Co-crystal CDK inhibitors

Abstract

The present invention relates to fumaric acid compounds of formula (I) and crystalline forms thereof, as well as methods for their preparation. (I) The present invention also relates to preparations suitable for pharmaceutical use for treating various diseases or disorders mediated by CDK7, in particular cancer or other proliferative diseases. [Formula 1] TIFF2023554492000020.tif48165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of Provisional Application No. 202041055174 of India, filed on 18 December 2020, the specification of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to fumarate compounds of formula (I), including crystalline forms, and methods for preparing them. The present invention also relates to pharmaceutical compositions comprising the above-mentioned fumarate compounds of formula (I), their crystalline forms, and their use as therapeutic agents. [Background technology]

[0003] CDK7, which forms a complex with cyclin H and MAT1, phosphorylates cell cycle CDKs and promotes their activity in T-loop activation (Fisher et al., Cell., Aug 26;78(4):713-24, 1994). Therefore, inhibiting CDK7 has been shown to provide a powerful means of inhibiting cell cycle progression, particularly in most cell types, where there is noteworthy evidence from gene knockout studies that it may be related to the lack of absolute requirements for CDK2, CDK4, and CDK6 in relation to the cell cycle (Malumbres et al., Nature Cell Biology, 11, 1275-1276, 2009). On the other hand, different tumors appear to be independent of other interfacial CDKs (CDK2, CDK4, CDK6), although some are required. Recent genetic and biochemical studies have confirmed the importance of CDK7 in cell cycle progression (Larochelle et al., Mol Cell., Mar ar 23;25(6):839-50.2007; Ganuza et al., EM BO J., May 30;31(11):2498-510,2012).

[0004] Cyclin-dependent kinase 7 (CDK7) activates cell cycle CDKs and is a member of basal transcription factor II human (TFIIH). CDK7 also plays a role in transcription and, in some cases, in DNA repair. The trimer Cak complex CDK7 / cyclin H / MAT1 is also a component of TFIIH, a basal transcription / DNA repair factor IIH (Morgan, D.O., Annu. Rev. Cell Dev. Biol. 13, 261-91, 1997). As a TFIIH subunit, CDK7 phosphorylates the CTD (carboxy-terminal domain), the largest subunit of RNA polymerase II (pol II). The mammalian pol II CTD consists of 52 7-nucleotide repeats containing the consensus sequence 1YSPTSPS7, and the phosphorylation state of the Ser residues at positions 2 and 5 likely plays a decisive role in CTD function, and has been shown to be important for RNAP-II activation. In contrast to CDK9 (Pinhero et al., Eur.J.Biochem., 271, pp.1004-1014, 2004), which phosphorylates both Ser-2 and Ser-5 of the CTD 7 bases, CDK7 (Gomes et al., Genes Dev. 2006 Mar l;20(5):601-12, 2006), primarily phosphorylates Ser-5 (PSS) of RNAP-II in the promoter as part of transcription initiation.

[0005] In addition to CDK7, other CDKs have also been reported to regulate RNA pol(II)CTD by phosphorylating it. Other CDKs include Cdk9 / cyclin T1 or T2 (Peterlin and Price, Mol Cell., Aug 4;23(3):297-305, 2006), which constitute the active form of positive transcription elongation factor (P-TEFb), and Cdkl2 / cyclin K and Cdkl3 / cyclin K (Bartkowiak et al., Genes Dev., Oct 1 5;24(20):2303-16, 2010; Blazek et al., Genes Dev. Oct 15;25(20):2158-72, 2011), which are the latest members of the RNAPII CTD kinase group.

[0006] Interference with RNAP II CTD phosphorylation has been shown to preferentially affect short-half-life proteins, including those of the anti-apoptotic BCL-2 family (Konig et al., Blood, 1, 4307-4312, 1997; The transcriptional non-selective cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1; Gojo et al., Clin. Cancer Res. 8, 3527-3538, 2002).

[0007] This suggests that the CDK7 enzyme complex is involved in multiple intracellular functions: cell cycle regulation, transcriptional control, and DNA repair. It is surprising that a single kinase has been found to be involved in such diverse cellular processes (some of which are even mutually exclusive). It is also puzzling that several attempts to discover cell cycle-dependent changes in CDK7 kinase activity have remained unsuccessful. This is unexpected, as the activity and phosphorylation state of its substrate, CDC2, fluctuate during the cell cycle. In fact, cdk7 activity has been shown to be required for both the Cdc2 / 2 cyclin A and Cdc2 / cyclin B complexes, as well as for cell division (Larochelle, S. et al. Genes Dev 12, 370-81, 1998). In fact, flavopyridol, a non-selective pan-CDK inhibitor that targets CTD kinase, has shown efficacy in treating chronic lymphocytic leukemia (CLL), but suffers from an unsatisfactory toxicity profile (Lin et al., Clin. Oncol. 27, 6012-6018, 2009; Christian et al., Clin. Lymphoma Myeloma, 9, Suppl. 3, Sl79-S185, 2009).

