Pharmaceutical compositions of therapeutically active compounds

Abstract

Providing therapeutically active compound pharmaceutical compositions. [Solution] Compounds and pharmaceutical compositions useful for the treatment of cancer, and methods for treating cancer comprising administering the compounds or pharmaceutical compositions described herein to a subject in need thereof. The present invention discloses methods for treating advanced hematopoietic malignancies characterized by the presence of a mutant allele of IDH1, comprising administering a solid dispersion, or a pharmaceutical composition containing a solid dispersion and at least one pharmaceutically acceptable carrier, to a subject in need thereof.

Description

[Technical Field]

[0001] Claim of priority This application claims priority to USSN61 / 953,487, filed on 14 March 2014, and USSN62 / 081,542, filed on 18 November 2014, both of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). These enzymes belong to two distinct subgroups: one utilizing NAD(+) as an electron acceptor, and the other utilizing NADP(+). Five isocitrate dehydrogenases have been reported to date: three NAD(+)-dependent isocitrate dehydrogenases localized in the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one mitochondrial and the other primarily cytoplasmic. Each NADP(+)-dependent isozyme is a homodimer.

[0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytoplasmic) is also known as IDH, IDP, IDCD, IDPC, or PICD. The protein encoded by this gene is an NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisome target signal sequence. The presence of this enzyme in peroxisomes suggests a role in NADPH regeneration for intraperoxisomal reduction reactions, such as the conversion of 2,4-dienoyl-CoA to 3-enoyl-CoA, as well as peroxisomal reactions that consume 2-oxoglutarate, i.e., α-hydroxylation of phytanic acid. Cytoplasmic enzymes play a major role in NADPH production in the cytoplasm.

[0004] The human IDH1 gene codes for a 414-amino acid protein. The nucleotide and amino acid sequences of human IDH1 can be found in GenBank registrations NM_005896.2 and NP_005887.2, respectively. The nucleotide and amino acid sequences of IDH1 can also be found, for example, in Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684(1998); It is also described in: al., J. Biol. Chem. 274:30527-30533 (1999); Wiemann et al., Genome Res. 11:422-435 (2001); The MGC Project Team, Genome Res. 14:2121-2127 (2004); Lubec et al., Submitted (DEC-2008) to UniProtKB; Kullmann et al., Submitted (JUN-1996) to the EMBL / GenBank / DDBJ databases; and Sjoeblom et al., Science 314:268-274 (2006).

[0005] For example, non-mutant IDH1, such as the wild type, catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, thereby enabling the forward reaction of NAD, for example. + (NADP + ) reduces to NADH (NADPH): Isocitric acid + NAD + (NADP + )→α-KG+CO2+NADH(NADPH)+H + .

[0006] Mutations in IDH1 present in certain cancer cells have been found to give rise to a novel ability of the enzyme that catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is thought to contribute to the development and progression of cancer (Dang, L et al, Nature 2009, 462:739-44).

[0007] Therefore, inhibiting mutant IDH1 and its novel activity is a promising therapeutic measure for cancer. Consequently, inhibitors of IDH1 mutants with novel α-hydroxyl activity are continuously needed. International Publication No. 2013 / 107291 and U.S. Patent Application Publication No. 2013 / 0190249 (both incorporated herein by reference in their entirety) disclose compounds that inhibit IDH1 mutants (e.g., IDH1R132H or IDH1R132C). These applications further disclose methods for preparing mutant IDH1 inhibitors, pharmaceutical compositions containing these compounds, and methods for treating diseases, disorders, or conditions (e.g., cancer) associated with the overexpression and / or amplification of mutant IDH1. There is a need for pharmaceutical compositions that are not only useful for treating advanced hematopoietic malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated IDH1 allele, but also possess properties suitable for large-scale manufacturing and formulation. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2013 / 107291 [Patent Document 2] U.S. Patent Application Publication No. 2013 / 0190249 [Non-patent literature]

[0009] [Non-Patent Document 1] Nekrutenko et al., Mol. Biol. Evol. 15:1674-1684 (1998) [Non-Patent Document 2] Geisbrecht et al., J. Biol. Chem. 274:30527-30533(1999) [Non-Patent Document 3] Wiemann et al., Genome Res. 11:422-435(2001) [Non-Patent Document 4] The MGC Project Team, Genome Res. 14:2121-2127(2004) [Non-Patent Document 5] Lubec et al., Submitted (DEC-2008) to UniProtKB [Non-Patent Document 6] Kullmann et al., Submitted (JUN-1996) to the EMBL / GenBank / DDBJ databases [Non-Patent Document 7] Sjoeblom et al., Science 314:268-274(2006) [Non-Patent Document 8] Dang,L et al,Nature 2009,462:739-44 [Summary of the Invention] [Means for Solving the Problems]

[0010] In this specification, a method for treating advanced hematopoietic malignancies, including administering to a subject in need thereof a solid dispersion or a pharmaceutical composition containing a solid dispersion and at least one pharmaceutically acceptable carrier, characterized by the presence of mutant alleles of IDH1, is disclosed. The advanced hematopoietic malignancies include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma). In some embodiments, the advanced hematopoietic malignancy is characterized by mutant alleles of IDH1, and the IDH1 mutation gives rise to a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutaric acid to R(-)-2-hydroxyglutaric acid (2HG) in the patient. In certain embodiments, the mutant IDH1 has an R132X mutation. In certain embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In certain embodiments, the R132X mutation is R132H or R132C. In certain embodiments, the R132X mutation is R132H. In some embodiments, the advanced hematopoietic malignancy has a co-mutation, for example, the co-mutation is selected from NPM1, FLT3, TET2, CEBPA, DNMT3A, and MLL.

[0011] In one aspect, the present invention provides a method for evaluating a subject, the method comprising evaluating the subject by obtaining, for example, directly, a value of the level of the compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; or the level of an α-hydroxy new active product such as, for example, 2HG such as R-2HG (2HG) in a subject treated with Compound 1.

[0012] In another aspect, the present invention provides a method for evaluating a subject, the method comprising administering to a subject in need thereof a compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound 1) or a pharmaceutically acceptable salt thereof; and evaluating the subject by obtaining a value of the level of Compound 1 in the subject or the level of an α-hydroxy new active product such as 2HG, for example R-2HG (2HG).

[0013] In some embodiments, obtaining comprises receiving a sample from the subject. In some embodiments, obtaining comprises transmitting the value to another party, such as the party that administered Compound 1.

[0014] In some embodiments, the value of the level of Compound 1 is obtained by analyzing the concentration of Compound 1 in a body fluid such as blood, plasma, or urine. In some embodiments, the value of the level of Compound 1 is obtained by analyzing the level of Compound 1 in bone marrow, for example, by analyzing a sample from a bone marrow biopsy and / or bone marrow aspiration for the level of Compound 1.

[0015] In some embodiments, the value of the 2HG level is obtained by analyzing the level of 2HG in a body fluid such as blood, plasma, or urine. In some embodiments, the value of the 2HG level is obtained by analyzing the level of 2HG in bone marrow, for example, by analyzing a sample from a bone marrow biopsy and / or bone marrow aspiration for the level of 2HG.

[0016] In some embodiments, the analysis is performed by chromatographic analysis of bodily fluids such as blood, plasma, or urine, for example, by mass spectrometry such as LC-MS. In some embodiments, the analysis is performed by spectroscopic analysis such as magnetic resonance (MRI) and / or MRS measurements.

[0017] In some embodiments, the subject was administered compound 1 within approximately 30 days prior to evaluation, for example, within approximately 29 days, for example, within approximately 28 days, for example, within approximately 27 days, for example, within approximately 26 days, for example, within approximately 25 days, for example, within approximately 24 days, for example, within approximately 23 days, for example, within approximately 22 days, for example, within approximately 21 days, for example, within approximately 20 days, for example, within approximately 19 days, for example, within approximately 18 days, for example, within approximately 17 days, for example, within approximately 16 days, for example, within approximately 15 days, for example, within approximately 14 days, for example, within approximately 7 days, within approximately 6 days, within approximately 5 days, within approximately 4 days, within approximately 3 days, or within approximately 72 hours prior to evaluation, for example, within 48 hours prior to evaluation, within approximately 24 hours, within approximately 12 hours, within approximately 10 hours, within approximately 8 hours, within approximately 6 hours, within approximately 4 hours, within approximately 3 hours, within approximately 2 hours, within approximately 1.5 hours, within approximately 1 hour, within approximately 45 minutes, within approximately 30 minutes, or within approximately 15 minutes.

[0018] In some embodiments, subjects were administered compound 1 orally, for example, once or twice a day in doses of about 10 mg to about 3000 mg, for example, once or twice a day (e.g., every 8 to 16 hours, e.g., every 12 hours), or (e.g., every 12 to 36 hours, e.g., every 24 hours), for example, about 10 mg to about 60 mg, about 60 mg to about 200 mg, about 200 mg to about 500 mg, about 500 mg to about 1200 mg, about 1200 mg to about 2000 mg, or about 2000 mg to about 3000 mg, for example, about 50 mg, about 100 mg, about 300 mg, about 500 mg, about 800 mg, once or twice a day, for example, every 12 hours, or for example, every 24 hours, prior to evaluation.

[0019] In some embodiments, the subject has been diagnosed with or will be diagnosed with a disease. In some embodiments, the disease is an advanced hematopoietic malignancy, such as an advanced hematopoietic malignancy characterized by the presence of a mutant allele of IDH1. In some embodiments, the advanced hematopoietic malignancy is characterized by a mutant allele of IDH1, and the IDH1 mutation results in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG) in the patient. In some embodiments, the mutant IDH1 has an R132X mutation. In some embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In some embodiments, the R132X mutation is R132H or R132C. In some embodiments, the R132X mutation is R132H. In some embodiments, advanced hematopoietic malignancies have comutations, which are selected from, for example, NPM1, FLT3, TET2, CEBPA, DNMT3A, and MLL.

[0020] In some embodiments, the disease is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated IDH1 allele. In some embodiments, the disease is selected from advanced IDH1 mutation-positive relapsed and / or refractory AML (R / R AML), untreated AML, and MDS.

[0021] In some embodiments, the subject has prior experience of treatment with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacitidine, decitabine, SGN33A, salglamostim, WT-1 analog peptide vaccine, tipifurnib, MK-8242, campus, and 6-mercaptopurine (6MP).

[0022] In another aspect, the present invention provides a method for evaluating a subject, the method comprising obtaining, for example, directly obtaining a value of the level of blast cells, such as leukemic blast cells, such as myeloblasts or myeloid blasts, in a subject treated with compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1).

[0023] In another aspect, the present invention provides a method for evaluating a subject, the method comprising: administering the compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1) or a pharmaceutically acceptable salt thereof to a subject requiring it; and evaluating the subject by obtaining a value for the level of blast cells, such as leukemic blast cells, such as myeloblasts or myeloid blasts.

[0024] In some embodiments, acquisition includes receiving a sample from the subject. In some embodiments, acquisition includes transmitting the value to another party, for example, the party that administered compound 1.

[0025] In some embodiments, the evaluation involves obtaining a value for the level of blast cells, such as leukemia blast cells, such as myeloblasts or myeloid blasts, in a sample from the subject, such as the number of blast cells, and comparing that value to a reference standard. In some embodiments, the reference standard is the total number of cells in the sample. In some embodiments, the sample includes blast cells, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes.

[0026] In some embodiments, the level of blast cells, such as leukemia blast cells, such as myeloblasts or myeloid blasts, is obtained by analyzing the bone marrow, for example, by analyzing the number of blast cells in bone marrow aspirate. In some embodiments, the bone marrow is analyzed, for example, every two weeks, for example (between days 12 and 18, e.g., day 15), (between days 26 and 32, e.g., day 29), (between days 54 and 60, e.g., day 57), and then every 50 to 60 days thereafter, for example every 56 days thereafter, e.g., on days 15, 29, and 57 and every 56 days thereafter.

[0027] In some embodiments, the subject was administered compound 1 within approximately 30 days prior to evaluation, for example, within approximately 29 days, for example, within approximately 28 days, for example, within approximately 27 days, for example, within approximately 26 days, for example, within approximately 25 days, for example, within approximately 24 days, for example, within approximately 23 days, for example, within approximately 22 days, for example, within approximately 21 days, for example, within approximately 20 days, for example, within approximately 19 days, for example, within approximately 18 days, for example, within approximately 17 days, for example, within approximately 16 days, for example, within approximately 15 days, for example, within approximately 14 days, for example, within approximately 7 days, within approximately 6 days, within approximately 5 days, within approximately 4 days, within approximately 3 days, or within approximately 72 hours prior to evaluation, for example, within 48 hours prior to evaluation, within approximately 24 hours, within approximately 12 hours, within approximately 10 hours, within approximately 8 hours, within approximately 6 hours, within approximately 4 hours, within approximately 3 hours, within approximately 2 hours, within approximately 1.5 hours, within approximately 1 hour, within approximately 45 minutes, within approximately 30 minutes, or within approximately 15 minutes.

[0028] In some embodiments, subjects were administered compound 1 orally, for example, once or twice a day in doses of about 10 mg to about 3000 mg, for example, once or twice a day (e.g., every 8 to 16 hours, e.g., every 12 hours), or (e.g., every 12 to 36 hours, e.g., every 24 hours), for example, about 10 mg to about 60 mg, e.g., about 60 mg to about 200 mg, e.g., about 200 mg to about 500 mg, e.g., about 50 mg to about 100 mg, e.g., about 300 mg, e.g., about 1200 mg to about 2000 mg, or about 2000 mg to about 3000 mg, for example, about 50 mg, about 100 mg, e.g., about 300 mg, e.g., about 50 mg, e.g., about 100 mg, e.g., every 300 mg, e.g., every 500 mg, e.g., every 12 hours, e.g., every 24 hours), for example, once or twice a day, for example, every 24 hours, prior to evaluation.

[0029] In some embodiments, the subject has been diagnosed with or will be diagnosed with a disease. In some embodiments, the disease is an advanced hematopoietic malignancy, such as an advanced hematopoietic malignancy characterized by the presence of a mutant allele of IDH1. In some embodiments, the advanced hematopoietic malignancy is characterized by a mutant allele of IDH1, and the IDH1 mutation results in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG) in the patient. In some embodiments, the mutant IDH1 has an R132X mutation. In some embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another embodiment, the R132X mutation is R132H or R132C. In some embodiments, the R132X mutation is R132H.

[0030] In some embodiments, advanced hematopoietic malignancies are characterized by comutas, for example, selected from NPM1, FLT3, TET2, CEBPA, DNMT3A, and MLL.

[0031] In some embodiments, the disease is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1. In some embodiments, the disease is selected from advanced IDH1 mutation-positive relapsed and / or refractory AML (R / R AML), untreated AML, and MDS.

[0032] In some embodiments, the subject has prior experience of treatment with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacitidine, decitabine, SGN33A, salglamostim, WT-1 analog peptide vaccine, tipifurnib, MK-8242, campus, and 6-mercaptopurine (6MP).

[0033] In another aspect, the present invention provides a method for treating a disease in a subject, the method comprising administering a compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1) or a pharmaceutically acceptable salt thereof to a subject in need in an amount sufficient to reduce blast cells, such as leukemia blast cells, such as myeloblasts or myeloid blasts, thereby treating the disease.

[0034] In some embodiments, the disease is an advanced hematopoietic malignancy, such as an advanced hematopoietic malignancy characterized by a mutated allele of IDH1. In some embodiments, the advanced hematopoietic malignancy is characterized by a mutated allele of IDH1, and the IDH1 mutation results in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG) in the patient. In some embodiments, the mutated IDH1 has an R132X mutation. In some embodiments, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another embodiment, the R132X mutation is R132H or R132C. In some embodiments, the R132X mutation is R132H.

[0035] In some embodiments, the disease is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1. In some embodiments, the disease is selected from advanced IDH1 mutation-positive relapsed and / or refractory AML (R / R AML), untreated AML, and MDS.

[0036] In some embodiments, the subject has prior experience of treatment with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacitidine, decitabine, SGN33A, salglamostim, WT-1 analog peptide vaccine, tipifurnib, MK-8242, campus, and 6-mercaptopurine (6MP).

[0037] In some embodiments, the reduction in blast cells, such as leukemia blast cells, such as myeloblasts or myeloid blasts, is, for example, at least about 1 / 10 of the reference standard, for example at least about 1 / 11 of the reference standard, for example at least about 1 / 12 of the reference standard, for example at least about 1 / 13 of the reference standard, for example at least about 1 / 14 of the reference standard, for example at least about 1 / 15 of the reference standard, for example at least about 1 / 16 of the reference standard, for example at least about 1 / 17 of the reference standard, for example at least about 1 / 18 of the reference standard, for example at least about 1 / 19 of the reference standard, for example at least about 1 / 20 of the reference standard.

[0038] In another embodiment, blast cells such as leukemia blast cells, such as myeloblasts or myeloid blasts, are reduced to, for example, less than 10% of a reference standard, less than 9% of a reference standard, less than 8% of a reference standard, less than 7% of a reference standard, less than 6% of a reference standard, less than 5% of a reference standard, less than 4% of a reference standard, less than 3% of a reference standard, less than 2% of a reference standard, or even complete remission (CR).

