxide, calcium silicate, magnesium silicate, silica hydrogel, corn starch, talc, combinations thereof, and other such materials known to those of ordinary skill in the art.

[0082] Lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate and myristic acid, suitable combinations thereof, and other such materials known to those of ordinary skill in the art.

[0083] Suitable pH adjusting agents for maintaining the pH of the formulations of the present invention include, but are not limited to, citric acid and other similar excipients and suitable combinations thereof and other materials known to those of ordinary skill in the art.

[0084] The suspending agent or viscous agent of the present invention includes, but is not limited to, microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel CL 611) and other similar excipients and suitable combinations thereof and other materials known to those of ordinary skill in the art.

[0085] Sweeteners are selected from sucrose and all such materials known to those of ordinary skill in the art.

[0086] The flavoring agent is selected from cherry flavoring, orange flavoring, mango flavoring and all fruit flavoring agents known to those of ordinary skill in the art.

[0087] The premix coating agent (coating redimix) is selected from Opadry Pink, all of which are well known to those skilled in the art.

[0088] In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose in the range of 1 mg to 500 mg, or in the range of 50 mg to 450 mg, or in the range of 100 mg to 400 mg, or in the range of 150 mg to 350 mg, or in the range of 200 mg to 300 mg, or in the range of 1 mg to 50 mg, or in the range of 1 mg to 25 mg. In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject, providing the compound of formula (Ia) or a pharmaceutically acceptable salt thereof at a dose of 1 mg to 150 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose of 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 7.5 mg, or 7.5 mg to 10 mg, or 10 mg to 12.5 mg, or 12.5 mg to 15 mg, or 15 mg to 17.5 mg, or 17.5 mg to 20 mg, or 20 mg to 22.5 mg, or 22.5 mg to 25 mg, or 25 mg to 30 mg, or 30 mg to 35 mg, or 35 mg to 40 mg, or 40 mg to 45 mg, or 45 mg to 50 mg, or 50 mg to 55 mg, or 55 mg to 60 mg, or 60 mg to 65 mg, or 65 mg to 70 mg, or 70 mg to 75 mg, or 75 mg to 80 mg, or 80 mg to 85 mg, or 85 mg to 90 mg, or 90 mg to 95 mg, or 95 mg to 100 mg.

[0089] Table 1: Stable oral pharmaceutical composition of formula (Ia)

[0090]

[0091] Suitable thrombopoietin (TPO) receptor agonists are eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof and rutrombopag or a pharmaceutically acceptable salt thereof.

[0092] In a further embodiment, eltrombopag is orally administered to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment, avatrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, rutrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg.

[0093] In further embodiments, eltrombopag is orally administered to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg, and 100 mg. In further embodiments, avatrombopag is orally administered to a subject in an amount of about 20 mg. In further embodiments, rutrombopag is orally administered to a subject in an amount of about 3 mg.

[0094] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof can be further characterized according to the dose of the compound administered to a subject, wherein the subject is an animal or a human.

[0095] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered as a composition. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered continuously. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.

[0096] Parenteral:

[0097] The pharmaceutical composition of the combination of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and romiplostim is in parenteral form.

[0098] The pharmaceutical composition of the combination of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and romiplostim may be administered by parenteral route.

[0099] In one embodiment, parenteral formulations of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof can be prepared according to methods known in the art.

[0100] The parenteral formulation of the compound of formula (Ia) or a pharmaceutically acceptable salt thereof comprises one or more pharmaceutically acceptable excipients for use in the treatment of aplastic anemia (AA).

[0101] The pharmaceutically acceptable excipient is selected from at least one of a glucose aqueous solution, a Captisol aqueous solution, a microemulsion, and a cosolvent or emulsifier for adjusting pH, and is used for treating aplastic anemia (AA).

[0102] Cosolvent or emulsifier selected from Captex TM 300. Solutol TM H15, Propylene glycol, Phospholipon TM 90G, Solutol TM HS15, dimethylacetamide with ethanol, PEG400 and N-methylpyrrolidone.

[0103] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is parenterally administered to a subject at a dose ranging from 1 mg to 50 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

[0104] A pharmaceutical composition of a suitable thrombopoietin (TPO) receptor agonist comprises one or more pharmaceutically acceptable excipients for use in treating aplastic anemia (AA).

[0105] The pharmaceutical composition as described above is in parenteral form.

[0106] A suitable thrombopoietin (TPO) receptor agonist is romiplostim or a pharmaceutically acceptable salt thereof.

[0107] The pharmaceutically acceptable excipient is selected from at least one of a buffer, a bulking agent, a stabilizer and a surfactant for treating aplastic anemia (AA).

[0108] The buffer is selected from the group consisting of glycine, histidine, glutamate, succinate, phosphate, acetate and aspartic acid.

[0109] The filler is selected from mannitol, glycine, sucrose, dextran, polyvinyl pyrrolidone, carboxymethyl cellulose, lactose, sorbitol, trehalose or xylitol.