[0008] International Publication WO2016193939 describes CDK7 inhibitors, the preparation process for said inhibitors, pharmaceutical compositions containing said inhibitors, and the use of said inhibitors as therapeutic agents as protein kinase inhibitors in the treatment of various disorders, particularly cancer and other proliferative disorders, and is incorporated herein by reference for all purposes. CDK7 inhibitors are currently being developed for the treatment of cancer. For drug discovery, it is generally advantageous to use a drug form that has desirable properties with respect to its preparation, purification, reproducibility, stability, bioavailability, and other characteristics.

[0009] Therefore, there is a need for novel forms, salts, and / or cocrystals of CDK7 inhibitor molecules to prepare pharmaceutically useful formulations and dosage forms that have desirable properties for facilitating the manufacture of safe, effective, and high-quality pharmaceuticals, for example. [Overview of the Initiative]

[0010] The compound of formula (I) is also known as (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide. This disclosure provides a process and synthesis of the compound of formula (I) in high yield and purity. The invented fumarate compound of formula (I) exhibits unexpected physicochemical properties, such as high stability, high purity, and low hygroscopicity, compared to its free base form.

[0011] In one embodiment, the present invention provides a fumarate compound of formula (I): [ka]

[0012] In one embodiment, the present invention provides a cocrystal comprising a compound of formula (I) and fumaric acid.

[0013] In another embodiment, the present invention provides a compound-fumaric acid (1:1) cocrystal of formula (I): [ka]

[0014] In a further embodiment, the present invention relates to a method for preparing a fumarate compound of formula (I).

[0015] In a further embodiment, the present invention relates to a method for preparing a fumarate crystalline compound of formula (I).

[0016] In a further embodiment, the present invention provides a pharmaceutical composition comprising a fumarate compound of formula (I).

[0017] In another aspect, the present invention provides the use of a fumaric acid compound of formula (I) for treating various diseases, disorders, or medical conditions described herein.

Brief Description of the Drawings

[0018] [Figure 1] Shows the asymmetric unit of a single crystal of the fumaric acid compound of formula (I). [Figure 2] Shows the XRPD pattern of Compound 1 in the fumaric acid form of formula (I) collected at 25 °C. [Figure 3] Shows the differential scanning calorimetry (DSC) thermogram of the fumaric acid compound of formula (I). [Figure 4] Shows the thermogravimetric measurement (TGA) of the fumaric acid compound of formula (I). [Figure 5A] Shows the optical and polarized light microscopy studies of the fumaric acid compound of formula (I). [Figure 5B] Shows the polarized light microscopy study of the fumaric acid compound of formula (I). [Figure 6A] Shows the overlay of VT-XRD patterns of Compound 1 in the fumaric acid form of formula (I) collected at 25 °C, 40 °C, and 60 °C. [Figure 6B] Shows the overlay of VH-XRPD patterns of Compound 1 in the fumaric acid form of formula (I) collected under various humidity conditions. [Figure 7] Shows the overlay of XRPD patterns of Compound 1 in the fumaric acid form of formula (I) exposed to different conditions. [Figure 8] Shows the dynamic vapor sorption (DVS) of Compound 1 in the fumaric acid form of formula (I).

Modes for Carrying Out the Invention

[0019] As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0020] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, most preferably human, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates.

[0021] As used herein, the terms “to treat,” “to treat,” or “to cure” mean (1) inhibiting a disease, for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or overall symptoms of a disease, condition, syndrome, or disorder (i.e., halting the further development of the pathology and / or overall symptoms), and (2) improving or suppressing a disease, for example, improving a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or overall symptoms of a disease, condition, or disorder (i.e., reversing the pathology and / or overall symptoms), for example, reducing the severity of the disease. In one embodiment, the terms “to treat,” “to treat,” or “to cure” mean preventing or delaying the onset, onset, or progression of a disease, condition, syndrome, or disorder.

[0022] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, within the bounds of safe medical judgment, and that is commensurate with a reasonable benefit / risk ratio.

[0023] As used herein, the term “pharmaceutically acceptable carrier or excipient” means a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, not biologically or otherwise scientifically undesirable, and are acceptable for veterinary use, as well as for pharmaceutically acceptable use in humans. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams & Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0024] As used herein, “pharmaceutically acceptable salt” means a derivative of the disclosed compound in which the parent compound is modified by converting the present acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (e.g., amines) and alkali or organic salts of acidic residues (e.g., carboxylic acids). Examples of pharmaceutically acceptable salts of the disclosed herein include conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the disclosed herein can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof (generally, non-aqueous media such as ether, ethyl acetate, alcohol, or acetonitrile (ACN) are preferred).