[0039] In some embodiments, the reference standard is the level of blast cells, such as myeloblasts or myeloid blasts, or leukemic blast cells, in subjects who have not previously received treatment with compound 1, for example, in untreated subjects, or in subjects before administration of compound 1. In some embodiments, the subjects have prior experience of treatment with one or more chemotherapeutic agents. In some embodiments, the chemotherapeutic agent is selected from cytarabine (Ara-C), daunorubicin, etoposide, mitoxantrone, idarubicin, 5-azacitidine, decitabine, SGN33A, salglamostim, WT-1 analog peptide vaccine, tipifurnib, MK-8242, campus, and 6-mercaptopurine (6MP).

[0040] In some embodiments, the reference standard is the total number of cells in the specimen. In some embodiments, the specimen includes blast cells, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes.

[0041] In some embodiments, subjects are monitored for adverse events. In some embodiments, adverse events include, but are not limited to, febrile neutropenia, dyspnea, hypotension, altered mental state, neutropenia, elevated blood uric acid levels, bronchopulmonary aspergillosis, dizziness, QT prolongation on electrocardiogram, malaise, intracranial hemorrhage, hypoxia, leukocytosis, leukocytosis, pulmonary infection, metabolic acidosis, nausea, organ failure, pericardial effusion, fungal pneumonia, fever, renal dysfunction, retinoic acid syndrome, septic shock, systemic candidiasis, tachycardia, and vertigo.

[0042] In some embodiments, the adverse event is differentiation syndrome, which includes symptoms of fever and / or dyspnea. In some embodiments, the subject is monitored for differentiation syndrome, and if the subject develops differentiation syndrome, they are treated with steroids.

[0043] In some embodiments, subjects are monitored for adverse events, such as serious adverse events (SAEs), and if an adverse event such as an SAE occurs in the patient, the treatment is modified or discontinued.

[0044] The therapeutic methods described herein may further include various evaluation steps before and / or after treatment with compound 1. In some embodiments, the method further includes a step of evaluating PK and PD parameters (e.g., concentrations of compound 1 or 2HG in tissue, blood, plasma, and / or urine) before and / or after treatment with compound 1. This evaluation can be achieved by sample analysis of body tissue or fluids such as blood, plasma, or urine, for example by mass spectrometry, such as LC-MS.

[0045] This specification also discloses solid dispersions containing an inhibitor of mutant IDH1 or a pharmaceutically acceptable salt thereof and one or more polymers. Furthermore, this specification discloses steps for preparing such solid dispersions. These solid dispersions have improved solubility and enhanced exposure to the therapeutic compound compared to the as-is crystalline form of the therapeutic compound.

[0046] Furthermore, this specification also discloses the pharmaceutically acceptable use of these solid dispersions for the treatment of advanced hematopoietic malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1.

[0047] This specification also discloses pharmaceutical compositions comprising a solid dispersion and at least one pharmaceutically acceptable carrier. Furthermore, this specification also discloses methods for preparing pharmaceutical compositions. The present invention provides, for example, the following items: (Item 1) (a) Compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1 as part of a solid dispersion A method for treating advanced hematopoietic malignancies, characterized in that each is a mutant allele of IDH1, comprising administering a pharmaceutical composition containing (4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1) or a pharmaceutically acceptable salt thereof, or form 1 of compound 1, or form 2 of compound 1; and (b) one or more pharmaceutically acceptable carriers, to a subject requiring the treatment thereof. (Item 2) The method according to item 1, wherein the advanced hematopoietic malignancy is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), and lymphoma. (Item 3) The method according to item 1, wherein at least a specific weight percent of compound 1 is crystalline. (Item 4) The method according to item 3, wherein the specific weight percent of compound 1 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%. (Item 5) The method according to item 3, wherein the specific weight percentage of compound 1 is 10% to 100%. (Item 6) The method according to item 1, wherein a certain weight percent of compound 1 is crystalline and the remainder of compound 1 is in an amorphous form. (Item 7) The method according to item 1, wherein compound 1 comprises a single-crystal form of compound 1, or a mixture of different single-crystal forms. (Item 8) The method according to item 1, wherein at least 90% by weight of compound 1 is crystalline. (Item 9) The method according to item 1, wherein at least 95% by weight of compound 1 is crystalline. (Item 10) The method according to item 1, wherein at least 99% by weight of compound 1 is crystalline. (Item 11) The method according to item 1, wherein form 1 of compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 1 and the data shown in Table 1. (Item 12) The method according to item 11, wherein the single crystal morphology is shown in Figure 1 and Table 1, characterized by one or more peaks. (Item 13) The method according to item 11, wherein the single crystal morphology is characterized by one, two, three, four, five, six, seven, eight, or nine of the peaks shown in Table 1. (Item 14) The method according to item 11, wherein morphology 1 is characterized by peaks identified at 2θ angles of 8.6, 15.6, 18.5, 20.6, 21.6, and 26.4°. (Item 15) The method according to item 11, wherein morphology 1 is characterized by peaks identified at 2θ angles of 8.6, 15.6, 18.5, and 21.6°. (Item 16) The method according to item 1, wherein form 2 of compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in Figure 4 and the data shown in Table 2. (Item 17) The method of item 16, wherein form 2 is characterized by one or more peaks as shown in Figure 4 and Table 2. (Item 18) The method according to item 16, wherein form 2 is characterized by one, two, three, four, five, six, seven, eight, or nine of the peaks shown in Table 2. (Item 19) The method according to item 16, wherein morphology 2 is characterized by peaks identified at 2θ angles of 9.8, 11.6, 19.6, 22.5, 23.0, and 31.4°. (Item 20) The method according to item 11, wherein morphology 2 is characterized by peaks identified at 2θ angles of 9.8, 11.6, 19.6, and 23.0°. (Item 21) The method according to item 1, wherein the solid dispersion contains a water-soluble polymer. (Item 22) The method according to item 1, wherein the solid dispersion contains a polymer that is at least partially water-soluble. (Item 23) The method according to item 21, wherein the polymer is a cellulose polymer. (Item 24) The method according to item 21, wherein the effectiveness of the treatment of the advanced hematopoietic malignancy is monitored by measuring the 2HG level in the subject. (Item 25) A method for Item 1, wherein a subject is evaluated before and / or after treatment with a pharmaceutical composition comprising (a) compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion, or form 1 of compound 1, or form 2 of compound 1; and (b) one or more pharmaceutically acceptable carriers, the method comprising determining the 2HG level in the subject. (Item 26) The method according to item 25, wherein the 2HG level is determined by spectroscopic analysis. (Item 27) The method of item 26, wherein the spectroscopic analysis includes analysis based on magnetic resonance. (Item 28) The method according to item 26, wherein the spectroscopic analysis includes MRI and / or MRS measurement, fluid sample analysis, or surgical material analysis. (Item 29) The method according to item 28, wherein the bodily fluid includes blood, plasma, urine, or cerebrospinal fluid. (Item 30) The method described in item 28, wherein the surgical material is analyzed by mass spectrometry. (Item 31) The method according to item 30, wherein the mass spectrometry includes LC-MS or GC-MS. (Item 32) The method according to item 1, wherein the advanced hematopoietic malignancy is characterized by a mutated allele of IDH1, and the IDH1 mutation results in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG) in the patient. (Item 33) The method according to item 32, wherein the mutant IDH1 has the R132X mutation. (Item 34) The method according to item 33, wherein the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. (Item 35) The method according to item 33, wherein the R132X mutation is R132H or R132C. (Item 36) The method according to item 1, wherein the advanced hematopoietic malignancy is characterized by comutas selected from NPM1, FLT3, TET2, CEBPA, DNMT3A, and MLL. (Item 37) The method according to item 1, wherein the method comprises administering compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion to a subject requiring it. (Item 38) The method according to item 1, wherein the method comprises administering form 1 of compound 1 to a subject requiring it. (Item 39) The method according to item 1, wherein the method comprises administering form 2 of compound 1 to a subject requiring it. [Brief explanation of the drawing]

[0048] [Figure 1] This is X-ray powder diffraction (XRPD) of form 1. [Figure 2] This is a differential scanning calorimetry (DSC) profile of form 1. [Figure 3] This is the thermogravimetric analysis (TGA) profile of form 1. [Figure 4] This is X-ray powder diffraction (XRPD) of form 2. [Figure 5] This is a differential scanning calorimetry (DSC) profile of form 2. [Figure 6] This is a thermogravimetric analysis (TGA) profile of type 2. [Figure 7A] Figure 7A is a line graph showing the decrease in 2HG after a single dose (50 mg / kg) of compound ((S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1) in an IDH1 mutant R132H xenograft model. Figure 7B is a bar graph showing that compound 1 (at concentrations of 0.5 μM, 1 μM, and 5 μM) reduced intracellular 2HG in primary human IDH mutant blast cells (in vitro). [Figure 7B] Figure 7A is a line graph showing the decrease in 2HG after a single dose (50 mg / kg) of compound ((S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1) in an IDH1 mutant R132H xenograft model. Figure 7B is a bar graph showing that compound 1 (at concentrations of 0.5 μM, 1 μM, and 5 μM) reduced intracellular 2HG in primary human IDH mutant blast cells (in vitro). [Figure 8A] Figure 8A is a bar graph showing the PK profile after oral administration of compound 1 in patients treated with a single dose of 100 mg BID, 300 mg QD, or 500 mg QD on day -3 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2, respectively. Figure 8B is a bar graph showing the decrease in plasma concentrations of 2HG to the normal range on day -3 of a single dose, day 15 of cycle 1, and day 1 of cycle 2, respectively, for doses of 100 mg BID, 300 mg QD, or 500 mg QD. [Figure 8B] Figure 8A is a bar graph showing the PK profile after oral administration of compound 1 in patients treated with a single dose of 100 mg BID, 300 mg QD, or 500 mg QD on day -3 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2, respectively. Figure 8B is a bar graph showing the decrease in plasma concentrations of 2HG to the normal range on day -3 of a single dose, day 15 of cycle 1, and day 1 of cycle 2, respectively, for doses of 100 mg BID, 300 mg QD, or 500 mg QD. [Figure 9A] Figures 9A, 9B, and 9C are images of bone marrow aspirate showing blasts, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes in baseline patients, for example, untreated, after day 15 of cycle 1, and after day 28 of cycle 1, respectively. [Figure 9B]Figures 9A, 9B, and 9C are images of bone marrow aspirate showing blasts, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes in baseline patients, for example, untreated, after day 15 of cycle 1, and after day 28 of cycle 1, respectively. [Figure 9C] Figures 9A, 9B, and 9C are images of bone marrow aspirate showing blasts, myelocytes, neutrophils, promyelocytes, metamyelocytes, and monocytes in baseline patients, for example, untreated, after day 15 of cycle 1, and after day 28 of cycle 1, respectively. [Modes for carrying out the invention]

[0049] The details of the configuration and arrangement of components described or shown in the drawings below are not intended to be limiting. Other embodiments and different methods for carrying out the invention are also expressly encompassed. Furthermore, the expressions and terms used herein are for illustrative purposes only and should not be considered limiting. The use of “including,” “comprising,” or “having,” “containing,” “involving,” and their variations herein is intended to encompass not only the items listed below and their equivalents, but also additional items.

[0050] definition The following terms used above and throughout this description of the present invention shall be interpreted as having the following meanings unless otherwise indicated.

[0051] In this specification, the terms “obtain” or “acquire” mean to acquire ownership of a physical entity (e.g., a sample, such as a blood or plasma sample) or a value (e.g., a numerical value) by “directly obtaining” or “indirectly obtaining” the physical entity or value. “Directly obtaining” means performing a method (e.g., an analytical technique) to obtain the physical entity or value. “Indirectly obtaining” means receiving the physical entity or value from another party or source (e.g., a third-party clinical laboratory that directly obtains the physical entity or value). Directly obtaining a value includes performing a method that involves a physical change in a sample or another substance, performing an analytical method that involves a physical change in a substance (e.g., such as a sample), and performing an analytical technique (e.g., the method described herein) by mass spectrometry (e.g., LC-MS) of a body fluid (e.g., blood or plasma).

[0052] In this specification, “crystal” means a solid having a highly regular chemical structure. In particular, the form of a crystalline free base or salt can be produced as one or more single crystal forms. For the purposes of this application, the terms “crystalline form,” “single crystal form,” and “polymorph” are synonyms and distinguish crystals having different properties (e.g., different XRPD patterns and / or different DSC scanning results). The term “polymorph” includes pseudopolymorphs, which are typically different solvates of a substance. Therefore, their properties are different from each other. Accordingly, distinct polymorphs and pseudopolymorphs of the form of a free base or salt are considered distinct single crystal forms in this specification.

[0053] The term "substantial crystalline" refers to a form in which at least a specific weight percentage is crystalline. A specific weight percentage is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. In some embodiments, substantial crystalline refers to a form of free base or salt in which at least 70% is crystalline. In other embodiments, substantial crystalline refers to a form of free base or salt in which at least 90% is crystalline.

[0054] "Form 1" or "Compound 1 Form 1" may be used interchangeably and represents the crystalline form synthesized in Example 2 of the Examples section below, described below, and represented by the data shown in Figures 1, 2, and 3.

[0055] "Form 2" or "Compound 1 Form 2" are used interchangeably and represent the crystalline form synthesized in Example 3 of the Examples section below, which is described thereafter, and is represented by the data shown in Figures 4, 5, and 6.

[0056] In this specification, "amorphous" refers to a solid material whose atomic arrangement lacks long-range order. Amorphous solids are generally supercooled liquids in which molecules are randomly arranged, and therefore lack distinct arrangement and long-range order. Amorphous solids are generally isotropic; that is, they exhibit similar properties in all directions and do not have a distinct melting point. For example, amorphous materials are solid materials that do not have sharp, characteristic crystalline peaks in their X-ray powder diffraction (XRPD) patterns (i.e., they are not crystals as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in their XRPD patterns. Broad peaks are characteristic of amorphous solids. The amorphous preparations of the compounds described herein are substantially free of impurities and / or crystalline compounds.

[0057] The term "substantially free" means forms and compositions that may be free of impurities and / or crystalline compounds in at least a certain weight percentage. A certain weight percentage is 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 60% and 100% of impurities and / or crystalline compounds. In some embodiments, substantially free means in the form of a free base or salt with a purity of at least 70%. In other embodiments, substantially crystalline means in the form of a free base or salt with a purity of at least 90%. In other embodiments, substantially free of crystalline compounds means a composition containing less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than 1% of crystalline compounds.

[0058] In this invention, “isolated” means a form in which at least a specific weight percent of the compound may be a specific crystalline form. The specific weight percent is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 90% and 100%.

[0059] The term "solvate or solvated" means a physical association of one or more solvent molecules with a compound of the present invention, including the crystalline form of the compound of the present invention. This physical association includes hydrogen bonding. In some examples, a solvate may be isolated if, for example, one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate or solvated" includes both liquid phases and isolateable solvates. Typical solvates include, for example, hydrates, ethanolates, or methanolates.

[0060] The term "hydrate" refers to a solvate in which H2O, present in a specified stoichiometric amount, is the solvent molecule. Examples include hemihydrate, monohydrate, dihydrate, or trihydrate.

[0061] The term "mixture" is used to refer to the combined components of a mixture, regardless of the combination of phase states (e.g., liquid or liquid / crystal).

[0062] The term "seed crystal addition" is used to refer to the addition of a crystalline substance to initiate recrystallization or crystallization.

[0063] The term "poor solvent" is used to refer to a solvent in which compounds, including their crystalline form, are poorly soluble.

[0064] In this specification, the term "about" means approximately, around, roughly, or periphery. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundary above and below the stated value. Typically, the term "about" is used in this specification to modify a numerical range above and below the stated value with a 10% variation.

[0065] In this specification, the term “elevated 2HG level” means 10%, 20%, 30%, 50%, 75%, 100%, 200%, 500%, or more than the amount of 2HG present in subjects without the mutant IDH1 allele. The term “elevated 2HG level” may also refer to the amount of 2HG in cells, tumors, tumor-containing tissues, or body fluids.

[0066] The term "body fluids" includes one or more of the following surrounding the fetus: amniotic fluid, aqueous humor, blood (e.g., plasma), serum, cerebrospinal fluid, earwax, oat erosion, Cowper's gland fluid, vaginal fluid, interstitial fluid, lymph, breast milk, mucus (e.g., rhinorrhea or sputum), pleural fluid, pus, saliva, sebum, semen, serum, sweat, tears, urine, vaginal secretions, or vomit.

[0067] In this specification, the terms “inhibit” or “prevent” include complete and partial inhibition and prevention. Inhibitors completely or partially inhibit their target.

[0068] The term "treatment" means reducing, suppressing, weakening, shrinking, inhibiting, or stabilizing the onset or progression of a disease / malfunction (i.e., advanced solid tumors such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated allele of IDH1, respectively. This means reducing the severity of disease / disorders (i.e., acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or advanced solid tumors such as lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated IDH1 allele.

[0069] In this specification, the amount of a compound effective in treating a disorder, or "therapeutic dose," means the amount of a compound administered to a subject in a single or multiple doses that is effective in treating cells or in curing, alleviating, reducing, or improving a subject with a disorder beyond what would be expected without such treatment.