[0110] The stabilizer is selected from sucrose, trehalose, mannose, maltose, lactose, glucose, raffinose, cellobiose, gentiobiose, isomaltose, arabinose, glucosamine, fructose, mannitol, sorbitol, glycine, arginine hydrochloride, polyols including dextran, starch, hydroxyethyl starch, cyclodextrin, N-methylpyrrolidine, cellulose and hyaluronic acid and other polysaccharides, and sodium chloride.

[0111] The surfactant is selected from sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, sodium dioctyl sulfonate, chenodeoxycholic acid, sodium N-dodecyl sarcosine, lithium dodecyl sulfate, sodium 1-octane sulfonate, sodium cholate hydrate, sodium deoxycholate, sodium glycodeoxycholate, benzalkonium chloride or benzethonium chloride, cetylpyridinium chloride monohydrate, cetyltrimethylammonium bromide, CHAPS, CHAPSO, SB3-10, SB3-12, digitonin, Triton X-100, Triton X-114, lauroyl alcohol 400, polyoxyethylene 40 stearate, polyoxyethylene hydrogenated castor oil 10, 40, 50 and 60, monostearate, polysorbate 20, 40, 60, 65 and 80, soybean lecithin, DOPC, DMPG, DMPC, DOPG; sucrose fatty acid esters, methylcellulose, carboxymethylcellulose.

[0112] In further embodiments, romiplostim is administered parenterally to a subject at a dose of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg, about 150 μg to about 350 μg, about 200 μg to about 300 μg.

[0113] In certain embodiments, romiplostim is administered parenterally to a subject at a dose of about 125 μg, 250 μg, and 500 μg.

[0114] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof can be further characterized according to the dose of the compound administered to a subject, wherein the subject is an animal or a human.

[0115] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and romiplostim are administered as a composition. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and romiplostim are administered separately. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and romiplostim are administered continuously. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and romiplostim are administered simultaneously.

[0116] Parenteral formulations can be administered subcutaneously, intramuscularly, intravenously, and intrathecally.

[0117] Compounds of formula (Ia) or pharmaceutically acceptable salts thereof and suitable thrombopoietin (TPO) receptor agonists for treating aplastic anemia (AA)

[0118] In one embodiment, the present invention provides a use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in combination with a suitable thrombopoietin (TPO) receptor agonist for treating aplastic anemia (AA).

[0119] The pharmaceutically acceptable salt of the compound of formula (Ia) may be selected from suitable inorganic metal salts or organic amine salts.

[0120] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium, and the like.

[0121] The organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tri-(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2 -Butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, daneol, hydrabamine, betaine, amantadine, L-amantadine, triphenylamine, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

[0122] Suitable thrombopoietin (TPO) receptor agonists are romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

[0123] The above combinations may be administered by oral, rectal, topical, nasal, pulmonary, ocular, enteral or parenteral routes.

[0124] In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose in the range of 1 mg to 500 mg, or in the range of 50 mg to 450 mg, or in the range of 100 mg to 400 mg, or in the range of 150 mg to 350 mg, or in the range of 200 mg to 300 mg, or in the range of 1 mg to 50 mg, or in the range of 1 mg to 25 mg. In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject, providing the compound of formula (Ia) or a pharmaceutically acceptable salt thereof at a dose of 1 mg to 150 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is for oral administration to a subject at a dose of 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 7.5 mg, or 7.5 mg to 10 mg, or 10 mg to 12.5 mg, or 12.5 mg to 15 mg, or 15 mg to 17.5 mg, or 17.5 mg to 20 mg, or 20 mg to 22.5 mg, or 22.5 mg to 25 mg, or 25 mg to 30 mg, or 30 mg to 35 mg, or 35 mg to 40 mg, or 40 mg to 45 mg, or 45 mg to 50 mg, or 50 mg to 55 mg, or 55 mg to 60 mg, or 60 mg to 65 mg, or 65 mg to 70 mg, or 70 mg to 75 mg, or 75 mg to 80 mg, or 80 mg to 85 mg, or 85 mg to 90 mg, or 90 mg to 95 mg, or 95 mg to 100 mg.

[0125] In a further embodiment, eltrombopag is orally administered to a subject in an amount of about 1 mg to about 500 mg. In a further embodiment, avatrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg. In a further embodiment, rutrombopag is orally administered to a subject in an amount of about 1 mg to 100 mg.

[0126] In further embodiments, eltrombopag is orally administered to a subject in an amount of about 12.5 mg, 25 mg, 50 mg, 75 mg, and 100 mg. In further embodiments, avatrombopag is orally administered to a subject in an amount of about 20 mg. In further embodiments, rutrombopag is orally administered to a subject in an amount of about 3 mg.