[0025] "Cancer" includes: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyomas, fibromas, lipomas and teratomas; Head and neck: squamous cell carcinoma of the head and neck, laryngeal and hypopharyngeal carcinoma, nasal cavity and paranasal sinus carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, oral cancer and pharyngeal carcinoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma, non-small cell lung carcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, muscle Tumors, lymphomas, chondromatous hamartomas, mesothelioma; Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumors, lymphoma, carcinoid tumors, Turcott syndrome; Gastrointestinal tract: gastric cancer, gastroesophageal junction adenocarcinoma, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, bipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, carposi sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); Breast cancer: Metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular adenocarcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple-negative breast cancer; Urogenital system: Kidney (adenocarcinoma, Wilms' tumor [nephroblastoma], lymphoma, leukemia, renal cell carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate (adenocarcinoma, sarcoma, castration-resistant prostate cancer), testes (seminocarcinoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma), clear cell carcinoma, papillary carcinoma; Liver: Hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma , Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell chondroma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Thyroid: medullary thyroid carcinoma, differentiated thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Hürthle cell carcinoma, and undifferentiated thyroid carcinoma; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meningioma (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ blastoma [pineal tumor], glioblastoma pleomorphic, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, pre-neoplastic cervical dysplasia), ovaries (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer], granuloma-melaninic cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); Hematology: Blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia) This refers to a state of cell proliferation disorder, including but not limited to: diseases, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes, Hodgkin's disease, non-Hodgkin lymphoma [malignant lymphoma]; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus moles, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and adrenal gland: neuroblastoma. Therefore, the term “cancerous cells” as provided herein includes cells suffering from any one of the conditions identified above.

[0026] As used herein, “cocrystal” means a single-phase crystalline material containing at least two non-volatile components in the same crystal lattice in a specific stoichiometric (molar) ratio, wherein the arrangement within the crystal lattice is not based on ionic bonding (as in salts) or covalent interactions, and at least two of the components are solid at room temperature. A cocrystal is composed of two or more components that form a unique crystal structure with unique properties. Cocrystals can include hydrates, solvates, and inclusion compounds.

[0027] As used herein, the term “crystal morphology” refers to a particular lattice configuration of a crystalline material. Different crystal morphologies of the same material generally have different crystal lattices (e.g., unit cells), which result from different physical properties specific to each crystal morphology. In some cases, different lattice configurations have different water or solvent content.

[0028] As used herein, “therapeutic dose” means an amount sufficient to produce a therapeutic effect when administered to a mammal in need of such treatment. The therapeutic dose varies depending on the subject being treated, the subject’s weight and age, the severity of the condition, the mode of administration, etc., and can be quickly determined by those skilled in the art.

[0029] As used herein, the term "substantially pure" means a crystalline polymorph that is 90% or more pure and contains less than 10% of any other compound or alternative polymorph of the crystalline form. Preferably, the crystalline polymorph is more than 95% pure, or even more than 98% pure.

[0030] The phrase "substantially as shown in Figure ~" means a pattern having at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the values ​​that appear in that figure.

[0031] As used herein, the term “approximately” when referring to a number or range of numbers means that the number or range referred to is an approximation within experimental variability (or statistical experimental error), and therefore the number or range may vary, for example, from 1% to 15% of the specified number or range.

[0032] Each embodiment is provided as an explanation of the present invention and not as a limitation of the present invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described in the present invention without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment may be applied to another embodiment to produce yet another embodiment. Thus, the present invention is intended to include such modifications and variations, as well as their equivalents. Other objects, features, and aspects of the present invention are disclosed in or evident therefrom in the following detailed description. It should be understood by those skilled in the art that this description is only an illustrative description of embodiments and should not be construed as limiting broader aspects of the present invention.

[0033] Fumarate compound of formula (I) In one embodiment, the present invention provides a fumarate compound of formula (I): [ka]

[0034] In one embodiment, the present invention provides a cocrystal of the compound of formula (I) - fumaric acid.

[0035] In one embodiment, the molar ratio of the compound of formula (I) to fumaric acid is 1:1.

[0036] In one embodiment, the present invention provides a fumarate crystalline compound of formula (I).

[0037] In one embodiment, the present invention provides a fumarate crystalline compound of formula (I) having form 1.

[0038] Identification and analysis of the fumarate compound of formula (I). Different crystalline morphologies can be identified by solid-state characterization methods, such as X-ray powder diffraction (XRPD). Other characterization methods, such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic water vapor adsorption (DVS), not only further aid in morphological identification but also determine stability and solvent / water content.