[0070] In this specification, "%w / w" is used to mean the weight-based percentage of the total weight percentage, which is used as the basis for calculating the weight percentage of individual components. For example, with respect to a bulk composition, the %w / w of an individual component can be calculated as the percentage of the total weight percentage of all components in the bulk composition. As another example, with respect to a single-dose oral dosage form, the %w / w of an individual component can be calculated as the percentage of the total weight of all components in the single-dose oral dosage form. For example, if the single-dose oral dosage form is a tablet, the total weight can be the total weight of all components in the tablet.

[0071] In this specification, the term "subject" is intended to mean a human being. Typical human subjects include human patients (also referred to as patients) or healthy individuals who have the ailments described herein.

[0072] In this specification, the term “physically stable” means that a particular form of a free base or salt does not change into one or more different physical forms (e.g., different solid forms measured by XRPD, DSC, etc.) when placed under specific conditions, e.g., room temperature ambient humidity or 40°C / 75% relative humidity conditions, for a specific period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or longer. In some embodiments, less than 25% of the form of the compound changes into one or more different physical forms when placed under specific conditions. In some embodiments, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the form of a particular compound changes into one or more different physical forms of the particular compound when placed under specific conditions. In some embodiments, an undetectable amount of a particular form of the compound changes into one or more different physical forms of the compound.

[0073] In this specification, the term “chemically stable” means that, when placed under specific conditions, such as room temperature ambient humidity or 40°C / 75% relative humidity, the chemical structure of a particular compound does not change to another compound (e.g., decompose) for a specific period of time, such as one day, two days, three days, one week, two weeks, one month, two months, three months, six months, twelve months, eighteen months, twenty-four months, or longer. In some embodiments, when placed under specific conditions, less than 25% of the form of a particular compound changes to one or more other compounds. In some embodiments, when placed under specific conditions, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the form of a particular compound changes to one or more other compounds. In some embodiments, an undetectable amount of the form of a particular compound changes to one or more different physical forms of the particular compound.

[0074] The term "dispersion" refers to a dispersion system in which a single substance, which is the dispersed phase, is distributed in discontinuous units throughout a second substance (continuous phase or medium). The size of the dispersed phase can vary considerably (for example, from nanometer-sized colloidal particles to several microns in size). Typically, the dispersed phase may be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. In pharmaceutical applications, solid dispersions may include crystalline therapeutic compounds (dispersed phase) in an amorphous polymer (continuous phase), or amorphous therapeutic compounds (dispersed phase) in an amorphous polymer (continuous phase).

[0075] The term "amorphous solid dispersion" typically refers to a solid dispersion of two or more components, usually a therapeutic compound and a polymer (or multiple polymers). However, when the therapeutic compound is in the amorphous phase, other components such as surfactants or other pharmaceutical additives may also be present, and these other components improve the physical stability and / or dispersibility and / or solubility of the amorphous therapeutic compound. In some embodiments, the amorphous solid dispersion includes a polymer (and optionally a surfactant) constituting the dispersed phase and a therapeutic compound constituting the continuous phase. In some embodiments, the amorphous solid dispersion includes a polymer (and optionally a surfactant) constituting the continuous phase and a therapeutic compound constituting the dispersed phase.

[0076] Typical solid dispersions are coprecipitates or comelts of a specific therapeutic compound with one or more polymers. A “coprecipitate” is prepared by dissolving the therapeutic compound and one or more polymers in a solvent or solvent mixture, followed by the removal of the solvent or solvent mixture. In some cases, the one or more polymers may be suspended in the solvent or solvent mixture. The solvent or solvent mixture may include organic solvents and supercritical fluids. The solvent or solvent mixture may also include non-volatile solvents. A “comelt” is prepared by heating and melting the therapeutic compound and one or more polymers, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent (if applicable), and cooling to room temperature at a selected rate. In some cases, solid dispersions are prepared by adding a solution of the therapeutic compound and solid polymer, followed by mixing and removal of the solvent or solvent mixture. Vacuum drying, spray drying, box drying, freeze-drying, and other drying methods can be used for the removal of the solvent or solvent mixture. By applying any of these methods based on this disclosure, using appropriate processing parameters, a specific therapeutically active compound present in an amorphous state in the final solid dispersion product will be provided.

[0077] In this specification, the term “direct compression dosage form” usually refers to a form (e.g., a tablet) obtained by compressing a dry blend of a powder (e.g., a solid dispersion such as an aggregated dispersion) containing a compound (e.g., a sparingly soluble therapeutic compound, such as compound 1, such as amorphous compound 1, for example, in the form of a solid dispersion, e.g., a solid dispersion, e.g., a solid dispersion) and one or more additives, e.g., an aggregated dispersion. For example, a product (e.g., a solid dispersion) obtained by the process described herein may have improved properties (e.g., fluidity) that allow for direct compression into, for example, an oral dosage form such as a tablet, or formulation into capsules or pouches.

[0078] Pharmaceutical composition and therapeutic method (a) Compound (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1 as part of a solid dispersion A method is provided for treating advanced solid tumors such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1, comprising administering a pharmaceutical composition containing (4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1) or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable carriers to a subject requiring the treatment thereof.

[0079] Compositions comprising compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion (e.g., an amorphous solid dispersion) are also provided. Pharmaceutical compositions comprising (a) compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion, and (b) one or more pharmaceutically acceptable carriers are also provided.

[0080] These therapeutic methods and pharmaceutical compositions will be further described by the detailed descriptions and exemplary examples provided below.

[0081] Pharmaceutical compositions containing solid dispersions in which therapeutically active compounds are dispersed within a matrix can exhibit improved chemical and physical properties. These can be prepared by forming a homogeneous solution or melt of the therapeutically active compound and matrix material, followed by solidification of the mixture by cooling or removal of the solvent. Such solid dispersions of therapeutically active compounds often show improved bioavailability when administered orally compared to oral compositions containing undispersed compounds.

[0082] Spray drying is the most widely used industrial process, involving particle formation and drying, and can be used to produce solid dispersions of therapeutic compounds. It is particularly well-suited for the continuous production of dried solids in the form of powders, granules, or aggregates from liquid raw materials such as solutions, emulsions, or pumpable suspensions. Therefore, spray drying is a useful process when the final product must meet precise quality standards in terms of particle size distribution, residual water content, bulk density, and particle shape.

[0083] Important quality characteristics of spray-dried dispersions include efficacy, related substances, residual solvent content, homogeneity, lack of crystallinity, solubility, particle morphology, and flow characteristics of bulk powders.

[0084] Important process parameters include the spray solution composition and viscosity, nozzle type and dimensions, spray pressure, spray solution supply rate, drying gas flow rate, inlet and outlet temperatures, condenser temperature (for example, for closed-loop drying processes), and secondary drying parameters.

[0085] In some embodiments, at least a specific weight percent of compound 1 is crystalline. The specific weight percent may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. If a specific weight percent of compound 1 is crystalline, the remainder of compound 1 is in an amorphous form. Non-limiting examples of crystalline compound 1 include the single-crystal form of compound 1, or a mixture of different single-crystal forms. In some embodiments, compound 1 is at least 90% by weight crystalline. In some embodiments, compound 1 is at least 95% by weight crystalline. In some embodiments, compound 1 is at least 99% by weight crystalline.

[0086] In another embodiment, a specific weight percent of crystalline compound 1 is a specific single-crystal form or a combination of single-crystal forms. The specific weight percent may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 10% and 100%. In another embodiment, at least 90% by weight of compound 1 is in single-crystal form. In another embodiment, at least 95% by weight of compound 1 is in single-crystal form. In another embodiment, at least 99% by weight of compound 1 is in single-crystal form.

[0087] In the following description of Compound 1, embodiments of the present invention may be described with reference to specific crystalline forms of Compound 1 characterized by one or more properties described herein. Descriptions characterizing crystalline forms may also be used to describe mixtures of different crystalline forms that may exist in crystalline Compound 1. However, specific crystalline forms of Compound 1 may be characterized by one or more properties of the crystalline forms disclosed herein, with or without reference to specific crystalline forms.

[0088] The crystal morphology is further described by the detailed explanation and specific examples shown below. The XRPD peaks listed in Tables 1 and 2 may vary by ±0.2 depending on the instrument used to obtain the data.

[0089] Form 1 In one embodiment, form 1, which is a single-crystal form of compound 1, is characterized by X-ray powder diffraction (XRPD) obtained by CuKa irradiation, as shown in Figure 1, and the data shown in Table 1. In a particular embodiment, the polymorph can be characterized by one or more peaks extracted from Figure 1, as shown in Table 1. For example, the polymorph can be characterized by one, two, three, four, five, six, seven, eight, or nine of the peaks shown in Table 1. [Table 1]

[0090] In another embodiment, morphology 1 can be characterized by peaks identified at 2θ angles of 8.6, 15.6, 18.5, 20.6, 21.6, and 26.4°.

[0091] In another embodiment, Embodiment 1 can be characterized by a differential scanning calorimetry profile (DSC) shown in Figure 2. The DSC graph plots the heat flow from the sample as a function of temperature, with a temperature change rate of approximately 10°C / min. This profile is characterized by an endothermic phase transition with an onset temperature of approximately 140.1°C, melting at approximately 149.9°C.

[0092] In another embodiment, Embodiment 1 can be characterized by thermogravimetric analysis (TGA) shown in Figure 3. The TGA profile graphs the rate of weight loss of the sample as a function of temperature, with a temperature change rate of approximately 10°C / min. The weight loss indicates that approximately 0.44% of the sample's weight was lost as the temperature changed from approximately 29.0°C to 125.0°C.

[0093] Form 2 In one embodiment, form 2, which is a single-crystal form of compound 1, is characterized by X-ray powder diffraction (XRPD) obtained by CuKa irradiation, as shown in Figure 4, and the data shown in Table 2. In a particular embodiment, the polymorph can be characterized by one or more peaks extracted from Figure 4, as shown in Table 2. For example, the polymorph can be characterized by one, two, three, four, five, six, seven, eight, nine, or ten of the peaks shown in Table 2. [Table 2]

[0094] In another embodiment, form 2 can be characterized by peaks identified at 2θ angles of 9.8, 11.6, 19.6, 22.5, 23.0, and 31.4°. In yet another embodiment, form 2 can be characterized by peaks identified at 2θ angles of 9.8, 11.6, 19.6, and 23.0°.

[0095] In another embodiment, Embodiment 2 can be characterized by a differential scanning calorimetry profile (DSC) shown in Figure 5. The DSC graph plots the heat flow from the sample as a function of temperature, with a temperature change rate of approximately 10°C / min. This profile is characterized by an endothermic phase transition with an onset temperature of approximately 62.7°C that melts at approximately 72.5°C, and another endothermic phase transition with an onset temperature of approximately 145.6°C that melts at approximately 153.6°C.

[0096] In another embodiment, Embodiment 2 can be characterized by thermogravimetric analysis (TGA) shown in Figure 6. The TGA profile graphs the rate of weight loss of the sample as a function of temperature, with a temperature change rate of approximately 10°C / min. The weight loss indicates that approximately 0.57% of the sample's weight was lost as the temperature changed from approximately 29.3°C to 170.3°C.

[0097] Another embodiment relates to a single-crystal morphology of compound 1 characterized by a combination of the aforementioned properties of any of the single-crystal morphologies described herein. Characterization can be performed by any combination of one or more of XRPD, TGA, and DSC, as described for specific polymorphs. For example, the single-crystal morphology of compound 1 can be characterized by any combination of XRPD results relating to the location of major peaks during an XRPD scan, and / or any combination of one or more parameters derived from the data obtained by the XRPD scan. The single-crystal morphology of compound 1 can also be characterized by the weight loss related to the sample over a specified temperature range; and / or by the determination by TGA of the temperature at which a specific weight loss transition begins. The crystal morphology can also be characterized by the crystal morphology by the determination by DSC of the temperature related to the maximum heat flow during the heat flow transition and / or the temperature at which the sample begins to undergo the heat flow transition. The single-crystal morphology of compound 1 can also be characterized by the weight change of the sample, and / or by the change in water adsorption / desorption per molecule of compound 1, determined by water adsorption / desorption measurements over a wide range of relative humidity (e.g., 0% to 90%).

[0098] solid dispersion A composition is provided containing compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers as part of a solid dispersion (e.g., an amorphous solid dispersion). In some embodiments, the solid dispersion contains compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers. In some embodiments, the solid dispersion contains compound 1 or a pharmaceutically acceptable salt thereof, one or more polymers, and one or more surfactants. In some embodiments, the solid dispersion contains compound 1 or a pharmaceutically acceptable salt thereof and one polymer. In some embodiments, the solid dispersion contains compound 1 or a pharmaceutically acceptable salt thereof, one polymer, and a surfactant.

[0099] Solid dispersions provided herein, containing compound 1 or a pharmaceutically acceptable salt thereof, can improve the solubility of compound 1 compared to the as-is crystalline form of compound 1 (e.g., form 1 or form 2), thereby improving the exposure of the subject to oral administration of the solid dispersion. In some embodiments, the solid dispersion contains compound 1 or a pharmaceutically acceptable salt thereof, one or more polymers, and one or more optionally solubility-enhancing surfactants.

[0100] For example, the water solubility of Form 1 is approximately 0.025 mg / mL to approximately 0.035 mg / mL, and the water solubility of Form 2 is approximately 0.008 mg / mL to approximately 0.010 mg / mL.

[0101] Form 2 has a solubility in fasting artificial intestinal fluid (FASSIF) of approximately 0.018 mg / mL at pH 6.1 after 4 hours. In contrast, the amorphous spray-dried dispersion has a solubility in FASSIF of approximately 0.05 mg / mL to approximately 0.50 mg / mL after 3 hours.

[0102] In some embodiments, when administered to a subject, the solid dispersion exhibits at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% higher exposure to compound 1 or a pharmaceutically acceptable salt compared to administration of the amorphous compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, when administered to a subject, the solid dispersion exhibits at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% higher exposure to compound 1 or a pharmaceutically acceptable salt compared to administration of the crystalline compound 1 or a pharmaceutically acceptable salt thereof.

[0103] Pharmacokinetic studies in rats and monkeys have shown a slight improvement in exposure when administered in solid dispersion form compared to when the compound was administered in its amorphous state. For example, in male SD rats, a solid dispersion containing 50% w / w compound 1 and 50% w / w polyvinyl acetate phthalate (PVAP) resulted in approximately twice the exposure compared to the amorphous compound 1 itself. A solid dispersion containing 70% w / w compound 1 and a 30% w / w oral administration form did not show a significant difference in exposure compared to the amorphous compound 1 itself. In male cynomolgus monkeys, exposure to a solid dispersion containing 50% w / w compound 1 and 50% w / w hydroxypropyl methylcellulose acetate succinate (HPMCAS, also known as hypromellose acetate succinate) did not show a significant difference compared to the amorphous compound 1 itself. Similarly, a solid dispersion containing 50% w / w compound 1 and 50% w / w hydroxypropyl methylcellulose (also known as hypromellose phthalate (HPMC-phthalate)) shows no significant difference compared to the amorphous compound 1 as is. While amorphous therapeutic compounds are commonly used for administration in animal studies, these are not appropriate forms of administration for human use.

[0104] As described in the rat pharmacokinetic study of Example 4, exposure to compound 1 is improved when the solid dispersion form is administered compared to the as-is crystalline compound 1 form 2.

[0105] In some embodiments, at least a portion of compound 1 or its pharmaceutically acceptable salt in the solid dispersion is in an amorphous state (e.g., at least 50%, at least about 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99%). In other embodiments, the solid dispersion is substantially free of crystalline compound 1 or its pharmaceutically acceptable salt.

[0106] In some embodiments, the composition is an amorphous solid (e.g., spray-dried) dispersion containing compound 1 or a pharmaceutically acceptable salt thereof and a polymer. The amorphous solid dispersion may contain, for example, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of crystalline compound 1 or a pharmaceutically acceptable salt thereof, or substantially no crystalline compound 1 or a pharmaceutically acceptable salt thereof, for example.

[0107] In some embodiments, the solid dispersion exhibits a predetermined level of physical and / or chemical stability. For example, when stored at 25°C in a sealed, waterproof container such as a brown glass vial, a high-density polyethylene (HDPE) container, or a double-layer polyethylene bag with a nylon tie wrapped around it and placed in an HDPE container containing a desiccant, the solid dispersion retains, for example, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 99% of amorphous compound 1 or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the polymer improves the chemical or physical stability (e.g., measured by modulated differential scanning calorimetry) of compound 1 or a pharmaceutically acceptable salt when stored (e.g., at 2–8°C, e.g., 4°C, or at room temperature) by at least about 10% (e.g., at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%) of the amorphous compound 1 or a pharmaceutically acceptable salt thereof when the polymer is not present.

[0109] Solid dispersions typically exhibit a glass transition temperature, which is the temperature at which the dispersion transitions from a glassy solid to a rubbery composition. Generally, a higher glass transition temperature indicates greater physical stability of the dispersion. The presence of a glass transition temperature generally indicates that at least a large portion of the composition (e.g., the dispersion) is in an amorphous state. A glass transition temperature (Tg) suitable for solid dispersions for pharmaceutical applications is typically at least about 50°C. In some embodiments, higher temperatures are preferred. Therefore, in some embodiments, the solid dispersions disclosed herein have a Tg of at least about 100°C (e.g., at least about 100°C, at least about 105°C, at least about 110°C, at least about 115°C, at least about 120°C, at least about 125°C, at least about 130°C, at least about 135°C, at least about 140°C, at least about 150°C, at least about 160°C, at least about 170°C, at least about 175°C, at least about 180°C, or at least about 190°C). In some embodiments, the Tg is at most about 200°C. In some embodiments, the Tg is at most about 130°C (e.g., at least about 110°C, at least about 111°C, at least about 112°C, at least about 113°C, at least about 114°C, at least about 115°C, at least about 116°C, at least about 117°C, at least about 118°C, at least about 119°C, at least about 120°C, at least about 121°C, at least about 122°C, at least about 123°C, at least about 124°C, at least about 125°C, at least about 1216°C, at least about 127°C, at least about 128°C, at least about 129°C, at least about 130°C). Unless otherwise specified, the glass transition temperatures disclosed herein are measured under dry conditions.