[0127] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is parenterally administered to a subject at a dose ranging from 1 mg to 50 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22.5 mg to 25 mg or 27.5 mg to 30 mg or 30 mg to 32.5 mg or 32.5 mg to 35 mg or 35 mg to 37.5 mg or 37.5 mg to 40 mg or 40 mg to 42.5 mg or 42.5 mg to 45 mg or 45 mg to 47.5 mg or 47.5 mg to 50 mg. In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof is used for parenteral administration to a subject at a dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

[0128] In further embodiments, romiplostim is administered parenterally to a subject at a dose of about 1 μg to about 500 μg, about 50 μg to about 450 μg, about 100 μg to about 400 μg, about 150 μg to about 350 μg, about 200 μg to about 300 μg.

[0129] In a certain embodiment, romiplostim is administered parenterally to a subject at a dose of about 125 μg, 250 μg, and 500 μg. In a further embodiment.

[0130] In certain embodiments, the combination of a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist can be further characterized by the dose of the compound administered to a subject, wherein the subject is an animal or a human.

[0131] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered as a composition. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered separately. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered continuously. In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt and a suitable thrombopoietin (TPO) receptor agonist are administered simultaneously.

[0132] Methods for treating aplastic anemia (AA) using compounds of formula (Ia)

[0133] In one embodiment, the present invention provides a method of treating aplastic anemia (AA) in a subject, comprising administering an effective amount of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

[0134] The pharmaceutically acceptable salt of the compound of formula (Ia) may be selected from suitable inorganic metal salts or organic amine salts.

[0135] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium, and the like.

[0136] The organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tri-(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2 -Butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, daneol, hydrabamine, betaine, amantadine, L-amantadine, triphenylamine, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

[0137] In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used to be administered to a subject at a dose in the range of 1 mg to 500 mg, or in the range of 50 mg to 450 mg, or in the range of 100 mg to 400 mg, or in the range of 150 mg to 350 mg, or in the range of 200 mg to 300 mg, or in the range of 1 mg to 50 mg, or in the range of 1 mg to 25 mg. In certain embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used to be administered to a subject, providing the compound of formula (Ia) or a pharmaceutically acceptable salt thereof at a dose of 1 mg to 150 mg. In a further embodiment, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is used to administer to a subject at a dose of 1 mg to 2.5 mg, or 2.5 mg to 5 mg, or 5 mg to 7.5 mg, or 7.5 mg to 10 mg, or 10 mg to 12.5 mg, or 12.5 mg to 15 mg, or 15 mg to 17.5 mg, or 17.5 mg to 20 mg, or 20 mg to 22.5 mg, or 22.5 mg to 25 mg, or 25 mg to 30 mg, or 30 mg to 35 mg, or 35 mg to 40 mg, or 40 mg to 45 mg, or 45 mg to 50 mg, or 50 mg to 55 mg, or 55 mg to 60 mg, or 60 mg to 65 mg, or 65 mg to 70 mg, or 70 mg to 75 mg, or 75 mg to 80 mg, or 80 mg to 85 mg, or 85 mg to 90 mg, or 90 mg to 95 mg, or 95 mg to 100 mg.

[0138] In certain embodiments, the compound of Formula (Ia) or a pharmaceutically acceptable salt thereof can be further characterized according to the dose of the compound administered to a subject, wherein the subject is an animal or a human.

[0139] The composition of formula (Ia) or a pharmaceutically acceptable salt thereof can be prepared as disclosed anywhere in the present specification.

[0140] A compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist (optionally used in combination with cyclosporine)

[0141] Suitable thrombopoietin (TPO) receptor agonists are eltrombopag or a pharmaceutically acceptable salt thereof, romiplostim or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

[0142] The pharmaceutically acceptable salt of the compound of formula (Ia) may be selected from suitable inorganic metal salts or organic amine salts.

[0143] The inorganic metal salt may be selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium, and the like.

[0144] The organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tri-(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2 -Butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, daneol, hydrabamine, betaine, amantadine, L-amantadine, triphenylamine, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

[0145] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist, and optionally further comprising cyclosporine.

[0146] Pharmaceutical compositions, dosage forms and routes of administration as described above or anywhere in the specification.

[0147] The compound of formula (Ia) can be prepared by any method known in the art, including those methods disclosed in the prior art, such as those methods mentioned elsewhere in this specification. Romiplostim can be prepared by any method known in the art, including those methods disclosed in the prior art, such as those methods mentioned elsewhere in this specification.

[0148] Example

[0149] The following shows the effect of the combination of a compound of formula (Ia) and a suitable thrombopoietin (TPO) receptor agonist in the treatment of an animal model of aplastic anemia (AA).