[0039] The XRPD pattern of refraction (peaks) is typically considered a fingerprint of a particular crystal morphology. The relative intensity of XRPD peaks can vary widely, particularly depending on the sample preparation technique, crystal size distribution, the various filters used, the sample mounting procedure, and the specific instrument used. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or setting of the instrument. As used herein, the term “peak” refers to refraction with a relative height intensity of at least about 4% relative height / intensity. Furthermore, instrument variations and other factors may affect the 2θ value. Thus, peak assignments, such as those reported herein, may vary by plus or minus about 0.2°(2θ), and the terms “substantially” and “about” when used herein in the context of XRPD mean that these variations are included.

[0040] In one embodiment, the polymorphism of a crystalline compound is characterized by powder X-ray diffraction (XRD), where θ represents the diffraction angle and is measured in degrees. In one embodiment, the diffractometer used in the XRD measures the diffraction angle as twice the diffraction angle theta (θ). Therefore, in one embodiment, the diffraction pattern described herein represents the X-ray intensity measured for an angle of 2 theta (2θ).

[0041] Similarly, temperature measurements for DSC, TGA, or other thermal experiments can vary by approximately ±3°C depending on the instrument, specific settings, sample preparation, etc. Therefore, it is understood that the crystal morphologies reported herein, as indicated in either figure or in the DSC thermogram as "substantially" or "approximately," correspond to such variations.

[0042] In one embodiment, the fumarate compound of formula (I) is in crystalline form. In another embodiment, the fumarate compound of formula (I) is substantially crystalline.

[0043] In one embodiment, “substantially crystalline” means a fumarate compound of formula (I) in which at least a certain weight percentage is crystalline. Specific weight percentages include 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, and 99.9%. In one embodiment, “substantially crystalline” means a fumarate compound of formula (I) in which at least 70% is crystalline. In one embodiment, “substantially crystalline” means a fumarate compound of formula (I) in which at least 80% is crystalline. In one embodiment, “substantially crystalline” means a fumarate compound of formula (I) in which at least 85% is crystalline. In one embodiment, “substantially crystalline” means a fumarate compound of formula (I) in which at least 90% is crystalline. In some embodiments, "substantially crystalline" means a fumarate compound of formula (I) that is at least 95% crystalline. In one embodiment, the fumarate compound of formula (I) is 99.9% crystalline.

[0044] In one embodiment, the fumarate compound of formula (I) takes the crystalline form 1.

[0045] In one implementation, the fumaric acid crystalline compound of formula (I) is anhydrous.

[0046] In one embodiment, the present invention provides a cocrystal of a fumarate compound of formula (I).

[0047] In one embodiment, the fumarate crystalline compound of formula (I) is characterized by X-ray diffraction analysis.

[0048] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of about 5.0 ± 0.2.

[0049] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of about 10.0 ± 0.2.

[0050] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of about 15.0 ± 0.2.

[0051] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of about 12.0 ± 0.2.

[0052] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of about 18.0 ± 0.2.

[0053] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of about 22.0 ± 0.2.

[0054] In one embodiment, the compound-fumaric acid cocrystal of formula (I) is characterized by an X-ray powder diffraction pattern containing at least one peak at a 2θ angle of approximately 24.0 ± 0.2.

[0055] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has 2θ values ​​characterized by an X-ray powder diffraction pattern containing peaks at approximately 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2.

[0056] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has 2θ values ​​characterized by an X-ray powder diffraction pattern containing at least one, two, or three peaks at approximately 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2.

[0057] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has 2θ values ​​characterized by an X-ray powder diffraction pattern containing peaks at approximately 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 22.0±0.2, and 22.5±0.2.

[0058] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has 2θ values ​​characterized by an X-ray powder diffraction pattern that includes at least four peaks at approximately 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 22.0±0.2, and 22.5±0.2.

[0059] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has 2θ values ​​of 5.0±0.2, 10.0±0.2, 10.5±0.2, 12.0±0.2, 13.6±0.2, 14.8±0.2, 15.0±0.2, 17.6±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 21.2±0.2, 22.0±0.2, 22.5±0.2, 24.0±0.2, 25.0±0.2, 26.1±0.2, and 27.4±0.2.

[0060] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has 2θ values ​​characterized by an X-ray powder diffraction pattern that includes peaks at approximately 5.0±0.2, 10.0±0.2, 10.5±0.2, 12.0±0.2, 14.8±0.2, 15.0±0.2, 15.6±0.2, 17.6±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 20.1±0.2, 21.2±0.2, 22.0±0.2, 22.5±0.2, 23.4±0.2, 24.0±0.2, 25.0±0.2, 26.1±0.2, 26.8±0.2, 27.4±0.2, and 36.6±0.2.