[0110] In some embodiments, the solid dispersion has a glass transition temperature higher than that of amorphous compound 1 or a pharmaceutically acceptable salt thereof, in which the polymer is absent. In some embodiments, the solid dispersion has a relaxation rate lower than that of amorphous compound 1 or a pharmaceutically acceptable salt thereof, in which the polymer is absent.

[0111] Examples of polymers in solid dispersions include cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), also known as hypromellose; hydroxypropyl methylcellulose phthalate (HPMCP), also known as hypromellose phthalate; hydroxypropyl methylcellulose acetate succinate (HPMCAS), also known as hypromellose acetate succinate; hydroxypropyl cellulose (HPC)), ethyl cellulose, or cellulose acetate phthalate; polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinyl alcohol (PVA); polyvinyl esters such as polyvinyl acetate phthalate (PVAP); acrylates such as polymethacrylate (e.g., Eudragit.RTM.E); cyclodextrin (e.g., β-cyclodextrin); poly(D,L-lactide) (PLA), poly( Examples include D,L-lactide co-glycolic acid (PLGA); and copolymers and derivatives thereof (e.g., polyvinylpyrrolidone-vinyl acetate (PVP-VA), polyvinylcaprolactam-polyvinyl, and acetate-polyethylene glycol copolymer, methacrylate / methacrylic acid copolymer, etc.); Soluplus; Copovidone; and mixtures thereof.

[0112] In some embodiments, the solid dispersion contains one water-soluble polymer. In some embodiments, the solid dispersion contains one partially water-soluble polymer. In some embodiments, the polymer is a cellulose polymer.

[0113] In some embodiments, the polymer is HPMCAS (e.g., various grades of HPMCAS: HPMCAS-M, HPMCAS-MG, or HPMCAS-HG). In some embodiments, the polymer is PVAP. In some embodiments, the polymer is HPMC (e.g., various grades of HPMC: HMPC60SH50, HPMCE50, or HPMCE15). In some embodiments, the polymer is HPMCP (e.g., various grades of HPMCP: e.g., HMPCP-HP55).

[0114] In some embodiments, the polymer is a pH-dependent enteric polymer. Examples of such pH-dependent enteric polymers include, but are not limited to, cellulose derivatives (e.g., cellulose acetate phthalate (CAP)), HPMCP, HPMCAS, carboxymethylcellulose (CMC) or its salts (e.g., sodium salts such as (CMC-Na)); cellulose acetate trimellitate (CAT), hydroxypropyl cellulose acetate phthalate (HPCAP), hydroxypropyl methyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP), polymethacrylate (e.g., Eudragit S), or mixtures thereof.

[0115] In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS, e.g., HMPCAS-HG), also known as hypromellose acetate succinate.

[0116] In another embodiment, the polymer is an insoluble crosslinked polymer, such as polyvinylpyrrolidone (e.g., crospovidone). In yet another embodiment, the polymer is polyvinylpyrrolidone (PVP).

[0117] In some embodiments, one or more polymers are present in the solid dispersion in amounts of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w, about 30% w / w to about 70% w / w, about 40% w / w to about 60% w / w, or about 15% w / w to about 35% w / w). In some embodiments, the polymer is present in the solid dispersion in amounts of about 10% w / w to about 80% w / w, for example, about 30% w / w to about 75% w / w, or about 40% w / w to about 65% w / w, or about 45% w / w to about 55% w / w, for example, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, or about 54% w / w. In some embodiments, the polymer is present in the solid dispersion in amounts of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0118] In some embodiments, the polymer is present in the solid dispersion at an amount of about 30% w / w to about 70% w / w. In some embodiments, the polymer is present in the solid dispersion at an amount of about 35% w / w to about 65% w / w. In some embodiments, the polymer is present in the solid dispersion at an amount of about 40% w / w to about 60% w / w. In some embodiments, the polymer is present in the solid dispersion at an amount of about 45% w / w to about 55% w / w. In some embodiments, the polymer is present in the solid dispersion at an amount of about 50% w / w.

[0119] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion in amounts of about 10% w / w to 90% w / w (e.g., about 20% w / w to about 80% w / w, about 30% w / w to about 70% w / w, about 40% w / w to about 60% w / w, or about 15% w / w to about 35% w / w). In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion in amounts of about 10% w / w to about 80% w / w, for example, about 30% w / w to about 75% w / w, or about 40% w / w to about 65% w / w, or about 45% w / w to about 55% w / w, for example, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, or about 54% w / w. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion in amounts of about 48% w / w, about 48.5% w / w, about 49% w / w, about 49.5% w / w, about 50% w / w, about 50.5% w / w, about 51% w / w, about 51.5% w / w, about 52% w / w, or about 52.5% w / w.

[0120] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion at an amount of about 30% w / w to about 70% w / w. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion at an amount of about 35% w / w to about 65% w / w. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion at an amount of about 40% w / w to about 60% w / w. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion at an amount of about 45% w / w to about 55% w / w. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is present in the solid dispersion at an amount of about 50% w / w.

[0121] In another embodiment, the solid dispersion contains about 20% w / w to about 80% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 20% w / w to about 80% w / w of polymer. In another embodiment, the solid dispersion contains about 25% w / w to about 75% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 25% w / w to about 75% w / w of polymer. In another embodiment, the solid dispersion contains about 30% w / w to about 70% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 30% w / w to about 70% w / w of polymer. In another embodiment, the solid dispersion contains about 35% w / w to about 65% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 35% w / w to about 65% w / w of polymer. In another embodiment, the solid dispersion contains about 40% w / w to about 60% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 40% w / w to about 60% w / w of polymer. In yet another embodiment, the solid dispersion contains about 45% w / w to about 55% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 45% w / w to about 55% w / w of polymer. In yet another embodiment, the solid dispersion contains about 50% w / w of compound 1 or a pharmaceutically acceptable salt thereof and about 50% w / w of polymer.

[0122] In another embodiment, the solid dispersion contains about 45% w / w to about 55% w / w of compound 1 or a pharmaceutically acceptable salt thereof, and about 45% w / w to about 55% w / w of HPMCAS (e.g., HPMCAS-MG or HPMCAS-HG, or other grades such as LF, MF, HF, or LG) or PVAP. In yet another embodiment, the solid dispersion contains about 50% w / w of compound 1 or a pharmaceutically acceptable salt thereof, and about 50% w / w of HPMCAS.

[0123] In some embodiments, the solid dispersion also contains a surfactant or a pharmaceutically acceptable inert substance. Examples of surfactants in the solid dispersion include sodium lauryl sulfate (SLS), vitamin E or its derivatives (e.g., vitamin E TPGS), and doxate sodium. Examples include lium, sodium dodecyl sulfate, polysorbates (such as Tween 20 and Tween 80), poloxamers (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, Span 65, Span 25, Capryol 90, pluronic copolymers (e.g., Pluronic F108, Pluronic P-123), and mixtures thereof. In some embodiments, interfaces are used. The activator is SLS. In some embodiments, the surfactant is vitamin E or a derivative thereof (e.g., vitamin E TPGS).

[0124] In some embodiments, the surfactant is present in the solid dispersion in amounts of about 0.1% w / w to about 10% w / w, for example, about 0.5% w / w to about 2% w / w, or 1% w / w to about 3% w / w, 1% w / w to about 4% w / w, or 1% w / w to about 5% w / w. In some embodiments, the surfactant is present in the solid dispersion in amounts of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, or about 1% w / w. In some embodiments, the surfactant is present in the solid dispersion in amounts of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, or about 5% w / w.

[0125] Preparation process for solid dispersions In some embodiments, solid dispersions can be prepared according to the processes described herein. Methods that can typically be used include rapid removal of the solvent or solvent mixture from the mixture, or cooling of the molten sample. Such methods, but are not limited to, include rotary evaporation, freeze-drying (i.e., lyophilization), vacuum drying, melt solidification, and melt extrusion. Some embodiments of this disclosure involve solid dispersions obtained by spray drying. In some embodiments, the product obtained by spray drying is dried to remove the solvent or solvent mixture.

[0126] The formulations disclosed herein, such as pharmaceutical compositions, can be obtained by spray drying a mixture containing compound 1 or a pharmaceutically acceptable salt thereof, one or more polymers, and a suitable solvent or solvent mixture. Spray drying includes, for example, spraying a liquid mixture containing a solid and a solvent or solvent mixture, and removing the solvent or solvent mixture. The solvent or solvent mixture may also include non-volatile solvents such as glacial acetic acid. Spraying may be performed, for example, by two fluids, or by pressure, or by an electroacoustic nozzle, or on a rotating disk.

[0127] Spray drying converts a liquid feed into a dry, particulate form. Spray drying typically involves spraying the liquid feed into droplets and bringing the droplets into contact with hot air or gas in a drying chamber. The droplets are usually produced by either a rotary (wheel) atomizer or a nozzle atomizer. Evaporation of vapor from the droplets and formation of dry particles occur under controlled temperature and airflow conditions.

[0128] Optionally, a second drying step, such as fluidized bed drying or vacuum drying, may be used to reduce residual solvent (and other additives such as glacial acetic acid) to a pharmaceutically acceptable level. Typically, spray drying involves contacting a highly dispersed liquid suspension or solution (e.g., the sprayed solution) with a sufficient amount of hot air or gas (e.g., pure nitrogen) to evaporate and dry droplets. The preparation to be spray-dried may be any solution, coarse-particulate suspension, slurry, colloidal dispersion, or paste that can be sprayed using a selected spray drying apparatus. In a standard procedure, the preparation is sprayed into a filtered stream of hot air (or into a gas such as nitrogen). This stream carries the product, which has had the solvent evaporated and dried, to a particle collector (e.g., a cyclone). The used air or gas is then exhausted along with the solvent (or solvent mixture containing any additives such as glacial acetic acid). (e.g., then filtered) or the used air or gas is sent to a condenser for capture and possibly recycling of the solvent or solvent mixture. For example, if a gas (e.g., nitrogen) is used, the gas may optionally be recycled and reheated and returned to a closed-loop unit. Commercially available equipment may be used for spray drying. For example, commercially available spray dryers are manufactured by Buchi Ltd. and Niro (e.g., Niro's PSD line of spray dryers).

[0129] Spray drying typically uses a solid content load of about 1 to about 30%, or up to about 50%, of the raw material solids (i.e., therapeutic active compound + additives), preferably at least about 10%. In some embodiments, a solid content load of less than 10% may result in low yields or unacceptably long operating times. Typically, the upper limit of the solid content load depends on the viscosity of the resulting solution (e.g., the pump capacity) and the solubility of the components in the solution. Typically, the viscosity of the solution can determine the particle size in the resulting powder product.

[0130] Techniques and methods for powder drying can be found in Perry's Chemical Engineering Handbook, 6th Ed., RH Perry, DW Green & JO Maloney, eds., McGraw-Hill Book Co. (1984), and in Marshall "Atomization and Spray-Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). Typically, spray drying is carried out at an inlet temperature of about 40°C to about 200°C, for example, about 70°C to about 150°C, preferably about 40°C to about 60°C, about 50°C to about 55°C, or about 80°C to about 110°C, for example, about 90°C. Spray drying is typically performed at outlet temperatures ranging from approximately 20°C to 100°C, for example, approximately 25°C to 30°C (e.g., approximately 26°C), approximately 40°C to 50°C, and approximately 50°C to 65°C, for example, approximately 56°C to 58°C.

[0131] Removal of the solvent or solvent mixture may require a subsequent drying process such as box drying, fluidized bed drying (e.g., room temperature to approximately 100°C), vacuum drying, microwave drying, rotary drum drying, or biconical vacuum drying (e.g., room temperature to approximately 200°C).

[0132] In one embodiment, spray drying is fluidized spray drying (FSD). The FSD process may include, for example, preparing a liquid feed solution (containing, for example, compound 1 or a pharmaceutically acceptable salt thereof, and an optional polymer and / or surfactant, dissolved or suspended in a solvent); spraying the feed solution (e.g., using a pressure nozzle, rotary atomizer or disc, two-component nozzle, or other spraying method) while simultaneously transporting it into a drying chamber of a spray dryer operating in FSD mode; drying the feed solution in the drying chamber with hot air or a heated gas (e.g., nitrogen) to obtain a product, wherein larger particles of the product are separated (e.g., detached), and fine particles are transported by air or gas flow to the top of the drying chamber (e.g., by natural convection) and to a cyclone; and reintroducing the fine particles into the drying chamber (e.g., at the top of the drying chamber or to the axial middle of the chamber), wherein the reintroduced fine particles can aggregate with the newly formed product to form an aggregate product, which is separated if it is large enough, and if it is not large enough to be separated, the aggregate product is transported by convection to the top of the chamber and to a cyclone and reintroduced into the chamber. This process is repeated until aggregated products large enough to detach are formed. The fine particles can be reintroduced from the cyclone to the drying chamber via a feed pipe.

[0133] In some embodiments, the feed liquid can be spray-condensed instead of drying it with hot air or a heated gas, for example, the chamber may be at room temperature (e.g., 21±4°C) or cooled, and a cooling gas (e.g., nitrogen) may be used for the process.

[0134] The FSD may further include collecting the agglomeration product in a first fluidization chamber, which can be done before transferring the agglomeration product from the first fluidization chamber to a second fluidization chamber where post-drying treatment may be performed.

[0135] The agglomerated product (e.g., one removed in a drying chamber) can then be transferred from a second fluidization chamber to a third fluidization chamber, where it is cooled. The agglomerated product (e.g., a solid dispersion of an amorphous compound) can then be further processed. For example, the product can be directly compressed. Optionally, the product can be blended with a surfactant, additive, or pharmaceutically acceptable carrier, for example, before direct compression. Optionally, the product can be further processed, such as by grinding, granulation, blending, and / or mixing with molten granules, surfactants, additives, and / or pharmaceutically acceptable carriers.

[0136] FSD can be performed using a commercially available spray dryer operating in a fluidized spray drying (FSD) system. FSD can be performed using either an open-circulation or closed-circulation system (where drying gases such as nitrogen are recycled). A suitable example of a spray dryer for use in FSD is Niro (e.g., Niro's PSD line spray dryers: PHARMASD.TM.: chemical or SD line dryers). FSD can essentially be performed in any spray dryer configured to allow reintroduction of particulate matter into the drying chamber.

[0137] If further solvent removal is necessary or appropriate, additional post-drying can be performed, for example, using a vacuum or fluidized bed dryer, a double-cone or biconical post-dryer, or a rotary dryer. In some embodiments, a post-drying step is performed.

[0138] To remove the solvent or solvent mixture, vacuum drying, spray drying, fluidized spray drying, box drying, freeze-drying, drying by rotary evaporation, and other drying methods can be used. By performing any of these methods with appropriate processing parameters according to this disclosure, compound 1 or a pharmaceutically acceptable salt thereof in an amorphous state in the final solid dispersion product will be obtained. The dispersion can be directly compressed into a dosing form by using appropriate conditions (e.g., low outlet temperature of the spray dryer, use of a low boiling point solvent, use of a heating gas) to obtain a dispersion such as a dry powder having desirable properties (e.g., median particle size (d50) of 40-200 microns, e.g., 40-150 microns), a powder bulk density of >0.2 g / ml (e.g., 0.2-0.5 g / ml) or >0.25 g / ml, improved powder flowability (e.g., low cohesive force, low interparticle internal friction); and / or low OVI (organic volatile impurities), e.g., below ICH limits and / or user specifications).

[0139] In some embodiments, the inlet temperature is approximately 50°C to approximately 200°C, for example, approximately 60°C to approximately 150°C, approximately 70°C to approximately 100°C, approximately 60°C to approximately 95°C, approximately 65°C to approximately 85°C, approximately 70°C to approximately 90°C, approximately 85°C to approximately 95°C, or approximately 70°C to approximately 85°C.

[0140] In some embodiments, the outlet temperature is approximately room temperature (e.g., USP room temperature (e.g., 21±4°C)) to approximately 80°C, for example, approximately 25°C to approximately 75°C, approximately 30°C to approximately 65°C, approximately 35°C to approximately 70°C, approximately 40°C to approximately 65°C, approximately 45°C to approximately 60°C, approximately 35°C to approximately 45°C, approximately 35°C to approximately 40°C, or approximately 37°C to approximately 40°C.

[0141] In some embodiments, the temperature setpoints for the fluidized beds (the temperature of each bed is selected independently of the temperature selected for other beds) are approximately room temperature (e.g., USP room temperature (e.g., 21±4°C)) to approximately 100°C, for example, approximately 30°C to approximately 95°C, approximately 40°C to approximately 90°C, approximately 50°C to approximately 80°C, approximately 60°C to approximately 85°C, approximately 65°C to approximately 95°C, or approximately 80°C to approximately 95°C.