[0150] Aplastic Anemia (AA) Animal Model

[0151] Example 1: Effects of Formula (Ia), Romiplostim and Combinations Thereof on Busulfan-Induced Aplastic Anemia in Balb / c Mice

[0152] Aplastic anemia (AA) was induced by injecting BALB / c mice with busulfan (BU). BU was dissolved in acetone at a concentration of 5–10 mg / mL. Deionized water was added to the BU-acetone solution immediately before administration, and then injected intraperitoneally (ip) at a dose of 9 mg / kg. Control mice were given the same dose volume of vehicle. 9 The compound of formula (Ia) (15 mg / kg, oral, once daily) and romiplostim (50 μg / kg, subcutaneous, once weekly) were administered in combination.

[0153] The mice were dosed with vehicle or BU 10 times over 21 days (days 1, 3, 6, 8, 10, 13, 15, 17, 19, and 21). Mice from each group were necropsied and blood was drawn 1 to 127 days after the last dose of BU. 9

[0154] Changes in white blood cell (WBC) and platelet counts were measured after 44 days of treatment. Data are mean ± SEM (n = 6 per group).

[0155] Table 2. Effects of Formula (Ia) alone, romiplostim alone, and combinations thereof on white blood cells (WBC) and platelets in busulfan-induced aplastic anemia in Balb / c mice.

[0156]

[0157]

[0158] #P<0.05 compared with normal control and *P<0.05 compared with vehicle control were considered significant.

[0159] Conclusion: The combination of formula (Ia) and romiplostim significantly augmented both hematopoietic lineages in busulfan-induced aplastic anemia in Balb / c mice.

[0160] Example 2: Effects of Formula (Ia) and its combination with Romiplostim on cyclophosphamide-induced aplastic anemia in C57 mice

[0161] Aplastic anemia (AA) was induced by administration of cyclophosphamide to C57 mice. Cyclophosphamide was dissolved in deionized water at a concentration of 20 mg / mL. Deionized water was added to the stock solution immediately before administration and then injected intraperitoneally (ip) at a dose of 100 mg / kg. Mice were injected with vehicle or cyclophosphamide for 4 consecutive days. Control mice were given the same dose volume of vehicle.10 The compound of formula (Ia) (15 mg / kg, oral, once daily) and romiplostim (30 μg / kg, subcutaneous, once weekly) were administered in combination.

[0162] After 11 days of treatment, blood was collected from each group. Changes in white blood cell (WBC) and platelet counts were measured. Data are mean ± SEM (n = 6 per group).

[0163] Table 3. Effects of Formula (Ia) and its combination with romiplostim on white blood cells (WBC) and platelets in cyclophosphamide-induced aplastic anemia in C57 mice.

[0164]

[0165] #P<0.05 compared with normal control and *P<0.05 compared with vehicle control were considered significant.

[0166] Conclusion: The combination of Formula (Ia) and romiplostim significantly increased both lineage hematopoiesis in cyclophosphamide-induced aplastic anemia in C57 mice.

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[0175] 8.Joharapurkar AA,Patel VJ,Kshirsagar SG,Patel MS,Savsani HH,Kajavadara C,Valani D,Jain MR.Prolyl hydroxylase inhibitor desidustatimproves anemia in erythropoietin hyporesponsive state.Curr Res PharmacolDrug Discov.2022 Apr 30;3:100102.doi:10.1016 / j.crphar.2022.100102.PMID:35570856;PMCID:PMC9096675。

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Claims

1. A combination of a suitable prolyl hydroxylase inhibitor and a suitable thrombopoietin (TPO) receptor agonist.

2. The combination according to claim 1, wherein: Suitable prolyl hydroxylase inhibitors are selected from Roxadustat, Vadadustat, Daprodustat, Molidustat, Enardust and Formula (Ia) or a pharmaceutically acceptable salt thereof.

3. The combination according to claim 1, wherein: Suitable thrombopoietin (TPO) receptor agonists are selected from romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

4. A combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist, wherein formula (Ia) is represented by:

5. The combination according to claim 4, wherein the pharmaceutically acceptable salt of the compound of formula (Ia) is selected from a suitable inorganic metal salt or an organic amine salt; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; wherein the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-butylamine, Amine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, alanine , lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiophenylamine, (2S)-3,3-dimethyl-2-butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4-methyl phenylethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, danol, hydrabamine, betaine, amantadine, L-adamantanamine, triphenylmethane, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

6. The combination according to claim 4, wherein: Suitable thrombopoietin (TPO) receptor agonists are selected from eltrombopag or a pharmaceutically acceptable salt thereof, romiplostim or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

7. The combination according to claim 4, which can be administered orally or parenterally.

8. The combination according to claim 4, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to a subject in an amount of 1 mg to 500 mg or 50 mg to 450 mg or 100 mg to 400 mg or 150 mg to 350 mg or 200 mg to 300 mg or 1 mg to 50 mg or 1 mg to 25 mg.