[0061] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has approximately: 5.0±0.2, 10.0±0.2, 10.5±0.2, 12.0±0.2, 13.6±0.2, 14.8±0.2, 15.0±0.2, 15.6±0.2, 16.5±0.2, 17.6±0.2, 18.7±0.2, 19.3±0.2, 19.8±0.2, 20.0±0.2, 20.1±0.2, 21.2±0.2, 22.0±0.2, 22.5±0.2, 23.0±0.2, 23.4±0.2, 24.0±0. It has 2θ values ​​characterized by an X-ray powder diffraction pattern that includes peaks at 0.2, 25.0±0.2, 25.6±0.2, 26.1±0.2, 26.8±0.2, 27.4±0.2, 28.9±0.2, 29.3±0.2, 30.1±0.2, 30.5±0.2, 31.4±0.2, 32.2±0.2, 33.4±0.2, 36.1±0.2, 36.6±0.2, 38.0±0.2, 39.2±0.2, 40.2±0.2, 40.6±0.2, and 41.0±0.2. [Table 1]

[0062] Characterization information for describing any solid-state fumarate compound of formula (I) is provided herein. However, it should be understood that not all of such information is required for a person skilled in the art to determine that such a particular form is present in a given composition. Identification of a particular form can be achieved using any part of the characterization information that a person skilled in the art would recognize as sufficient to confirm the presence of a particular form. For example, a characteristic peak may be sufficient for a person skilled in the art to determine that such a particular form is present.

[0063] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has an XPRD pattern substantially as shown in Figure 2.

[0064] In one embodiment, differential scanning calorimetry (DSC) reveals that the compound-fumaric acid cocrystal of formula (I) exhibits endothermic activity with a peak temperature of approximately 190°C to approximately 210°C, corresponding to melting. In some embodiments, the compound-fumaric acid cocrystal of formula (I) exhibits endothermic activity with a peak temperature in a range selected from approximately 195°C to approximately 210°C, corresponding to melting. In some embodiments, DSC corresponding to melting reveals that the compound-fumaric acid cocrystal of formula (I) exhibits endothermic activity with peak temperatures in a range selected from approximately 195°C to approximately 205°C, approximately 198°C to approximately 205°C, and approximately 199°C to approximately 204°C. In one embodiment, the compound-fumaric acid cocrystal of formula (I) exhibits endothermic activity with a peak temperature of 203°C ± 3°C. See Figure 3.

[0065] In one embodiment, the compound-fumaric acid cocrystal of formula (I) undergoes thermogravimetric analysis substantially as shown in Figure 4.

[0066] In one embodiment, the compound-fumaric acid cocrystal of formula (I) has dynamic water vapor adsorption substantially as shown in Figure 8.

[0067] Method for preparing the fumarate compound of formula (I) In one embodiment, the present invention is a method for preparing a fumarate compound of formula (I), a) Fumaric acid is used in the compound of formula (I) above. [ka] Adding to a mixture containing a solvent, b) Obtaining the fumarate compound of formula (I) from the above mixture, The above method is provided, including the following.

[0068] In one embodiment, the mixture comprises a solution of the compound of formula (I). In one embodiment, the solution comprises a crude solid containing the compound of formula (I) dissolved in the solution. In one embodiment, the crude solid contains about 70% to about 90% of the compound of formula (I).

[0069] In one embodiment, in step a) of preparing the fumaric acid compound of formula (I), fumaric acid is dissolved in a solvent.

[0070] In one embodiment, in the preparation of the fumarate compound of formula (I), the solvent is methanol, acetonitrile, acetone, anisole, dichloromethane, dichloroethane, ethanol, methyl acetate, n-propyl acetate, isopropyl alcohol, isopropyl acetate, propanol, butanol, pentanol, n-butyl acetate, isobutyl acetate, isobutylene, acetate, methylcyclohexane, methyl tert-butyl ether, n-hexane, n-heptane, tetrahydrofuran, or water, or a mixture thereof.

[0071] In one embodiment, in the preparation of the fumarate compound of formula (I), the solvent is methanol, acetone, dichloroethane, ethanol, methyl acetate, n-propyl acetate, isopropyl alcohol, isopropyl acetate, propanol, butanol, n-butyl acetate, methylcyclohexane, methyl-tert-butyl ether, n-hexane, n-heptane, tetrahydrofuran, or water, or a mixture thereof.

[0072] In one embodiment, in the preparation of the fumarate compound of formula (I), the solvent is methanol, ethanol, methyl acetate, isopropyl alcohol, isopropyl acetate, propanol, butanol, n-butyl acetate, methylcyclohexane, or water, or a mixture thereof.

[0073] In one embodiment, in the preparation of the fumarate compound of formula (I), the solvent is methanol, ethanol, methyl acetate, isopropyl alcohol, isopropyl acetate, propanol, n-hexane, n-heptane, or water, or a mixture thereof.

[0074] In one embodiment, the solvent used in the preparation of the fumarate compound of formula (I) is methanol, ethanol, isopropyl alcohol, isopropyl acetate, water, or a mixture thereof.

[0075] In one embodiment, the solvent used in the preparation of the fumarate compound of formula (I) is methanol or ethanol.