[0142] FSD can be performed on a mixture containing the compound of interest (e.g., a therapeutic agent (e.g., a therapeutically active compound) such as compound 1 or a pharmaceutically acceptable salt thereof). For example, FSD can be performed on a mixture containing compound 1 or a pharmaceutically acceptable salt thereof (e.g., and one or more polymers, and one or more optionally surfactants, and optionally additives) to obtain a solid dispersion of amorphous compound 1 or a pharmaceutically acceptable salt thereof that can be directly compressed into, for example, an oral dosage form (e.g., a tablet). Alternatively, the dispersion may be blended with one or more additives before compression.

[0143] In one embodiment, the steps for preparing a solid dispersion of compound 1 are: a) Forming a mixture of compound 1 or a pharmaceutically acceptable salt thereof, one or more polymers, and one or more solvents; and b) Rapidly remove the solvent from the solution to form a solid amorphous dispersion containing compound 1 or a pharmaceutically acceptable salt thereof and one or more polymers; This includes one or more polymers and one or more solvents, which may be any of those disclosed herein.

[0144] In some embodiments, the solvent is removed by spray drying. In some embodiments, the solid dispersion is tray-dried using a convection box dryer. In some embodiments, the solid dispersion is sieved.

[0145] In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is crystalline. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is amorphous.

[0146] As will be recognized by those skilled in the art, spray drying may, and often is, carried out in the presence of an inert gas such as nitrogen. In certain embodiments, the process including spray drying may be carried out in the presence of a supercritical fluid containing carbon dioxide or a mixture containing carbon dioxide.

[0147] In another embodiment, the step for preparing a solid dispersion of compound 1 or a pharmaceutically acceptable salt thereof is: a) forming a mixture of compound 1 or a pharmaceutically acceptable salt thereof, a polymer, and a solvent; and b) Spray-drying the mixture to form a solid dispersion containing compound 1 or a pharmaceutically acceptable salt thereof and a polymer; Includes.

[0148] Post-drying and / or polishing may be optionally performed on the moist spray-dried dispersion until the residual solvent is below ICH or a specified specification.

[0149] These steps can be used to prepare the pharmaceutical compositions disclosed herein. The amounts and characteristics of the components used in these steps may be as disclosed herein.

[0150] In some embodiments, the solvent comprises one or more volatile solvents for dissolving or suspending compound 1 or its pharmaceutically acceptable salts and polymers. In some embodiments, the one or more solvents completely dissolve compound 1 or its pharmaceutically acceptable salts and polymers.

[0151] In some embodiments, one or more solvents are volatile solvents (e.g., methylene chloride, acetone, methanol, ethanol, chloroform, tetrahydrofuran (THF), or mixtures thereof). Examples of suitable volatile solvents include those that dissolve or suspend the therapeutic compound, either alone or in combination with other co-solvents. In some embodiments, the solvent completely dissolves the therapeutic compound. In some embodiments, the solvent is acetone. In some embodiments, the solvent is methanol.

[0152] In some embodiments, the solvent is a non-volatile solvent (e.g., an organic acid such as glacial acetic acid, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or water). In some embodiments, the non-volatile solvent is a component of the solvent system. For example, the non-volatile solvent is present as a component in the solvent at a concentration of about 1% to about 20% w / w (e.g., about 3% w / w to about 15% w / w, about 4% w / w to about 12% w / w, or about 5% w / w to about 10% w / w).

[0153] In some embodiments, the solvent is a mixture of solvents. For example, the solvent may consist of about 0% to about 30% acetone and about 70% to about 100% methanol, or it may consist of about 0% to about 40% acetone and about 60% to about 100% methanol. Other typical methanol-to-acetone ratios include 80:20, 75:25, 70:30, 60:40, 55:45, and 50:50.

[0154] In some embodiments, the solvent is a combination of solvents, including at least one non-volatile solvent. For example, the solvent is a combination of components containing both a volatile solvent and a non-volatile solvent. In some embodiments, the solvent system is a combination of volatile solvents, or a combination of a solvent such as methanol or acetone and a non-volatile solvent such as glacial acetic acid. For example, the solvent system contains about 40% to about 80% methanol, about 20% to about 35% acetone, and about 1% to about 15% glacial acetic acid (e.g., about 50% to about 70% methanol, about 25% to about 30% acetone, and about 3% to about 12% glacial acetic acid).

[0155] In some embodiments, the solvent system is a combination of volatile solvents, or a combination of a solvent such as methanol or acetone and a non-volatile solvent such as water. For example, the solvent system contains about 40% to about 80% methanol, about 20% to about 35% acetone, and about 0.1% to about 15% water (for example, about 50% to about 70% methanol, about 25% to about 30% acetone, and about 1% to about 5% water).

[0156] Pharmaceutical composition Pharmaceutical compositions in solid dispersion can be prepared by the processes described herein. For example, a solid dispersion of (a) compound 1 or a pharmaceutically acceptable salt thereof, (b) one or more polymers, one or more optionally selected surfactants, and one or more optionally selected additional additives.

[0157] The present invention provides a pharmaceutical composition comprising (a) a solid dispersion containing compound 1 or a pharmaceutically acceptable salt thereof and a polymer; and (b) one or more pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers include excipients, disintegrants, wetting agents, fluidizing agents, and lubricants.

[0158] In some embodiments, the pharmaceutical composition can be administered orally in any orally administered form, such as (but not limited to) capsules, tablets, emulsions, aqueous suspensions, aqueous dispersions, and aqueous solutions.

[0159] In some embodiments, the pharmaceutical composition is a tablet.

[0160] In some embodiments, the pharmaceutical composition contains compound 1 or a pharmaceutically acceptable salt thereof in a directly compressed dosage form.

[0161] In some embodiments, the pharmaceutical composition also contains an excipient. The excipient may be, for example, microcrystalline cellulose, lactose, mannitol, ethylcellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicified microcrystalline cellulose, isomalt, or a mixture thereof. In some embodiments, the excipient is microcrystalline cellulose.

[0162] In some embodiments, the excipient is present in the pharmaceutical composition in an amount of about 10% w / w to 50% w / w (for example, about 15% w / w to about 45% w / w, about 20% w / w to about 40% w / w, about 25% w / w to about 35% w / w, or about 28% w / w to about 32% w / w). In some embodiments, the excipient is present in the pharmaceutical composition in an amount of about 20% w / w to about 35% w / w, for example, about 25% w / w to about 34% w / w, about 26% w / w to about 33% w / w, or about 27% w / w to about 32% w / w, for example, about 28% w / w, about 28.5% w / w, about 29% w / w, about 29.5% w / w, about 30% w / w, about 30.5% w / w, about 31% w / w, or about 31.5% w / w. In some embodiments, the excipient is present in the pharmaceutical composition in amounts of about 29% w / w, about 29.1% w / w, about 29.2% w / w, about 29.3% w / w, about 29.4% w / w, about 29.5% w / w, about 29.6% w / w, about 29.7% w / w, about 29.8% w / w, about 29.9% w / w, or about 30% w / w. In some embodiments, the excipient is present in the pharmaceutical composition in amounts of about 25% w / w to about 35% w / w. In some embodiments, the excipient is present in the pharmaceutical composition in amounts of about 29.5% w / w.

[0163] In some embodiments, the pharmaceutical composition also contains a disintegrant. The disintegrant may be, for example, colloidal silicon dioxide, powdered cellulose, calcium silicate, crospovidone, calcium alginate, methylcellulose, chitosan, carboxymethylcellulose, croscarmellose sodium, carboxymethyl starch, sodium alginate, sodium starch glycolate, pregelatinized starch, or a mixture thereof. In some embodiments, the disintegrant is croscarmellose sodium.

[0164] In some embodiments, the disintegrant is present in the pharmaceutical composition in amounts of approximately 1% w / w to 15% w / w (e.g., approximately 3% w / w to 12% w / w, approximately 4% w / w to 10% w / w, approximately 5% w / w to 7% w / w, or approximately 6% w / w to 7% w / w). In some embodiments, the disintegrant is present in the pharmaceutical composition in amounts of approximately 3% w / w, approximately 3.5% w / w, approximately 4% w / w, approximately 49.5% w / w, approximately 5% w / w, approximately 5.5% w / w, approximately 6% w / w, approximately 6.5% w / w, approximately 7% w / w, approximately 7.5% w / w, approximately 8% w / w, approximately 8.5% w / w, approximately 9% w / w, approximately 9.5% w / w, or approximately 10% w / w. In some embodiments, the disintegrant is present in the pharmaceutical composition in amounts of approximately 5% w / w to 7% w / w. In some embodiments, the disintegrant is present in the pharmaceutical composition at an amount of about 6% w / w.

[0165] In some embodiments, the pharmaceutical composition also contains a humectant. The humectant may be, for example, sodium lauryl sulfate, sodium dodecyl sulfate, polysorbate (such as Tween 20 and Tween 80), poloxamer (such as Poloxamer 335 and Poloxamer 407), glyceryl monooleate, or a mixture thereof. In some embodiments, the humectant is sodium lauryl sulfate.

[0166] In some embodiments, the wetting agent is present in the pharmaceutical composition in an amount of about 0.1% w / w to 2% w / w (e.g., about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1.5% w / w, or about 1% w / w to about 1.5% w / w). In some embodiments, the wetting agent is present in the pharmaceutical composition in amounts of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, or about 2% w / w. In some embodiments, the wetting agent is present in the pharmaceutical composition in amounts of about 0.5% w / w to about 1.5% w / w. In some embodiments, the wetting agent is present in the pharmaceutical composition in amounts of about 1% w / w.

[0167] In some embodiments, the pharmaceutical composition also contains a fluidizing agent. The fluidizing agent may be, for example, silicon dioxide, colloidal silicon dioxide, tricalcium phosphate, magnesium stearate, magnesium trisilicate, powdered cellulose, talc, starch, or mixtures thereof. In some embodiments, the fluidizing agent is colloidal silicon dioxide.

[0168] In some embodiments, the fluidizing agent is present in the pharmaceutical composition in an amount of about 0.1% w / w to 5% w / w (e.g., about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, or about 1.5 w / w to about 2.5% w / w). In some embodiments, the fluidizing agent is present in the pharmaceutical composition in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, or about 4% w / w, about 4.5% w / w, or about 5% w / w. In some embodiments, the fluidizer is present in the pharmaceutical composition in amounts of about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, or about 3% w / w. In some embodiments, the fluidizer is present in the pharmaceutical composition in amounts of about 1% w / w to about 3% w / w. In some embodiments, the fluidizer is present in the pharmaceutical composition in amounts of about 2% w / w.

[0169] In some embodiments, the pharmaceutical composition also contains a lubricant. The lubricant may be, for example, magnesium stearate, talc, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, zinc stearate, calcium stearate, sucrose stearate, polyvinyl alcohol, magnesium lauryl sulfate, or a mixture thereof. In some embodiments, the lubricant is magnesium stearate.

[0170] In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.1% w / w to 5% w / w (e.g., about 1% w / w to 4% w / w, about 1% w / w to 3% w / w, or about 1% w / w to 2% w / w). In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, or about 5% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition in amounts of about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, or about 2.5% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition at an amount of about 0.5% w / w to about 2.5% w / w. In some embodiments, the lubricant is present in the pharmaceutical composition at an amount of about 1.5% w / w.

[0171] In some embodiments, the solid dispersion accounts for approximately 25% to 85% by weight of the total weight of the pharmaceutical composition. In some embodiments, the solid dispersion accounts for approximately 50% to 70% by weight of the total weight of the pharmaceutical composition.

[0172] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof accounts for about 15% to 45% by weight of the total weight of the pharmaceutical composition, and one or more polymers account for about 15% to 45% by weight of the total weight of the pharmaceutical composition.

[0173] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof accounts for about 20% w / w of the pharmaceutical composition, and one or more polymers account for about 40% w / w of the pharmaceutical composition.

[0174] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof accounts for about 25% w / w of the pharmaceutical composition, and one or more polymers account for about 35% w / w of the pharmaceutical composition.

[0175] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof accounts for about 30% w / w of the pharmaceutical composition, and one or more polymers account for about 30% w / w of the pharmaceutical composition.

[0176] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof accounts for 35% w / w of the pharmaceutical composition, and one or more polymers account for approximately 25% w / w of the pharmaceutical composition.

[0177] In some embodiments, the solid dispersion accounts for approximately 50% w / w to 70% w / w of the pharmaceutical composition, the excipients for approximately 25% w / w to 35% w / w, the disintegrants for approximately 5% w / w to 7% w / w, the wetting agents for approximately 0.5% w / w to 1.5% w / w, the fluidizing agents for approximately 1% w / w to 3% w / w, and the lubricants for approximately 0.5% w / w to 2.5% w / w, resulting in a total composition of 100% by weight.

[0178] In some embodiments, the solid dispersion accounts for approximately 60% w / w of the pharmaceutical composition, the excipient accounts for approximately 29.5% w / w, the disintegrant accounts for approximately 6% w / w, the wetting agent accounts for approximately 1% w / w, the fluidizing agent accounts for approximately 2% w / w, and the lubricant accounts for 1.5% w / w.

[0179] In some embodiments, the pharmaceutical composition contains about 25% w / w to about 35% w / w of compound 1 or a pharmaceutically acceptable salt thereof, about 25% w / w to about 35% w / w of hypromellose acetate succinate (HPMCAS), about 25% w / w to about 35% w / w of microcrystalline cellulose, about 5% w / w to about 7% w / w of croscarmellose sodium, about 0.5% w / w to about 1.5% w / w of sodium lauryl sulfate, about 1% w / w to about 3% w / w of colloidal silicon dioxide, and about 0.5% w / w to about 2.5% w / w of magnesium stearate, resulting in a composition totaling 100% by weight.

[0180] In some embodiments, the pharmaceutical composition contains about 30% w / w of compound 1 or a pharmaceutically acceptable salt thereof, about 30% w / w of hypromellose acetate succinate (HPMCAS), about 29.5% w / w of microcrystalline cellulose, about 6% w / w of croscarmellose sodium, about 1% w / w of sodium lauryl sulfate, about 2% w / w of colloidal silicon dioxide, and about 1.5% w / w of magnesium stearate.

[0181] In some embodiments, solid dispersions, excipients, disintegrants, wetting agents, fluidizers, and lubricants are added within the granules. In some embodiments, additional amounts of excipients, disintegrants, fluidizers, and lubricants are added outside the granules.

[0182] In some embodiments, the pharmaceutical composition contains the following granular additives, namely, a solid dispersion comprising about 50% w / w to about 70% w / w of the pharmaceutical composition, an excipient comprising about 18% w / w to about 26% w / w of the pharmaceutical composition, a disintegrant comprising about 2% w / w to about 6% w / w of the pharmaceutical composition, a wetting agent comprising about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, a fluidizing agent comprising about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, and a lubricant comprising about 0.25% w / w to about 1% w / w of the pharmaceutical composition.

[0183] In some embodiments, the pharmaceutical composition contains the following extragranular components, namely, an additional amount of excipients comprising about 4% w / w to about 12% w / w of the pharmaceutical composition, an additional amount of disintegrant comprising about 1% w / w to about 3% w / w of the pharmaceutical composition, an additional amount of fluidizer comprising about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, and an additional amount of lubricant comprising about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, which are added at the end.

[0184] In some embodiments, the granules contain the following internally added components: a solid dispersion comprising approximately 60% w / w of the pharmaceutical composition; an excipient comprising approximately 21.5% w / w of the pharmaceutical composition; a disintegrant comprising approximately 4% w / w of the pharmaceutical composition; a wetting agent comprising approximately 1% w / w of the pharmaceutical composition; a fluidizing agent comprising approximately 1% w / w of the pharmaceutical composition; and a lubricant comprising approximately 0.5% w / w of the pharmaceutical composition.

[0185] In some embodiments, the pharmaceutical composition contains the following extragranular components, namely, an additional amount of excipients comprising about 8% w / w of the pharmaceutical composition, an additional amount of disintegrant comprising about 2% w / w of the pharmaceutical composition, an additional amount of fluidizer comprising about 1% w / w of the pharmaceutical composition, and an additional amount of lubricant comprising about 1% w / w of the pharmaceutical composition, which are added at the end.

[0186] In some embodiments, the pharmaceutical composition contains the following granular additives, namely, a solid dispersion containing compound 1 or a pharmaceutically acceptable salt thereof and hypromellose acetate succinate (HPMCAS), accounting for about 50% w / w to about 70% w / w of the pharmaceutical composition; microcrystalline cellulose, accounting for about 18% w / w to about 26% w / w of the pharmaceutical composition; croscarmellose sodium, accounting for about 2% w / w to about 6% w / w of the pharmaceutical composition; sodium lauryl sulfate, accounting for about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition; colloidal silicon dioxide, accounting for about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition; and magnesium stearate, accounting for about 0.25% w / w to about 1% w / w of the pharmaceutical composition.

[0187] In some embodiments, the pharmaceutical composition contains the following extragranular additives, namely, an additional amount of microcrystalline cellulose accounting for about 4% w / w to about 12% w / w of the pharmaceutical composition, an additional amount of croscarmellose sodium accounting for about 1% w / w to about 3% w / w of the pharmaceutical composition, an additional amount of colloidal silicon dioxide accounting for about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, and an additional amount of magnesium stearate accounting for about 0.5% w / w to about 1.5% w / w of the pharmaceutical composition, which are added at the end.