9. The combination according to claim 4, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to a subject at a dose of 1 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7.5 mg to 10 mg, 10 mg to 12.5 mg, 12.5 mg to 15 mg, 15 mg to 17.5 mg, 17.5 mg to 20 mg, 20 mg to 22.5 mg, 22.5 mg to 25 mg, 25 mg to 30 mg, 30 mg to 35 mg, 35 mg to 40 mg, 40 mg to 45 mg, 45 mg to 50 mg, 50 mg to 55 mg, 55 mg to 60 mg, 60 mg to 65 mg, 65 mg to 70 mg, 70 mg to 75 mg, 75 mg to 80 mg, 80 mg to 85 mg, 85 mg to 90 mg, 90 mg to 95 mg, or 95 mg to 100 mg.

10. The combination of claim 4, wherein eltrombopag is orally administered to the subject in an amount of 1 mg to 500 mg, avatrombopag is orally administered to the subject in an amount of 1 mg to 100 mg, and rutrombopag is orally administered to the subject in an amount of 1 mg to 100 mg.

11. The combination according to claim 4, wherein eltrombopag is orally administered to the subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, avatrombopag is orally administered to the subject in an amount of 20 mg and rutrombopag is orally administered to the subject in an amount of 3 mg.

12. The combination according to claim 4, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in an amount of 1 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7.5 mg to 10 mg, 10 mg to 12.5 mg, 12.5 mg to 15 mg, 15 mg to 17.5 mg, 17.5 mg to 20 mg, 20 mg to 22.5 mg, 22.5 mg to 25 mg, 27.5 mg to 30 mg, 30 mg to 32.5 mg, 32.5 mg to 35 mg, 35 mg to 37.5 mg, 37.5 mg to 40 mg, 40 mg to 42.5 mg, 42.5 mg to 45 mg, 45 mg to 47.5 mg, or 47.5 mg to 50 mg.

13. The combination according to claim 4, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in the following amounts: 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

14. The combination according to claim 4, wherein the thrombopoietin (TPO) receptor agonist is romiplostim, which is administered parenterally to the subject in an amount of 1 μg to 500 μg, 50 μg to 450 μg, 100 μg to 400 μg, 150 μg to 350 μg, 200 μg to 300 μg.

15. The combination according to claim 4, wherein the thrombopoietin (TPO) receptor agonist is romiplostim, administered parenterally to the subject in the following amounts: 125 μg, 250 μg and 500 μg.

16. The combination according to claim 4, wherein the combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, wherein the subject is an animal or a human.

17. The combination according to claim 4, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist are administered separately, consecutively or simultaneously as a composition.

18. A method of treating aplastic anemia (AA) in a subject, comprising administering a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in combination with a suitable thrombopoietin (TPO) receptor agonist.

19. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the pharmaceutically acceptable salt of the compound of formula (Ia) is selected from a suitable inorganic metal salt or an organic amine salt; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; and the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, methylamine, diisopropyl ... Propylamine, n-butylamine, tert-butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2 -aminopyrimidine, alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thienylamine, (2S)-3,3-dimethyl-2-butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S) -4-methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, danol, hydrabamine, betaine, amantadine, L-adamantanamine, triphenylmethane, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

20. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein: Suitable thrombopoietin (TPO) receptor agonists are selected from romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

21. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the combination is administered orally or parenterally.

22. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to the subject in an amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg.

23. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to the subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22. 5mg or 22.5mg to 25mg or 25mg to 30mg or 30mg to 35mg or 35mg to 40mg or 40mg to 45mg or 45mg to 50mg or 50mg to 55mg or 55mg to 60mg or 60mg to 65mg or 65mg to 70mg or 70mg to 75mg or 75mg to 80mg or 80mg to 85mg or 85mg to 90mg or 90mg to 95mg or 95mg to 100mg.

24. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein eltrombopag is orally administered to the subject in an amount of 1 mg to 500 mg, avatrombopag is orally administered to the subject in an amount of 1 mg to 100 mg, and rutrombopag is orally administered to the subject in an amount of 1 mg to 100 mg.

25. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein eltrombopag is orally administered to the subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, avatrombopag is orally administered to the subject in an amount of 20 mg and rutrombopag is orally administered to the subject in an amount of 3 mg.

26. The method of claim 18 for treating aplastic anemia (AA) in a subject, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to the subject in an amount of 1 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7.5 mg to 10 mg, 10 mg to 12.5 mg, 12.5 mg to 15 mg, 15 mg to 17.5 mg, 17.5 mg to 20 mg, 20 mg to 22.5 mg, 22.5 mg to 25 mg, 27.5 mg to 30 mg, 30 mg to 32.5 mg, 32.5 mg to 35 mg, 35 mg to 37.5 mg, 37.5 mg to 40 mg, 40 mg to 42.5 mg, 42.5 mg to 45 mg, 45 mg to 47.5 mg, or 47.5 mg to 50 mg.

27. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to the subject in an amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

28. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the thrombopoietin (TPO) receptor agonist is romiplostim and is administered parenterally to the subject in an amount of 1 μg to 500 μg, 50 μg to 450 μg, 100 μg to 400 μg, 150 μg to 350 μg, 200 μg to 300 μg.

29. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the thrombopoietin (TPO) receptor agonist is romiplostim and is administered parenterally to the subject in the following amounts: 125 μg, 250 μg, and 500 μg.

30. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein a combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist is administered to the subject, wherein the subject is an animal or a human.

31. The method of treating aplastic anemia (AA) in a subject according to claim 18, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist are administered separately, consecutively or simultaneously as a composition.

32. A pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist, optionally with one or more pharmaceutically acceptable excipients, for use in the treatment of aplastic anemia (AA).

33. The pharmaceutical composition for use according to claim 32, wherein the pharmaceutically acceptable salt of the compound of formula (Ia) is selected from a suitable inorganic metal salt or an organic amine salt; wherein the inorganic metal salt is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; wherein the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, Butylamine, 2-butylamine, 1,2-ethylenediamine, N-methylglucamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine , alanine, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiophenylamine, (2S)-3,3-dimethyl-2-butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4 -Methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, danol, hydrabamine, betaine, amantadine, L-adamantanamine, triphenylmethane, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

34. The pharmaceutical composition for use according to claim 32, wherein Suitable thrombopoietin (TPO) receptor agonists are selected from romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

35. The pharmaceutical composition for use according to claim 32, which is in oral or parenteral form.

36. The pharmaceutical composition for use according to claim 35, which is in oral form.

37. A pharmaceutical composition for use according to claim 36, wherein the pharmaceutically acceptable excipient is selected from diluents, binders, disintegrants, lubricants, glidants, sweeteners, pH regulators, suspending agents or viscosity regulators, flavoring agents and optional premixed coating agents; wherein the diluent is selected from monohydrate, lactose, microcrystalline cellulose, polymethacrylate selected from Eudragit, potassium chloride, sulfobutyl ether b-cyclodextrin, sodium chloride, spray-dried lactose, and preferably sulfobutyl ether b-cyclodextrin; the binder is selected from hypromellose 3Cps, carbomer selected from Carbopol, binder Cold gum, gum arabic, hydrogenated vegetable oil, polymethacrylate selected from Eudragit, xanthan gum, lactose and zein; disintegrant selected from cross-linked carboxymethyl cellulose sodium, bicarbonate, chitin, gellan gum, polylactide potassium and docusate sodium; lubricant selected from calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, myristic acid; glidant selected from colloidal silicon dioxide, calcium silicate, magnesium silicate, silica hydrogel, corn starch, talc; suspending agent selected from microcrystalline cellulose, sodium carboxymethyl cellulose (Avicel CL 611); sweetener selected from sucrose; flavoring selected from cherry flavor, orange flavor, mango flavor; premix coating agent selected from Opadry Pink.

38. The pharmaceutical composition for use according to claim 36, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to a subject in an amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg.

39. The pharmaceutical composition for use according to claim 36, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 2 2.5mg to 25mg or 25mg to 30mg or 30mg to 35mg or 35mg to 40mg or 40mg to 45mg or 45mg to 50mg or 50mg to 55mg or 55mg to 60mg or 60mg to 65mg or 65mg to 70mg or 70mg to 75mg or 75mg to 80mg or 80mg to 85mg or 85mg to 90mg or 90mg to 95mg or 95mg to 100mg.

40. The pharmaceutical composition for use according to claim 36, wherein eltrombopag is orally administered to the subject in an amount of 1 mg to 500 mg, avatrombopag is orally administered to the subject in an amount of 1 mg to 100 mg, and rutrombopag is orally administered to the subject in an amount of 1 mg to 100 mg.

41. The pharmaceutical composition for use according to claim 36, wherein eltrombopag is orally administered to the subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, avatrombopag is orally administered to the subject in an amount of 20 mg and rutrombopag is orally administered to the subject in an amount of 3 mg.

42. The pharmaceutical composition for use according to claim 36, wherein the combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist is orally administered to a subject, wherein the subject is an animal or a human.

43. The pharmaceutical composition for use according to claim 36, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist are orally administered separately, continuously or simultaneously as a composition.

44. The pharmaceutical composition for use according to claim 35, which is in parenteral form.

45. The pharmaceutical composition for use according to claim 44, wherein the excipient of formula (Ia) used is selected from aqueous glucose solution, Captisol aqueous solution, microemulsion and a cosolvent or emulsifier for adjusting pH; wherein the cosolvent or emulsifier is selected from Captex TM 300. Solutol TM H15, Propylene glycol, Phospholipon TM 90G, Solutol TM HS15, dimethylacetamide and ethanol, PEG400 and N-methylpyrrolidone.