[0076] In one embodiment, methanol is used as the solvent in the preparation of the fumarate compound of formula (I).

[0077] In one embodiment, in the preparation of a fumarate compound of formula (I), obtaining a fumarate compound of formula (I) is possible. i. Stirring a mixture containing the compound of formula (I) above and fumaric acid, ii. To form a suspension by cooling the above mixture to ambient temperature, iii. Isolating the fumarate compound of formula (I) from the above suspension, Includes.

[0078] In one embodiment, the mixture of the compound of formula (I) and fumaric acid in step (i) is stirred at a temperature in the range of 50°C to 70°C. In one embodiment, the stirring temperature in step (i) is 55°C to 65°C. In another embodiment, the stirring temperature in step (i) is 60°C to 65°C.

[0079] In one embodiment, the stirring time in step (i) is 2 to 16 hours. In one embodiment, the stirring time in step (i) is 4 to 10 hours. In one embodiment, the stirring time in step (i) is 4 to 10 hours. In one embodiment, the stirring time in step (i) is 4 hours.

[0080] In one embodiment, the step of isolating the fumarate compound of formula (I) from the suspension includes filtering the fumarate compound of formula (I) obtained from the suspension. In one embodiment, the step of filtering the fumarate compound of formula (I) obtained from the suspension further includes washing and drying the fumarate compound of formula (I) obtained from the suspension. In one embodiment, the fumarate compound of formula (I) filtered from the suspension is washed with a solvent. In one embodiment, the fumarate compound of formula (I) is washed with methanol.

[0081] In one embodiment, the fumarate compound of formula (I) prepared by the method described herein is substantially pure. In one embodiment, the purity of the fumarate compound of formula (I) is selected from about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, and about 99%. In one embodiment, the purity of the fumarate compound of formula (I) is selected from about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, and about 98%.

[0082] In one embodiment, the compound-fumaric acid cocrystal of formula (I) may have a free base:acid molar ratio of 1:1 or 1:>1, such as 1:1.3 or 1:2.

[0083] Crystallization method of the fumarate compound of formula (I) The solid forms (e.g., crystalline forms) described herein may have certain advantages, such as desirable properties including ease of handling, ease of processing, storage stability, and ease of purification. Furthermore, crystalline forms may be useful for improving performance characteristics of pharmaceutical products, such as solubility profile, shelf life, and bioavailability.

[0084] In one embodiment, the present invention is a method for preparing a fumaric acid crystalline compound of formula (I), a) Selectively heating a mixture containing the fumarate compound of formula (I) and a solvent, b) Crystallizing the fumarate compound of formula (I) from the above mixture, The above method is provided, including the following.

[0085] In one embodiment, the present invention is a method for preparing a cocrystal of a compound of formula (I) and fumaric acid, a) Selectively heating a mixture containing the fumarate compound of formula (I) and a solvent, b) Crystallizing the fumarate compound of formula (I) from the above mixture, The above method is provided, including the following.

[0086] In one embodiment of the method for preparing the fumaric acid compound of formula (I), the mixture is a solution of the fumaric acid compound of formula (I) dissolved in a solvent.

[0087] In one embodiment of a method for preparing a crystalline fumarate compound of formula (I), the solvent comprises the fumarate compound of formula (I) dissolved in a solvent or a mixture of solvents. In some embodiments, the solution comprises a reaction mixture.

[0088] In one embodiment, the mixture is a slurry or suspension. In one embodiment, the slurry or suspension comprises a crude solid substance containing a compound of formula (I).

[0089] In one embodiment of the method for preparing the fumaric acid crystalline compound of formula (I), the solvent is an alcohol, ether ketone, ester, chlorinated solvent, nitrile, or hydrocarbon, or a combination thereof.

[0090] In one embodiment of a method for preparing a fumaric acid crystalline compound of formula (I), the solvent is selected from methanol, ethanol, propanol, pentanol, anisole, isopropanol, butanol, 1,2-dimethoxyethanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, tetrahydrofuran, diethyl ether, 1,4-dioxane, diisopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, methyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, chloroform, isobutylene acetate, dichloromethane, dichloroethane, methylcyclohexane, methyl tert-butyl ether (MTBE), acetonitrile, benzene, toluene, xylene, n-hexane, n-heptane, water, and mixtures thereof. In one embodiment of a method for preparing a crystalline fumaric acid compound of formula (I), the solvent is methanol, ethanol, anisole, isopropanol, butanol, 1,2-dimethoxyethanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, tetrahydrofuran, diethyl ether, 1,4-dioxane, diisopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, chloroform, dichloromethane, acetonitrile, benzene, toluene, and xylene, or any combination thereof.

[0091] In one embodiment of the method for preparing the fumaric acid crystalline compound of formula (I), the solvent is methanol, ethanol, isopropanol, butanol, 1,2-dimethoxyethanol, 2-methoxyethanol, or 2-ethoxyethanol.