[0188] In some embodiments, the pharmaceutical composition contains the following granular additives: a solid dispersion containing compound 1 or a pharmaceutically acceptable salt thereof and hypromellose acetate succinate (HPMCAS), which constitutes about 60% w / w of the pharmaceutical composition; microcrystalline cellulose, which constitutes about 21.5% w / w of the pharmaceutical composition; croscarmellose sodium, which constitutes about 4% w / w of the pharmaceutical composition; sodium lauryl sulfate, which constitutes about 1% w / w of the pharmaceutical composition; colloidal silicon dioxide, which constitutes about 1% w / w of the pharmaceutical composition; and magnesium stearate, which constitutes about 0.5% w / w of the pharmaceutical composition.

[0189] In some embodiments, the pharmaceutical composition contains the following extragranular additives, namely, an additional amount of microcrystalline cellulose accounting for about 8% w / w of the pharmaceutical composition, an additional amount of croscarmellose sodium accounting for about 2% w / w of the pharmaceutical composition, an additional amount of colloidal silicon dioxide accounting for about 1% w / w of the pharmaceutical composition, and an additional amount of magnesium stearate accounting for about 1% w / w of the pharmaceutical composition, which are added at the end.

[0190] Subjects may receive administration of compound 1 or a pharmaceutically acceptable salt thereof, as described in Example 5. Higher or lower doses than those listed above may be required. Specific dosages and treatment plans for any individual patient will depend on a variety of factors, including the activity of the specific compound, workplace, age, weight, overall health, sex, diet, administration time, excretion rate, drug combinations, severity and course of the disease or condition or symptoms, the subject's willingness to accept the disease or condition or symptoms, and the judgment of the treating physician.

[0191] When the patient's condition improves, a maintenance dose of one embodiment of the compound, composition, or combination of the present invention may be administered as needed. Subsequently, if the symptoms have been alleviated to a desirable level, the dose, frequency, or both may be reduced according to the symptoms to a level at which the improved state is maintained. However, in some cases, long-term intermittent treatment may be required for the subject based on any form of recurrence of disease symptoms.

[0192] How to use The inhibitory activity of compound 1 provided herein or a pharmaceutically acceptable salt thereof against IDH1 variants (e.g., IDH1R132H or IDH1R132C) can be tested by the method described in Example A of PCT Publication No. WO2013 / 107291 and US Publication No. US2013 / 0190249 (these in whole are incorporated herein by reference) or by a similar method.

[0193] A method is provided for treating advanced solid tumors, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutant allele of IDH1, comprising administering a pharmaceutical composition comprising (a) compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion and (b) one or more pharmaceutically acceptable carriers to a subject requiring such treatment. In one embodiment, advanced solid tumors to be treated, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), are characterized by a mutant allele of IDH1, where the IDH1 mutation results in a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate in the patient. In one aspect of this embodiment, the mutant IDH1 has the R132X mutation. In one aspect of this embodiment, the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S, and R132G. In another embodiment, the R132X mutation is R132H or R132C. In yet another embodiment, the R132X mutation is R132H.

[0194] Advanced solid tumors such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated IDH1 allele, are treated by sequence analysis of cell specimens to determine the specific nature of the mutation at the 132nd amino acid of IDH1 (e.g., the changes in the amino acids present).

[0195] While not bound by theory, the applicant believes that mutations in IDH1 give rise to a novel ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate, particularly the R132H mutation of IDH1, characterize a subset of all types of cancer, regardless of their cellular characteristics or location in the body. Therefore, the compound and the method of one aspect of the present invention are useful for the treatment of advanced solid tumors such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), respectively, characterized by the presence of mutations in IDH1 that give rise to such activity, particularly the IDH1 R132H or R132C mutations.

[0196] In one embodiment, the efficacy of treating advanced hematopoietic malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated IDH1 allele, is monitored by measuring the level of 2HG in the subject. Typically, 2HG levels are measured before treatment, and high levels indicate the use of compound 1 or a pharmaceutically acceptable salt thereof for the treatment of advanced hematopoietic malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), each characterized by the presence of a mutated allele of IDH1, respectively. After high levels are confirmed, 2HG levels are measured during and / or after treatment to demonstrate efficacy. In some embodiments, 2HG levels are measured only during and / or after treatment. A decrease in 2HG levels during and after treatment indicates efficacy. Similarly, a determination that 2HG levels do not increase during or after treatment also indicates efficacy. Typically, these 2HG measurements are used in conjunction with other well-known methods for determining the effectiveness of cancer treatment, such as a reduction in the number and size of tumors and / or other cancer-related lesions, evaluation of bone marrow biopsies and / or bone marrow aspirations, examination of whole blood counts and peripheral blood smears, improvement in the subject's overall health status, and changes in other biomarkers related to the effectiveness of cancer treatment.

[0197] 2HG can be detected in a sample by the methods described in PCT Publication No. WO WO / 2011 / 050210 and US Publication No. US2012 / 0121515 (these in whole are incorporated herein by reference) or by similar methods.

[0198] Methods for evaluating specimens and / or subjects This section provides methods for collecting and analyzing specimens, as well as methods for analyzing test subjects.

[0199] Multiple embodiments of this method include evaluating one or more parameters related to α-hydroxy novel activity of IDH1, such as 2HG novel activity, for example, to evaluate the genotype or phenotype of 2HD novel activity of IDH1. The evaluation can be performed, for example, for subject selection, diagnosis, or prognosis studies, for example, for selecting therapeutic agents such as inhibitors, or for evaluating response to treatment or disease progression. In some embodiments, the evaluation can be performed before and / or after initiating treatment, which is at least in part based on the analysis of tumor specimens, cancer cell specimens, or precancerous cell specimens from the subject. For example, a specimen from a patient can be analyzed for the presence or level of α-hydroxy novel activity products, such as R-2HG, by evaluating parameters that correlate with the presence or level of α-hydroxy novel activity products, such as R-2HG, for example. α-hydroxy novel activity products, such as R-2HG, for example, in a specimen can be measured by chromatographic methods, such as LC-MS analysis. This can also be measured by contacting the sample with a specific binder, such as an antibody, that binds to an α-hydroxy novel activity product, such as 2HG, for example, R-2HG, to enable detection. In one embodiment, the sample is analyzed for the level of novel activity, such as α-hydroxy novel activity, such as 2HG novel activity. In another embodiment, the sample is analyzed for the presence of a mutant IDH1 protein (or corresponding RNA) having α-hydroxy novel activity, such as 2HG novel activity. To detect the novel activity mutant enzyme, a mutant protein-specific reagent can be used, such as an antibody that specifically binds to an IDH1 mutant protein, such as an antibody that specifically binds to an IDH1-R132H mutant protein. In one embodiment, nucleic acid sequencing is performed on the sample to determine whether a selected allele or IDH1 mutation as disclosed herein is present. In another embodiment, the analysis is other than the direct determination of the presence of a mutant IDH1 protein (or corresponding RNA) or sequencing of the IDH1 gene.In some embodiments, the analysis is other than a direct determination, for example, this is other than sequencing of genomic DNA or cDNA, or the presence of a mutation at residue 132 of IDH1. For example, the analysis may be the detection of α-hydroxylase novel activity products, such as 2HG, such as R-2HG, or the measurement of α-hydroxylase novel activity, such as 2HG novel activity, due to a mutation. In some embodiments, a sample is taken from a patient and analyzed. In some embodiments, evaluation may include one or more of the following: performing an analysis of a sample, requesting an analysis of a sample, requesting the results of an analysis of a sample, or receiving the results of an analysis of a sample. (As used herein, analysis may usually include performing a basic method and receiving data from another person who has performed the basic method, or both.)

[0200] In some embodiments, the evaluation can be performed before and / or after the initiation of treatment, and this is based at least in part on the analysis of tissues (e.g., tissues other than tumor specimens), or body fluids, or endogenous products. Typical tissues include lymph nodes, skin, hair follicles, and nails. Typical body fluids include blood, plasma, urine, lymph, tears, sweat, saliva, semen, and cerebrospinal fluid. An example of a typical endogenous product is exhaled breath. For example, tissues, fluids, or products can be analyzed for the presence or level of α-hydroxyleptic products, such as R-2HG, by evaluating parameters that correlate with the presence or level of α-hydroxyleptic products, such as R-2HG, for example. α-hydroxyleptic products, such as R-2HG, in a specimen can be measured by chromatographic methods, such as LC-MS analysis. This can also be measured by contacting the specimen with a specific binder, such as an antibody, that binds to the α-hydroxyleptic product, such as R-2HG, to enable detection. In embodiments where sufficient levels are available, tissues, fluids, or products can be analyzed for the level of novel activity, such as α-hydroxy novel activity, such as 2HG novel activity. In some embodiments, a sample is analyzed for the presence of a mutant IDH1 protein (or corresponding RNA) having α-hydroxy novel activity, such as 2HG novel activity. For example, to detect a novel-active mutant enzyme, a mutant protein-specific reagent can be used, such as an antibody that specifically binds to an IDH mutant protein, such as an antibody that specifically binds to an IDH1-R132H mutant protein. In some embodiments, nucleic acid sequencing is performed on a sample to determine whether a selected IDH1 allele or mutation disclosed herein is present. In some embodiments, the analysis is other than the direct determination of the presence of a mutant IDH1 protein (or corresponding RNA) or sequencing of the IDH1 gene. For example, the analysis may be the detection of an α-hydroxy novel activity product, such as 2HG, such as R-2HG, or the measurement of 2HG novel activity. In some embodiments, tissues, fluids, or products are collected from a patient and analyzed.In some embodiments, the evaluation may include one or more of the following: performing an analysis of tissue, liquid, or product; requesting an analysis of tissue, liquid, or product; requesting the results of the analysis of tissue, liquid, or product; or receiving the results of the analysis of tissue, liquid, or product.

[0201] In some embodiments, the evaluation may be performed before and / or after the initiation of treatment, and this is based at least in part on imaging of the subject for α-hydroxy navoactive products, such as 2HG, such as R-2HG. In some embodiments, magnetic resonance imaging is used to assess the presence, distribution, or level of α-hydroxy navoactive products, such as 2HG, such as R-2HG, in the subject. In some embodiments, the subject undergoes imaging and / or spectroscopic analysis, such as magnetic resonance-based analysis, such as MRI and / or MRS analysis, and optionally, images or tumor images corresponding to the presence, distribution, or level of α-hydroxy navoactive products, such as 2HG, such as R-2HG, are formed. Optionally, the images or values ​​related to the images are stored on a tangible medium and / or transmitted to a second location. In some embodiments, the evaluation may include one or more of the following: performing image analysis, requesting image analysis, requesting the results of image analysis, or receiving the results of image analysis.

[0202] In one embodiment, 2HG is evaluated directly.

[0203] In another embodiment, derivatives of 2HG produced in the process of performing an analytical method are evaluated. Examples of such derivatives may be derivatives produced by MS analysis. Examples of derivatives include salt adducts such as sodium adducts, hydrated mutants, or hydrated mutants that are also salt adducts such as sodium adducts produced by MS analysis.

[0204] In another embodiment, metabolic derivatives of 2HG are evaluated. Examples include species such as glutaric acid or glutamic acid that would correlate with 2HG, such as R-2HG, and which are formed, increased, or decreased as a result of the presence of 2HG.

[0205] Typical 2HG derivatives include the following compounds or their dehydrated derivatives such as salt adducts: [ka]

[0206] In one embodiment, advanced hematopoietic malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma) are tumors in which at least 30, 40, 50, 60, 70, 80, or 90% of tumor cells at diagnosis or treatment carry IDH1 mutations, particularly IDH1 R132H or R132C mutations.

[0207] In one embodiment, the advanced hematopoietic malignancy to be treated is AML characterized by the presence of a mutant allele of IDH1. In some embodiments, the AML is relapsed and / or refractory to primary AML. In some embodiments, the AML is relapsed AML. In some embodiments, the AML is refractory to primary AML. In another embodiment, the AML is untreated AML.

[0208] In another embodiment, the advanced hematopoietic malignancy to be treated is MDS characterized by the presence of a mutant allele of IDH1. In another embodiment, the advanced hematopoietic malignancy to be treated is MDS with refractory anemia having excess blast cells (subtype RAEB-1 or RAEB-2). In yet another embodiment, it is MDS considered high-risk by IPSS-R (Greenberg et al. Blood. 2012;120(12):2454-65). In yet another embodiment, the MDS is recurrent. In yet another embodiment, the MDS is refractory. In yet another embodiment, the subject having MDS is a subject who, by the treating physician, is unable to tolerate established therapies known to bring clinical efficacy to their condition.

[0209] In another embodiment, the advanced hematopoietic malignancy to be treated is CMML characterized by the presence of a mutant allele of IDH1. In another embodiment, the CMML is recurrent and / or refractory to primary disease. In another embodiment, it is recurrent CMML. In another embodiment, it is refractory to primary disease.

[0210] The therapeutic methods described herein may further include various evaluation steps before and / or after treatment with a pharmaceutical composition comprising (a) Compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion and (b) one or more pharmaceutically acceptable carriers, which are optional.

[0211] In one embodiment, the method further comprises evaluating the growth, size, weight, invasiveness, stage, and / or other phenotypes of advanced hematopoietic malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), characterized by the presence of a mutant allele of IDH1, before and / or after treatment with a pharmaceutical composition comprising (a) compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion and (b) one or more pharmaceutically acceptable carriers, respectively.

[0212] In one embodiment, the method further comprises evaluating the IDH1 genotype of an advanced hematopoietic malignancy, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), B-cell acute lymphoblastic leukemia (B-ALL), or lymphoma (e.g., T-cell lymphoma), characterized by the presence of a mutant allele of IDH1, before and / or after treatment with a pharmaceutical composition comprising (a) compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion and (b) one or more pharmaceutically acceptable carriers, respectively. This may be done by conventional methods of the art, such as DNA sequencing, immunoassay, and / or evaluation of the presence, distribution, or level of 2HG.

[0213] In one embodiment, the method further comprises determining the 2HG level in a subject before and / or after treatment with a pharmaceutical composition comprising (a) compound 1 or a pharmaceutically acceptable salt thereof as part of a solid dispersion and (b) one or more pharmaceutically acceptable carriers, optionally. This can be done by spectroscopic analysis, such as magnetic resonance analysis, such as MRI and / or MRS measurements; fluid sample analysis, such as analysis of blood, plasma, urine, or cerebrospinal fluid; or analysis of surgical material, such as mass spectrometry (e.g., LC-MS, GC-MS); or any method described herein. [Examples]

[0214] Examples Basic method In the following examples, the reagents can be purchased from commercially available suppliers (such as Alfa, Acros, Sigma Aldrich, TCI, and Shanghai Chemical Reagent Company) and can be used without further purification. X-ray Powder Diffraction (XRPD) Parameters: XRPD analysis is performed using a PANalytical Empyrean X-ray Powder Diffractometer (XRPD) with 12 automated sample stages. The XRPD parameters used are shown in Table 3. [Table 3] Differential Scanning Calorimetry (DSC) Parameters: DSC analysis is performed using TA Instruments' TA Q100 or Q200 / Q2000 DSC. A crimped pan is used, and N2 is used as the purge gas to raise the temperature from room temperature to the target temperature at a heating rate of 10°C / min. Thermogravimetric Analysis (TGA) Parameters: TGA analysis is performed using TA Instruments' TA Q500 / Q5000 TGA. N2 is used as the purge gas, and the temperature is raised from room temperature to the target temperature at a heating rate of 10°C / min or 20°C / min.

[0215] Example 1 By using Compound 1 and various amounts of hypromellose acetate succinate-MG (hypromellose acetate succinate, MG grade, Shin-Etsu Chemical Co., Ltd.) polymer, amorphous solid dispersion intermediates and formulations shown in Example 1 can be prepared. Success criteria may include not only meeting analytical and purity specifications, but also producing batches with reasonable yield (>60%) and low residual solvent (≤3000 ppm).

[0216] Step 1: Preparation of an amorphous solid dispersion of compound 1 Form 1 and hypromellose acetate succinate (HPMCAS) (50% / 50%, w / w) are weighed, dissolved in methanol, and spray-dried (Buchi B-290) to produce a solid dispersion of amorphous compound 1 and hypromellose acetate succinate (HPMCAS). Spray-drying parameters include nitrogen as the drying gas, an inlet temperature of approximately 85°C to 95°C, an outlet temperature of approximately 37°C to 40°C, a spray solution concentration of approximately 5% w / w / , and secondary drying at 40°C for 12 to 18 hours. The amorphous solid dispersion is further dried in a vacuum oven and then sieved. The amorphous solid dispersion may be placed in a double-layer polyethylene bag with a nylon tie and stored in a high-density polyethylene (HDPE) container with a desiccant at 2 to 8°C until the next processing step.

[0217] Step 2: Manufacturing of tablets of compound 1 Compound 1, the amorphous solid dispersion intermediate of hypromellose acetate succinate, and all other additives listed in Table 4 are weighed and sieved for mixing.

[0218] Weighing and sieving of components within granules The amorphous solid dispersion of compound 1 and hypromellose acetate succinate is mixed in a suitable mixer with microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, and magnesium stearate. [Table 4]

[0219] Intragranular mixing The granular mixture is passed through a roller compactor, and the compressed material is then sized to produce granules.