46. ​​A pharmaceutical composition for use according to claim 44, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in an amount of 1 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7.5 mg to 10 mg, 10 mg to 12.5 mg, 12.5 mg to 15 mg, 15 mg to 17.5 mg, 17.5 mg to 20 mg, 20 mg to 22.5 mg, 22.5 mg to 25 mg, 27.5 mg to 30 mg, 30 mg to 32.5 mg, 32.5 mg to 35 mg, 35 mg to 37.5 mg, 37.5 mg to 40 mg, 40 mg to 42.5 mg, 42.5 mg to 45 mg, 45 mg to 47.5 mg, or 47.5 mg to 50 mg.

47. A pharmaceutical composition for use according to claim 44, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in an amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

48. The pharmaceutical composition for use according to claim 44, wherein the suitable thrombopoietin (TPO) receptor agonist is romiplostim or a pharmaceutically acceptable salt thereof.

49. The pharmaceutical composition for use according to claim 44, wherein the pharmaceutically acceptable excipients used with romiplostim are selected from buffers, bulking agents, stabilizers and surfactants; wherein the buffer is selected from glycine, histidine, glutamic acid, succinate, phosphate, acetate and aspartic acid; the bulking agent is selected from mannitol, glycine, sucrose, dextran, polyvinyl pyrrolidone, carboxymethyl cellulose, lactose, sorbitol, trehalose or xylitol; the stabilizer is selected from sucrose, trehalose, mannose, maltose, lactose, glucose, raffinose, cellobiose, gentiobiose, isomaltose, arabinose, glucosamine, fructose, mannitol, sorbitol, saccharide, sucrose ... amino acid, arginine hydrochloride, polyols, including polysaccharides such as dextran, starch, hydroxyethyl starch, cyclodextrin, N-methylpyrrolidine, cellulose and hyaluronic acid, sodium chloride; surfactant selected from sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, sodium dioctyl sulfonate, chenodeoxycholic acid, sodium salt of N-dodecyl sarcosine, lithium dodecyl sulfate, sodium 1-octane sulfonate, sodium cholate hydrate, sodium deoxycholate, sodium glycodeoxycholate, benzalkonium chloride or benzethonium chloride, hexadecylpyridinium chloride monohydrate, hexadecyltrimethylammonium bromide, CHAPS, CHAPSO, SB3-10, SB3-12, digitonin, Triton X-100, Triton X-114, lauroyl macrogol 400, polyoxyethylene 40 stearate, polyoxyethylene hydrogenated castor oil 10, 40, 50 and 60, glyceryl monostearate, polysorbate 20, 40, 60, 65 and 80, soy lecithin, DOPC, DMPG, DMPC, DOPG; sucrose fatty acid esters, methylcellulose and carboxymethylcellulose.

50. The pharmaceutical composition for use according to claim 44, wherein the thrombopoietin (TPO) receptor agonist is romiplostim, which is administered parenterally to a subject in an amount of 1 μg to 500 μg, 50 μg to 450 μg, 100 μg to 400 μg, 150 μg to 350 μg, 200 μg to 300 μg.

51. The pharmaceutical composition for use according to claim 44, wherein the thrombopoietin (TPO) receptor agonist is romiplostim, which is administered parenterally to a subject in the following amounts: 125 μg, 250 μg and 500 μg.

52. The pharmaceutical composition for use according to claim 44, wherein a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, wherein the subject is an animal or a human.

53. The pharmaceutical composition for use according to claim 44, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist are orally administered separately, continuously or simultaneously as a composition.

54. Use of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof in combination with a suitable thrombopoietin (TPO) receptor agonist for treating aplastic anemia (AA).

55. The use of the combination according to claim 54, wherein the pharmaceutically acceptable salt of the compound of formula (Ia) is selected from a suitable inorganic metal salt or an organic amine salt; wherein the inorganic metal is selected from calcium, sodium, potassium, lithium, barium, strontium, magnesium, cesium, copper, cobalt, iron, manganese, lead, aluminum, cadmium, silver, zinc, ammonium; wherein the organic amine salt is selected from methylamine, dimethylamine, ethylamine, diethylamine, n-propylamine, isopropylamine, diisopropylamine, N-methylisopropylamine, n-butylamine, tert-butylamine, 2-Butylamine, 1,2-ethylenediamine, N-methylglucosamine, N,N,N-trimethylethanolamine hydroxide (choline), tromethamine, cyclohexylamine, N-methylcyclohexylamine, guanidine, N-(4-aminobutyl)guanidine, dicyclohexylamine, benzylamine, ethanolamine, diethanolamine, tris(hydroxymethyl)methylamine, hydroxylamine, methylamine, benzylamine, N-methylbenzylamine, N-ethylbenzylamine, 4-methoxybenzylamine, pyrrolidine, piperidine, piperazine, morpholine, 2-aminopyrimidine, propyl amino acid, lysine, arginine, histidine, threonine, proline, glutamine, glycine, 2-thiophenylamine, (2S)-3,3-dimethyl-2-butylamine, cyclopentylamine, cycloheptylamine, meglumine, phenethylamine, dibenzylamine, diphenylamine, α-naphthylamine, o-phenylenediamine, 1,3-diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenethylamine, (S)-4-methoxyphenethylamine, (S)-4-chlorophenethylamine, (S)-4- Methylphenethylamine, cinchonine, cinchonidine, (-)-quinine, triethanolamine, imidazole, ethylenediamine, eporamine, morpholine 4-(2-hydroxyethyl), NN-diethylethanolamine, danol, hydrabamine, betaine, amantadine, L-adamantanamine, triphenylmethane, glucosamine, N-methylpyrrolidine, urea, procaine, metformin, hexane-1-6-diamine, 2-(2-aminoethoxy)ethylamine, N-methylmorpholine and N-ethylmorpholine.