[0092] In one embodiment of the method for preparing the fumaric acid crystalline compound of formula (I), the solvent is methanol, ethanol, isopropanol, or butanol. In one embodiment, the solvent is methanol or ethanol.

[0093] In one embodiment of a method for preparing a fumaric acid crystalline compound of formula (I), the solvent is selected from acetonitrile, acetone, anisole, dichloromethane, dichloroethane, ethanol, methanol, methyl acetate, n-propyl acetate, isopropyl acetate, propanol, butanol, pentanol, n-butyl acetate, isobutyl acetate, isobutyl acetate, methylcyclohexane, methyl-tert-butyl ether (MTBE), n-hexane, n-heptane, tetrahydrofuran, water, and mixtures thereof.

[0094] In one embodiment, the step of crystallizing the fumarate compound of formula (I) from a mixture includes precipitating the fumarate compound of formula (I) from the solution by evaporating the solvent at ambient temperature. In another embodiment, the step of crystallizing the fumarate compound of formula (I) from a mixture includes precipitating the cocrystal of the fumarate cocrystal compound of formula (I) by cooling the mixture to below ambient temperature.

[0095] In one embodiment, the present invention is a method for preparing a fumaric acid crystalline compound of formula (I), [ka] a) Adding a poor solvent to a mixture containing the fumarate compound of formula (I) and the solvent, b) Crystallizing the fumarate compound of formula (I) from the above mixture, The above method is provided, including the following.

[0096] In one embodiment, the present invention is a method for preparing a cocrystal of a fumarate crystalline compound of formula (I), [ka] a) Adding a poor solvent to a mixture containing the fumarate compound of formula (I) and the solvent, b) Crystallizing the fumarate compound of formula (I) from the above mixture, The above method is provided, including the following.

[0097] In one embodiment, a solution is formed by heating a mixture containing a fumarate compound of formula (I) and a solvent.

[0098] In one embodiment of the method for preparing a crystalline fumaric acid compound of formula (I), the solvent is acetone, n-propyl acetate, acetonitrile, methanol, isopropyl acetate, isobutanol, 2-butanol, 1-butanol, n-butyl acetate, 1-pentanol, 1-propanol, chloroform, methyl acetate, isobutyl acetate, isobutanol, or ethanol.

[0099] In one embodiment, the mixture containing the fumarate compound of formula (I) is a solution, and the step of crystallizing the fumarate compound of formula (I) from the mixture includes precipitation of the fumarate compound of formula (I) from the solution by supersaturating the solution.

[0100] In one embodiment, the step of supersaturating the solution includes adding a poor solvent.

[0101] In one embodiment, the step of supersaturating the solution includes cooling the solution to below ambient temperature.

[0102] In one embodiment, the step of supersaturating the solution includes maintaining the solution temperature above approximately 20°C.

[0103] As used herein, “poor solvent” means a solvent in which the compound crystals are insoluble, slightly insoluble, or partially soluble, i.e., (solubility less than 1 mg / mL). In practice, adding a poor solvent to a solution in which the crystals dissolve reduces the solubility, i.e., supersaturation, of the crystals in the solution, thereby promoting the precipitation of the compound in question. In one embodiment, the crystals are washed with a combination of a poor solvent and an organic solvent. In one embodiment, the poor solvent is water, while in other embodiments, the poor solvent is an alkane solvent such as hexane or pentane, or an aromatic hydrocarbon solvent such as 1,2-dichloroethane, benzene, toluene, methylcyclohexane, or xylene.

[0104] In one embodiment, the poor solvents are dichloromethane, dichloroethane, ethanol, methanol, propanol, butanol, pentanol, isobutyl acetate, isobutylene acetate, methylcyclohexane, n-hexane, n-heptane, tetrahydrofuran, and mixtures thereof.

[0105] In one embodiment, the poor solvents are 1,2-dichloroethane, n-hexane, and methylcyclohexane.

[0106] In one embodiment, one or more impurities are removed from a sample of compound (I)-fumaric acid using a method for producing the crystalline form of the fumarate compound of formula (I).

[0107] In one embodiment, the fumarate compound of formula (I) is substantially pure after crystallization. In some embodiments, the fumarate compound of formula (I) in crystalline form is more than 90% pure. In some embodiments, the purity of the fumarate compound of formula (I) in crystalline form is selected from greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99%. In some embodiments, the purity of the fumarate compound of formula (I) in crystalline form is greater than 95%. In some embodiments, the purity of the fumarate compound of formula (I) in crystalline form is greater than 98%. In some embodiments, the purity of the fumarate compound of formula (I) in crystalline form is selected from about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, and about 99%.

[0108] In one embodiment, the fumaric acid crystalline compound of formula (I) is the fumaric acid crystalline compound of formula (I) described herein.