[0220] Dry granulation / sizing Extracrystalline cellulose, croscarmellose sodium, colloidal silicon, and magnesium stearate are weighed and sieved for mixing.

[0221] Weighing and sieving of the extra-granular components The sieved granules and the extra-granular additives are put into a suitable mixer and mixed.

[0222] Mixing of the extra-granular components The blend was compressed using a rotary tableting machine set to produce tablets of the appropriate shape / size and the required weight, thickness, and hardness.

[0223] Compression The tablets of bulk compound 1 are placed in a double-sealed polyethylene bag containing a 30 g silica gel bag placed in a foil-lined drum can and stored at 2 - 8°C. The tablets are then packaged.

Table 5

[0224] Synthesis of Form 1 of Example 2 A mixture of compound 1 (3.5 kg, 7.28 mol) in 1,4-dioxane (35 L) is degassed by blowing N2 for a maximum of 20 minutes. 2-Chloro-4-cyanopyridine (1.21 kg, 8.73 mol), tris(dibenzylideneacetone)-dipalladium(0) (167 g, 0.18 mol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos) (211 g, 0.36 mol) are added, and the reaction mixture is degassed by blowing N2 for a maximum of 10 minutes. K2CO3 (1.21 kg, 8.73 mol) is added, and the reaction mixture is degassed by blowing N2 for a maximum of 30 minutes. The reaction mixture is heated at 90 - 100°C for 4 - 24 hours until the reaction is complete. Then, the reaction mixture is cooled to 15 - 25°C, filtered through celite, washed with ethyl acetate, and the filtrate and washings are combined and concentrated.

[0225] Remove 1,4-dioxane and dissolve the remaining solid in ethyl acetate (77.5 L). Wash the ethyl acetate solution sequentially with 5% NaHSO3 aqueous solution, 2% EDTA disodium aqueous solution, and 1% EDTA disodium salt aqueous solution. Treat the organic phase with activated carbon at 55-65°C for up to 2 hours, and purify by silica gel chromatography. After chromatography, purify the obtained product by two recrystallizations. Dissolve the first compound 1 in ethyl acetate, heat to 60-70°C, and add heptane. Cool the reaction mixture to 15-25°C and stir for 1-3 hours. Filter the product and dissolve it in dichloromethane, then filter and precipitate with heptane, filter and dry to obtain form 1.

[0226] Example 3 Synthesis of Form 2 Method A: Mix approximately 100 mg of compound 1 with 0.4 mL of MeOH and stir at room temperature for 12 hours. Subsequently, centrifuge the suspension and isolate the white solid.

[0227] Method B: In a 3 mL glass vial, add approximately 10 mg of compound 1 to 0.2–0.4 mL of a MeOH:H2O (9:1) mixture. Cover the resulting visually clear solution with a lid and allow it to evaporate slowly to induce precipitation. Isolate the solid.

[0228] Method C: Dissolve approximately 15 mg of compound 1 in an EtOH:H2O (8:7 volume / vol) mixture or methyl ethyl ketone (MEK) at 50°C and stir at 50°C for 30 minutes. Then, slowly cool the solution to 5°C at 0.1°C / min and stir overnight at 5°C. Isolate the solid.

[0229] Example 4 The following three homogeneous suspensions of compound 1 are obtained. Form 2 in vehicle (1% d-α-tocopherol polyethylene glycol 1000 succinate (TPGS): 1% aqueous HPMCAS solution), an amorphous solid dispersion of 25% w / w Form 2 and 75% w / w HPMCAS-M in vehicle (Solid dispersion A), and an amorphous solid dispersion of 25% w / w Form 2 and 75% w / w PVAP in vehicle (Solid dispersion B) (200 mg / kg in 10 mL / kg).

[0230] Each suspension is prepared on the day of administration and orally administered to SD rats. Plasma samples are collected at various time points after administration. The concentration of Compound 1 in plasma is determined using a highly sensitive and specific LC / MS method. AUC 0-72h and PK parameters such as Cmax are calculated using WinNonlin software.

[0231] For Form 2, C max is 1600 ng / mL and AUC 0-72h is 21700 hr * ng / mL. For Solid dispersion A, C max is 6820 ng / mL and AUC 0-72h is 105635 hr * ng / mL. For Solid dispersion B, C max is 30467 ng / mL and AUC 0-72h is 406841 hr * ng / mL.

[0232] The ratio of the AUC 0-72h of Solid dispersion B to Form 2 is 19. The ratio of the AUC 0-72h of Solid dispersion A to Form 2 is 5.

[0233] Example 5. Phase 1 Clinical Trial Implementation Plan The safety, PK / PD, and clinical activity of compound 1 or a pharmaceutically acceptable salt thereof will be evaluated in subjects with advanced hematopoietic malignancies such as AML, MDS, MPN, or CMML with IDH1 mutations. The primary research objectives include: 1) evaluating the safety and tolerability of treatment with compound 1 or a pharmaceutically acceptable salt thereof when administered sequentially as a single agent orally twice daily (approximately every 12 hours) from day 1 to day 28 of a 28-day cycle; and 2) determining the maximum tolerated dose (MTD) and / or recommended phase 2 dose of compound 1 or a pharmaceutically acceptable salt thereof in subjects.

[0234] Secondary research objectives include: 1) an overview of the dose-limiting toxicity (DLT) of compound 1 or a pharmaceutically acceptable salt in subjects with advanced hematopoietic malignancies such as AML, MDS, MPN, or CMML, who have IDH1 mutations; 2) characterization of the pharmacokinetics (PK) of compound 1 or a pharmaceutically acceptable salt in subjects with advanced hematopoietic malignancies such as AML, MDS, MPN, or CMML, who have IDH1 mutations; 3) evaluation of the PK / pharmacodynamic (PD) relationship between compound 1 or a pharmaceutically acceptable salt and 2-hydroxyglutaric acid (2-HG); and 4) characterization of the clinical activity of compound 1 or a pharmaceutically acceptable salt in subjects with advanced hematopoietic malignancies such as AML, MDS, MPN, or CMML, who have IDH1 mutations.

[0235] Preliminary research objectives include: 1) evaluation of changes in Ki67 levels in tumor specimens; 2) characterization of the PD effect of compound 1 or a pharmaceutically acceptable salt thereof in subjects with advanced hematopoietic malignancies such as AML, MDS, MPN, or CMML with IDH1 mutations by evaluating changes in the cell differentiation pattern of isocitrate dehydrogenase-1 (IDH1)-mutant tumor cells, as well as changes in histone and deoxyribonucleic acid (DNA) methylation profiles in IDH1-mutant tumor cells; 3) evaluation of gene mutation status, comprehensive gene expression profiles, and other potential prognostic markers (cytogenetics) in IDH1-mutant tumor cells and subclonal populations of non-IDH1-mutant tumor cells to look for predictors of antitumor activity and / or resistance; and 4) monitoring of plasma cholesterol and 4β-OH-cholesterol levels as potential CYP3A4 transduction markers.

[0236] Compound 1 is administered orally twice daily (approximately every 12 hours) from day 1 to day 28 of a 28-day cycle. If justified by new data, alternative dosing schedules (e.g., once daily or three times daily) may be investigated, including administering the same total daily dose to the ongoing cohort using different dosing schedules. Dosing is continued starting from C1D1, with no breaks between cycles.

[0237] For subjects who do not meet any of the standard clinical treatment discontinuation criteria, treatment may be continued beyond cycle 1.

[0238] On the first day of each cycle, subjects will be dispensed with the appropriate number of tablets for 28 days of medication (plus two additional days' worth to account for scheduled visits). Subjects must return all unused tablets (or empty bottles) on the first day of each treatment cycle. Subjects will be given a medication diary for each treatment cycle. They must record relevant information about the investigational drug in the diary (confirmation of taking the medication each day, and reasons for not taking it). Adherence to the treatment plan will be evaluated based on the return of unused medication and the medication diary.

[0239] Subjects must be instructed to take the medication daily at approximately the same time each day. Each dose should be taken with a glass of water and swallowed as quickly as possible. Subjects must be instructed to swallow the tablet whole and not to chew it. Subjects may take Compound 1 or a pharmaceutically acceptable salt thereof with food or without food. If a subject forgets their daily morning (or evening) dose, they must take Compound 1 or a pharmaceutically acceptable salt thereof within six hours of the missed dose. If more than six hours have passed, the dose should be skipped and the subject should resume treatment with the next scheduled dose.

[0240] This study includes a dose escalation phase to determine the MTD and subsequent expanded cohorts to further evaluate the safety and tolerability of the MTD. A standard "3+3 design" will be used in the dose escalation phase. During the dose escalation phase, informed and eligible subjects will participate in sequential cohorts of increasing doses of compound 1 or a pharmaceutically acceptable salt thereof. Each dose cohort is scheduled to have a minimum of three subjects. The first three subjects to join each dose cohort during the dose escalation phase of the study will first receive a single dose of the investigational drug on day -3 (i.e., three days before the start of daily administration) and will undergo a 72-hour PK / PD assessment to evaluate drug concentration and 2HG levels. The next dose of the investigational drug will be on day 1 of cycle 1 (C1D1), when daily administration begins. The initial dosing schedule is twice daily (approximately every 12 hours). Where justified by new data, alternative dosing schedules (e.g., once or three times daily) may be investigated in the ongoing cohort, including administering the same total daily dose. If there are multiple patients in the selection process when the third patient in the cohort begins treatment, up to two additional subjects may be included with the approval of the medical monitor. For these additional subjects, PK / PD assessment throughout day 3 to day 1 is optional and subject to discussion with the medical monitor. Planned dose escalation schemes are shown in Table 1. [Table 6]

[0241] The severity of toxicity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. DLT is defined as follows. For hematological ones, persistent myelosuppression defined as the persistence of grade 3 or higher neutropenia or thrombocytopenia at least on the 42nd day after the start of treatment in cycle 1 (according to NCI CTCAE, version 4.03, criteria specific to leukemia, i.e., bone marrow cell density < 5% on the 28th day or later from the start of the investigational drug without leukemia findings) is included. The grading specific to leukemia should be used for blood cell reduction (based on the reduction rate from baseline: 50 - 75% = grade 3, > 75% = grade 4). All AEs that cannot be clearly determined to be unrelated to compound 1 or its pharmaceutically acceptable salts are considered relevant to the determination of DLT.

[0242] If no DLT is observed after the third subject completes the 28-day DLT evaluation period (i.e., cycle 1), after the safety review by the clinical research team, the study continues with dose escalation in the next cohort. If DLT is recognized in one of the three subjects during the first cycle, three additional subjects participate in that cohort. If no DLT is recognized in any of these three additional subjects, dose escalation can continue for the next cohort after the safety review. If DLT is recognized in two or more subjects in the cohort during the first cycle, dose escalation is stopped and the next lower dose level is认定 as the MTD. Alternatively, if DLT is recognized in < 2 of the six subjects at that dose, an intermediate dose level between the dose level exceeding the MTD and the previous dose level may be investigated and认定 as the MTD. If the MTD cohort includes only three subjects, three additional subjects participate at that dose level to confirm that DLT is recognized in < 2 of the six subjects.

[0243] For each dose cohort, the increase in compound 1 or a pharmaceutically acceptable salt thereof follows an accelerated escalation design. This is because compound 1 is involved in any of the subjects within the cohort. The dose is doubled (100% increase) from one cohort to the next until a toxicity of grade 2 or higher according to CTCAE version 4.03 is observed. Subsequent dose increases are based on observed toxicity and, if applicable, PK and PK / PD data until the MTD is determined. The absolute percentage increase in the daily dose is determined based on the type and severity of any toxicity observed in the previous dose cohort (but not exceeding 100%). If justified by new data, a different dosing schedule (e.g., once or three times daily) may be investigated, including administering the same total daily dose to parallel cohorts using a different dosing schedule. The MTD is the highest dose that causes DLT in <2 out of 6 subjects.

[0244] If a dose-limiting time (DLT) is not identified during the dose escalation phase, dose escalation may be continued up to two dose levels above the predicted maximum bioeffective dose, determined by continuous assessment of PK / PD and any observed clinical activity, in order to determine the recommended phase 2 dose.

[0245] To optimize the number of subjects treated with a clinically significant dose, intrasubjective dose escalation is permitted. Following the determination of the recommended phase 2 dose, three or more expanded cohorts (with AML, MDS, MPN, or CMML), each containing approximately 12 subjects, will be treated with that dose. The purpose of the expanded cohorts is to evaluate and confirm the safety and tolerability of the recommended phase 2 dose in specific disease symptoms. Subjects participating in these cohorts will undergo the same procedures as patients in the dose escalation cohorts, except that PK / PD assessments from day 3 to day 1 are optional.

[0246] Subjects will undergo screening procedures within 28 days prior to the commencement of investigational treatment to determine their eligibility. These screening procedures include medical history, surgical history, medication history, confirmation of IDH1 mutation by tumor biopsy or leukemic blasts (if not previously documented), health checkup, vital signs, East Coast Cancer Group (ECOG) performance status (PS), 12-lead electrocardiogram (ECG), left ventricular ejection fraction (LVEF) assessment, laboratory evaluation (hematology, chemistry, blood coagulation, urinalysis, and serum pregnancy test), bone marrow biopsy, bone marrow aspiration, blood and urine samples for 2HG measurement, and blood samples to determine plasma cholesterol and 4β-OH-cholesterol levels.

[0247] Three days prior to the start of twice-daily administration of compound 1 or a pharmaceutically acceptable salt (-3 days), the first three subjects participating in each cohort of the dose escalation phase receive a single dose of compound 1 or a pharmaceutically acceptable salt at the clinic and have time-course blood and urine samples obtained to determine the blood and urine concentrations of compound 1 or its pharmaceutically acceptable salt or its metabolites, and 2HG. A complete 72-hour PK / PD profile is performed: subjects remain at the research facility for 10 hours on -3 days and are required to return to the research facility for samples at 24, 48, and 72 hours on -2 days, -1 days, and 1 day, respectively.

[0248] Daily treatment with compound 1 or a pharmaceutically acceptable salt thereof begins with C1D1, Subjects who do not undergo PK / PD evaluation on day 3 will be observed in the clinic for 4 hours after C1D1 administration. The initial dosing schedule is twice daily (approximately every 12 hours). Safety evaluations performed during the treatment period include health checkups, vital signs, ECOG PS, 12-lead ECG, LVEF, and laboratory evaluations (hematology, chemistry, blood coagulation, and urinalysis).

[0249] All subjects undergo 10-hour PK / PD evaluations on both C1D15 and C2D1. Additional pre-administration urine and / or blood samples are taken on C1D8, C1D22, C2D15, C3D1, C3D15, and day 1 of all subsequent cycles. Available bone marrow biopsy samples are also evaluated for 2HG levels.

[0250] Subjects will undergo radiographic imaging (CT / MRI), as well as bone marrow aspiration, bone marrow biopsy, and peripheral blood evaluation to assess the extent of the disease at screenings on days 15, 29, 57, and thereafter every 56 days during the course of the investigational treatment, and / or whenever disease progression is suspected, regardless of delays and / or interruptions in administration. Two core tumor biopsies will be obtained at screenings at the time of the initial assessment of the response and at any time of disease progression within ±3 days before or after the scheduled assessment time. For patients with acute myeloid leukemia (AML), the response to treatment will be determined by the principal investigator based on the modified International Working Group (IWG) response criteria.

[0251] Subjects may continue treatment with compound 1 or a pharmaceutically acceptable salt thereof until disease progression, the appearance of DLT, or the occurrence of other unacceptable toxicity. All subjects must undergo a final evaluation at the end of treatment (within approximately 5 days of the last dose of the investigational drug). Furthermore, a follow-up evaluation must be scheduled 28 days after the last dose.

[0252] It is estimated that approximately 51 subjects will participate in the study. Unless the MTD requires 6 subjects, 15 subjects will participate in the dose escalation part of the study, assuming that evaluation of four dose levels of compound 1 or a pharmaceutically acceptable salt is required for MTD identification with only 3 subjects per dose level. Three additional cohorts of approximately 12 subjects each (36 subjects in total) with specific advanced hematopoietic malignancies will participate in the cohort expansion part of the study. Additional subjects may be needed for cohort expansion during dose escalation, to replace subjects who cannot be evaluated, or to evaluate the planned escalation plan or an alternative dosing plan other than the MTD, with the aim of optimizing the recommended phase 2 dose.