56. Use of a combination according to claim 54, wherein Suitable thrombopoietin (TPO) receptor agonists are romiplostim or a pharmaceutically acceptable salt thereof, eltrombopag or a pharmaceutically acceptable salt thereof, avatrombopag or a pharmaceutically acceptable salt thereof, and rutrombopag or a pharmaceutically acceptable salt thereof.

57. Use of a combination according to claim 54, wherein the combination can be administered orally or parenterally.

58. The use of a combination according to claim 54, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to a subject in an amount of 1 mg to 500 mg, 50 mg to 450 mg, 100 mg to 400 mg, 150 mg to 350 mg, 200 mg to 300 mg, 1 mg to 50 mg, 1 mg to 25 mg.

59. The use of the combination according to claim 54, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is orally administered to a subject at a dose of 1 mg to 2.5 mg or 2.5 mg to 5 mg or 5 mg to 7.5 mg or 7.5 mg to 10 mg or 10 mg to 12.5 mg or 12.5 mg to 15 mg or 15 mg to 17.5 mg or 17.5 mg to 20 mg or 20 mg to 22.5 mg or 22. 5mg to 25mg or 25mg to 30mg or 30mg to 35mg or 35mg to 40mg or 40mg to 45mg or 45mg to 50mg or 50mg to 55mg or 55mg to 60mg or 60mg to 65mg or 65mg to 70mg or 70mg to 75mg or 75mg to 80mg or 80mg to 85mg or 85mg to 90mg or 90mg to 95mg or 95mg to 100mg.

60. The use of the combination according to claim 54, wherein eltrombopag is orally administered to the subject in an amount of 1 mg to 500 mg, avatrombopag is orally administered to the subject in an amount of 1 mg to 100 mg and rutrombopag is orally administered to the subject in an amount of 1 mg to 100 mg.

61. The use of the combination according to claim 54, wherein eltrombopag is orally administered to the subject in an amount of 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg, avatrombopag is orally administered to the subject in an amount of 20 mg and rutrombopag is orally administered to the subject in an amount of 3 mg.

62. Use of a combination according to claim 54, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in an amount of 1 mg to 2.5 mg, 2.5 mg to 5 mg, 5 mg to 7.5 mg, 7.5 mg to 10 mg, 10 mg to 12.5 mg, 12.5 mg to 15 mg, 15 mg to 17.5 mg, 17.5 mg to 20 mg, 20 mg to 22.5 mg, 22.5 mg to 25 mg, 27.5 mg to 30 mg, 30 mg to 32.5 mg, 32.5 mg to 35 mg, 35 mg to 37.5 mg, 37.5 mg to 40 mg, 40 mg to 42.5 mg, 42.5 mg to 45 mg, 45 mg to 47.5 mg, or 47.5 mg to 50 mg.

63. The use of a combination according to claim 54, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof is administered parenterally to a subject in an amount of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 2.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg and 10 mg.

64. The use of the combination according to claim 54, wherein the thrombopoietin (TPO) receptor agonist is romiplostim, which is administered parenterally to a subject in an amount of 1 μg to 500 μg, 50 μg to 450 μg, 100 μg to 400 μg, 150 μg to 350 μg, 200 μg to 300 μg.

65. Use of the combination according to claim 54, wherein the thrombopoietin (TPO) receptor agonist is romiplostim, administered parenterally to the subject in the following amounts: 125 μg, 250 μg and 500 μg.

66. Use of the combination according to claim 54, wherein the combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist is administered to a subject, wherein the subject is an animal or a human.

67. The use of the combination according to claim 54, wherein the compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist are administered separately, consecutively or simultaneously as a composition.

68. A method of treating aplastic anemia (AA) in a subject, comprising administering an effective amount of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

69. A pharmaceutical composition for treating aplastic anemia (AA), comprising a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, and sucrose, citric acid, microcrystalline cellulose, sodium carboxymethylcellulose (Avicel CL 611) and xanthan gum.

70. A combination of a compound of formula (Ia) or a pharmaceutically acceptable salt thereof and a suitable thrombopoietin (TPO) receptor agonist, optionally with cyclosporine.

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