[0253] Patients must meet all of the following inclusion criteria to participate in the clinical study: 1) Subjects must be 18 years of age or older; 2) Subjects must be i) relapsed and / or refractory AML as defined by World Health Organization (WHO) criteria, ii) untreated AML, ≥60 years of age, and deemed by the treating physician not to be a candidate for standard treatment due to age, general condition, and / or adverse risk factors, and have approval for medical monitoring, iii) myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or relapsed or refractory and conform to the Revised International Prognostic Scoring System (IPSS-R) (Greenberg et al. Blood. 2012;120(12): Patients must have advanced hematopoietic malignancies, including those considered high-risk by 2454-65) or those deemed by the treating physician to be unable to tolerate established therapies known to be clinically effective for their condition (i.e., patients must not be candidates for established therapies known to be clinically effective) and who have approval from a medical monitor; and iv) subjects with other recurrent and / or primary refractory hematopoietic malignancies, such as CMML, who meet the inclusion / exclusion criteria that may be considered on an individual basis;3) subjects must have documentation indicating that they have an IDH1 gene mutation disorder based on local evaluation. Analysis of leukemic blasts for IDH1 gene mutations must be evaluated in a screening at the site's institutional laboratory to determine the subject's eligibility for study (if not previously evaluated). Evaluation by a central laboratory is also acceptable if the site does not have an institutional laboratory equipped to perform IDH1 gene mutation analysis. Pre-processed tumor specimens (blood and / or bone marrow-derived) are required for all screened subjects for biomarker analysis at the central laboratory. Genetic mutation analysis of tumor specimens (blood or bone marrow-derived) will be performed again at the end-of-treatment visit and submitted to the central laboratory for biomarker analysis;4) Subjects must accept timely bone marrow biopsies, peripheral blood collections, and urine collections during the study. (Diagnosis and evaluation of AML or MDS can be performed by bone marrow aspiration if core biopsy is unavailable and / or not part of standard treatment. Bone marrow biopsy is required if the aspiration is dry tapped or unsuccessful (mainly diluted);5) The subject or their legal representative must understand and be able to sign informed consent;6) Subjects must have an ECOG PS of 0-2;7) Subjects must have a platelet count ≥ 20,000 / μL (transfusions required to meet this level). Subjects must have (acceptable) baseline platelet count <20,000 / μL due to primary malignancy and be eligible with the approval of the medical monitor;8) Subjects must have sufficient liver function as demonstrated by a) serum total bilirubin ≤1.5 × upper limit of normal (ULN) (except when considered to be due to Gilbert's disease or leukemic organ lesions), and b) aspartate aminotransferase, ALT, and alkaline phosphatase (ALP) ≤3.0 × ULN (except when considered to be due to leukemic organ lesions);9) Subjects must have serum creatinine ≤2.0 × ULN, or Cockroft-Gault glomerular filtration rate (GFR) estimate: (1 Subjects must have adequate renal function, as demonstrated by a creatinine clearance > 40 mL / min based on (40 - age) × (weight in kg) × (0.85 (for women)) / 72 × serum creatinine; 10) Subjects must be recovered from any clinically relevant adverse events of any prior surgery, radiation therapy, or other therapy intended for the treatment of cancer (subjects with Grade 1 toxic sequelae, such as Grade 1 peripheral neuropathy or alopecia, are permitted with the approval of the medical monitor); and 11) Female subjects of reproductive capacity must have a negative serum pregnancy test within 7 days prior to the start of treatment. A subject of reproductive capacity is defined as a person who is biologically capable of becoming pregnant. Not only women of childbearing capacity, but also males of reproductive capacity and their partners must agree to abstain from sexual intercourse or use an effective form of contraception during the study and for 90 days after the last dose of compound 1 or a pharmaceutically acceptable salt thereof (women and men).

[0254] Compound 1 or a pharmaceutically acceptable salt thereof is provided as tablets containing 50 mg and 200 mg, to be administered orally twice daily or once daily.

[0255] The first three subjects in each cohort in the dose-escalation portion of the study will receive a single dose of the investigational drug on day 1-3. Their next dose of the investigational drug will be administered on C1D1, the day the subject begins taking the drug twice daily (approximately every 12 hours) from day 1 to day 28 in a 28-day cycle. Dosing will continue from C1D1, with no drug-free periods between cycles. Subjects who were not required to undergo PK / PD evaluation on day 3 will begin taking compound 1 or a pharmaceutically acceptable salt of it twice daily (approximately every 12 hours) on C1D1.

[0256] The dose of compound 1 or a pharmaceutically acceptable salt administered to subjects will depend on which dose cohort is accepting participants when the subjects become eligible to participate in the study. The starting dose of compound 1 or a pharmaceutically acceptable salt administered to subjects in the first cohort will be 100 mg (200 mg / day), administered orally twice daily.

[0257] Treatment of subjects with compound 1 or a pharmaceutically acceptable salt thereof can be continued until disease progression, DLT development, or other unacceptable toxicity occurs.

[0258] Evaluation Criteria safety The following will be monitored during the clinical study: decisions regarding DLTs, serious adverse events (SAEs), and AEs (including AEs leading to discontinuation); safety clinical laboratory items; physical examination findings; vital signs; 12-lead ECG; LVEF; and ECOG PS. The severity of AEs will be assessed using the NCI CTCAE. Evaluated by version 4.03.

[0259] Compound 1 or its pharmaceutically acceptable salts may cause sensitivity to direct and indirect sunlight. Subjects should be warned to avoid direct sunlight exposure. If exposure to sunlight for more than 15 minutes is anticipated, subjects should be instructed to apply sunscreen with a sunscreen index of 30 or higher to the exposed area and to wear protective clothing and sunglasses.

[0260] Pharmacokinetics and pharmacodynamics Blood samples over time are evaluated to determine the concentration-time profile of compound 1 or its pharmaceutically acceptable salt. Urine samples are evaluated to determine the urinary excretion of compound 1 or its pharmaceutically acceptable salt. Blood, bone marrow, and urine samples are evaluated to determine 2HG levels. Tumor biopsies are performed to evaluate 2HG and compound 1 or its pharmaceutically acceptable salt.

[0261] Pharmacokinetic evaluation: To determine the circulating plasma concentration of compound 1 or a pharmaceutically acceptable salt thereof, blood samples are taken at different time points before and after administration of compound 1 or a pharmaceutically acceptable salt thereof. The blood samples are also used to determine 2HG concentration and to evaluate cholesterol and 4β-OH-cholesterol levels.

[0262] For the first three subjects joining the cohort during the dose escalation phase, a single dose of compound 1 or a pharmaceutically acceptable salt is administered on day -3 (i.e., 3 days before the scheduled C1D1 administration). Blood samples are taken prior to the single dose of compound 1 or a pharmaceutically acceptable salt, and at 30 minutes, 1, 2, 3, 4, 6, 8, 10, 24, 48, and 72 hours after administration. Following the 72-hour blood sample, subjects begin taking compound 1 or a pharmaceutically acceptable salt twice daily (i.e., C1D1). For additional subjects joining the dose escalation phase (i.e., all subjects other than the first three joining the cohort), the PK / PD profile from day -3 to day 1 is optional and not required for subjects joining the expanded cohort.

[0263] 10-hour PK / PD sampling is performed on all subjects on C1D15 and C2D1 (i.e., days 15 and 29 of twice-daily administration). For this profile, one blood sample is taken immediately before the first administration of compound 1 or a pharmaceutically acceptable salt of that day (i.e., administration of compound 1 or a pharmaceutically acceptable salt is performed in clinical practice). Subsequent blood samples are taken 30 minutes, 1, 2, 3, 4, 6, 8, and 10 hours after administration. Blood samples are also taken on days 8 and 22 of cycle 1, day 15 of cycle 2, and day 1 and 15 of cycle 3, as well as on day 1 after each subsequent cycle. All samples are obtained before administration. In addition, one blood sample is taken upon the final visit at the end of treatment.

[0264] If new data indicates that a change in the sampling scheme is necessary to better characterize the PK profile of compound 1 or a pharmaceutically acceptable salt thereof, the timing of blood sampling for determining the concentration of compound 1 or a pharmaceutically acceptable salt thereof may be changed.

[0265] Pharmacodynamic evaluation: To determine the circulating concentration of 2HG, blood samples are taken at different time points before and after administration of compound 1 or a pharmaceutically acceptable salt thereof. Samples taken for PK evaluation are also used to assess 2HG levels. Furthermore, subjects have blood drawn during screening evaluation to determine their 2HG levels.

[0266] If new data indicate that a change in the sampling scheme is necessary to better characterize the 2HG response to the treatment of compound 1 or a pharmaceutically acceptable salt thereof, the timing of blood sampling for 2HG concentration determination may be changed.

[0267] Urine is collected at the time of screening evaluation, as well as on day 15 of cycle 1, day 1 of cycle 2, and before administration in each subsequent cycle, to determine the concentration of 2HG levels. At least 20 mL of urine is collected from each sample.

[0268] Each sample volume is measured and recorded and sent to a central laboratory to determine the 2HG concentration in the urine. A certain portion of each sample is analyzed for urinary creatinine concentration.

[0269] Tumor biopsy specimens are collected at the time of screening, initial disease assessment, and at any time disease progression is suspected, and 2HG levels are evaluated. For all biopsy specimens, a period of ±3 days before and after the scheduled evaluation time is acceptable. Tumor biopsies are evaluated for morphology and cell differentiation by hematoxylin and eosin (H&E) staining and ICH for specific cell type markers. Tumor specimens may also be evaluated for 2HG levels, Ki67 levels, and, if possible, intratumoral levels of compound 1 or a pharmaceutically acceptable salt thereof.

[0270] Blood samples taken over time are collected to obtain plasma cholesterol and 4β-OH-cholesterol levels as potential CYP3A4 induction markers. Samples are taken on day 3 (within 30 minutes), 24, 48, and 72 hours (±1 hour), days 8, 15, and 22 of cycle 1, days 1 and 15 of cycles 2 and 3, and day 1 of each subsequent cycle.

[0271] Clinical activity: For hematopoietic malignancies such as MDS, MDS, MPN, or AML, time-series blood and bone marrow biopsies are evaluated during clinical studies to determine the response to compound 1 or a pharmaceutically acceptable salt, in accordance with the 2006 modified IWG criteria (Cheson BD, et al. Blood. 2006;108(2):419-25).

[0272] The disease response to treatment is assessed by evaluation of bone marrow biopsy and / or puncture, in conjunction with whole blood count and peripheral blood smear examination. Subjects will be assessed and recorded for disease progression at screenings on days 15, 29, 57, and every 56 days while treatment with the investigational drug continues, and / or whenever disease progression is suspected, regardless of administration delays and / or discontinuation. Assessments will also be performed at the end-of-treatment visit for subjects who discontinue the study for reasons other than disease progression.

[0273] statistical analysis Since the goal of this study is to determine the MTD of compound 1 or a pharmaceutically acceptable salt thereof, the statistical analysis is essentially descriptive. Aggregations are performed for appropriate accumulation, demographics, baseline, safety, PK, PD, and clinical activity parameters, as well as for dose level and overall. Categorical variables are summarized by frequency distributions (number and proportion of subjects), and continuous variables are summarized by descriptive statistics (mean, standard deviation, median, minimum, and maximum). Adverse events are summarized in the organ-based major classifications and basic terms of the International Medical Terminology (MedDRA). All treatment-related adverse events (TEAEs), treatment-related adverse events (those considered by the principal investigator to be at least potentially drug-related), single-action adverse events (SAEs), treatment interruptions due to AEs, and AEs of at least grade 3 severity are tallied separately. The individual subject list shows deaths, SAEs, DLTs, and AEs that resulted in treatment interruption.

[0274] Descriptive statistics are provided for laboratory, ECG interval, LVEF, and vital sign data, presented as both actual values ​​and changes from baseline, for both the assessment during the study period and the final assessment of the study. Shift analysis is performed for laboratory items and ECOG PS.

[0275] Descriptive statistics are used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Potential relationships between plasma levels of compound 1 or its pharmaceutically acceptable salts and 2HG levels in blood, plasma, or urine are investigated using descriptive or graphical methods.

[0276] Treatment response assessed by the principal investigator at the site using a modified IWG (for subjects with hematopoietic malignancies such as MDS, MDS / MPN, or AML). Two-sided 90% confidence intervals for the response rate are calculated for each dose level and overall. Data are also grouped by the type of malignancy of the subject during the cohort expansion phase. Descriptive statistics are used to group Ki67 levels from tumor biopsies.

[0277] Research results Compound 1 is an 8-20 nM cell IC 50 The compound was found to have a value. A decrease in 2HG was observed after a single dose of compound 1 in an IDH1 mutant R132H xenograft model (Figure 7A). Furthermore, compound 1 reduced intracellular 2HG in in vitro primary human IDH mutant blast cells (Figure 7B). [Table 7]

[0278] The patients in Table 2 received treatment for an average (range) of 1.6 months (0.4 to 5.7 months). [Table 8]

[0279] At 800 mg QD, one case of dose-limiting toxicity (DLT) with grade 3 QT prolongation was observed. There were no associated cardiac symptoms, and QTc returned to normal 3 days after drug withholding. The patient's dose was reduced to 500 mg QD and the study continued, with grade 1 QTc prolongation in complete remission (CR). Eight subjects experienced serious adverse events. At 100 mg BID, one subject was discontinued from the study due to intracranial hemorrhage due to disease progression and subsequently died. At 300 mg QD, one subject developed differentiation syndrome, which recovered and achieved CR. At 800 mg QD, one subject developed tongue edema and QT prolongation (the DLT described above), which recovered and achieved CR. All other SAEs associated with disease progression resulted in death. In patients who developed differentiation syndrome, symptoms included fever and dyspnea. Patients were treated with steroids. The two events that led to the PD (Periodic Disorder) are described as events related to discontinuation due to adverse events (AEs).

[0280] Table 4. Adverse Events Notable grade ≥ 3 adverse events (AEs) included two cases of hypotension (12%), two cases of altered mental status (12%), and two cases of neutropenia (12%). AEs are typical of this patient population. Other QT prolongation events observed included: grade 1 QT prolongation in the 100 mg cohort (this patient had a history of right bundle branch block (R BBB) at the time of study participation); grade 1 intermittent QT prolongation in the 300 mg cohort; and grade 3 QT prolongation (DLT) in the 800 mg cohort. [Table 9]

[0281] Compound 1 exposure and 2HG suppression Figures 8A and 8B show the PK profile of compound 1 after oral administration. Compound 1 showed high plasma exposure, drug accumulation, and a half-life of 182 hours. Plasma levels of 2HG decreased to the normal range at all dose levels (up to 98% suppression). Baseline of 2HG was defined as pre-treatment point -3 days, and 2HG suppression was compared to the pre-treatment level of 2HG and AUC. 0-10hEstimates were made based on post-treatment status. For the 100 mg BID and 300 mg QD cohorts, 3–4 patients were measured per time point, while for the 500 mg QD cohort, 1–3 patients were measured per time point. [Table 10]

[0282] Differentiation effect in bone marrow Figures 9A–9C show images of aspirate from a 74-year-old female patient who was refractory to induction with 7+3. At baseline (Figure 9A), her bone marrow showed a monotonous cell distribution density derived from an overwhelming majority of blast cells. The inset shows the appearance of blast cells in the aspirate. Two weeks after treatment (Figure 9B), core biopsy showed continued cytoplasm but clear evidence of maturation, determined by cells of varying sizes and shapes, resembling the appearance of a "flower garden" in normal bone marrow. The inset no longer shows blast cells in the aspirate, instead showing mainly myelocytes. This is evidence of differentiation. At this point, blasts had been reduced to <5%, neutrophils and platelets were maintained, and the patient met the criteria for complete complete response (CR). This was maintained at day 28. At this point, cytoplasm was still present but mature, and no increase in blast cells was observed (Figure 9C).

[0283] While the invention described above is described in some detail for clarity and understanding, these specific embodiments should be considered illustrative and not limiting. By interpreting this disclosure, it will be understood that various modifications in form and detail are possible without departing from the true scope of the invention as defined by the appended claims rather than by specific embodiments.

[0284] The patents and scientific documents referenced herein demonstrate the knowledge available to those skilled in the art. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as they would ordinarily understood by those skilled in the art in which the invention pertains. Published patents, applications, and references cited herein are incorporated herein by reference to the same extent as they are specifically and individually directed to be incorporated by reference. In the event of any conflict, including definitions, the present disclosure shall prevail.

Claims

1. A crystal of (S)-N-((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridine-2-yl)-N-(5-fluoropyridine-3-yl)-5-oxopyrrolidine-2-carboxamide (compound 1), characterized by X-ray powder diffraction (XRPD) peaks including peaks at 2θ angles of (±0.2°)9.8°, 11.6°, 14.9°, 16.5°, 19.6°, 20.1°, 22.5°, 23.0°, 25.0°, and 31.4°.

2. The crystal of compound 1 has the following X-ray powder diffraction (XRPD) pattern shown in the figure below: 【Chemistry 2】 , and the data shown in the table below: Table 11 The crystal according to claim 1, characterized by...

3. A pharmaceutical composition comprising crystals of compound 1 according to claim 1 or 2.

4. The pharmaceutical composition according to claim 3, wherein at least a specific weight percent of compound 1 is crystalline.

5. The pharmaceutical composition according to claim 4, wherein the specific weight percent of the crystalline compound 1 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

6. The pharmaceutical composition according to claim 4, wherein the specific weight percentage of the crystalline compound 1 is 10% to 100%.

7. The pharmaceutical composition according to any one of claims 3 to 6, wherein a specific weight percent of compound 1 is crystalline and the remainder of compound 1 is in an amorphous form.

8. The pharmaceutical composition according to any one of claims 3 to 7, wherein compound 1 comprises a single crystal form of compound 1 or a mixture of different single crystal forms.

9. The pharmaceutical composition according to any one of claims 3 to 8, wherein at least 90% by weight of compound 1 is crystalline.

10. The pharmaceutical composition according to any one of claims 3 to 8, wherein at least 95% by weight of compound 1 is crystalline.

11. The pharmaceutical composition according to any one of claims 3 to 8, wherein at least 99% by weight of compound 1 is crystalline.

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