[0109] In some embodiments, the fumarate compound of formula (I) is substantially isolated.

[0110] "Substantially isolated" means that the salt, cocrystal, or compound is at least partially or substantially separated from the environment in which it was formed or detected. Examples of partial isolation include compositions rich in the salts described herein. Substantial isolation may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the salt or a salt of the present invention. Methods for isolating compounds and salts thereof are commonplace in the art.

[0111] In one embodiment, the preparation method further includes inducing crystallization. The method may also include, for example, drying the crystals under reduced pressure. In one embodiment, inducing precipitation or crystallization includes secondary nucleation, in which nucleation occurs in the presence of a seed crystal or interaction with the environment (such as the walls of the crystallizer, a stirring impeller, or sonic treatment).

[0112] Pharmaceutical composition In one embodiment, the present invention relates to a pharmaceutical composition comprising a fumarate compound of formula (I) and one or more pharmaceutically acceptable excipients.

[0113] In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of formula (I)-fumaric acid cocrystal (1:1) and one or more pharmaceutically acceptable excipients.

[0114] One embodiment of the present invention relates to a pharmaceutical composition comprising a fumarate compound of formula (I) or a cocrystal thereof, together with at least one other therapeutic agent and a pharmaceutically acceptable carrier or excipient.

[0115] Use of fumarate compound of formula (I) In one embodiment, the present invention provides the use of a pharmaceutical composition comprising a fumarate compound of formula (I) and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). In one embodiment, the present invention provides the use of a pharmaceutical composition comprising a compound-fumarate cocrystal (1:1) of formula (I) as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). The compound-fumarate cocrystal of formula (I) as described herein can be combined with a pharmaceutically acceptable excipient (such as a carrier or diluent), or can be diluted with a carrier, or can be encapsulated in a carrier which may be in the form of a capsule, sachet, paper, or other container.

[0116] In another embodiment, the present invention provides a pharmaceutical composition comprising a fumarate compound of formula (I) for use in the treatment and / or prevention of diseases and / or disorders associated with abnormal activity of selective transcription CDKs.

[0117] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I)-fumarate cocrystal (1:1) for use in the treatment of subjects suffering from diseases and / or disorders associated with abnormal activity of selective transcriptional CDKs.

[0118] One embodiment of the present invention relates to a pharmaceutical composition comprising a fumarate compound of formula (I) or a cocrystal thereof, together with at least one other therapeutic agent, for use in the treatment and / or prevention of diseases and / or disorders associated with abnormal activity of selective transcriptional CDKs.

[0119] In another embodiment, the present invention provides a method for selectively inhibiting a transcriptional CDK in a subject, comprising administering a therapeutically effective amount of a fumarate compound of formula (I) described herein to a subject requiring such inhibition.

[0120] In another embodiment, the present invention provides a method for treating a disease and / or disorder mediated by a selective transcription CDK in a subject, comprising administering to the subject in need of such treatment a therapeutically effective amount of a fumarate compound of formula (I) described herein.

[0121] In another embodiment, the present invention provides a pharmaceutical composition comprising a fumarate compound of formula (I) described herein for use in the treatment of subjects suffering from diseases and / or disorders associated with abnormal activity of transcriptional CDK9, CDK12, CDK13, or CDK18.

[0122] In another embodiment, the present invention provides a pharmaceutical composition comprising a fumarate compound of formula (I) described herein for use in the treatment of subjects suffering from diseases and / or disorders associated with abnormal activity of transcriptional CDK7.

[0123] In yet another embodiment, the present invention provides a method for treating a disorder and / or disease or condition mediated by a selective transcriptional CDK (CDK9, CDK12, CDK13, or CDK18) in a subject, comprising administering a therapeutically effective amount of a fumarate compound of formula (I) described herein.

[0124] In yet another embodiment, the present invention provides a method for treating a disorder and / or disease or condition mediated by transcription CDK7 in a subject, comprising administering a therapeutically effective amount of a fumarate compound of formula (I) described herein.

[0125] In yet another embodiment, the present invention provides a method for selectively inhibiting transcriptional CDKs. In yet another embodiment, the present invention provides a method for inhibiting transcriptional CDK7, CDK9, CDK12, CDK13, or CDK18 in a subject of interest; more specifically CDK7, by administering to the subject an amount of a fumarate compound of formula (I) described herein that is effective in causing inhibition of such receptor / kinase.

[0126] In another embodiment, the present invention relates to a method for inhibiting the activity of a kinase in a biological sample or subject. In one embodiment, the kinase is a selectively transcribed CDK. In another embodiment, the selectively transcribed CDK is CDK7, CDK9, CDK12, CDK13, or CDK18. In yet another embodiment, the selectively transcribed CDK is CDK7 in particular.

[0127] In one embodiment, the disease and / or disorder is cancer, inflammatory disorder, autoinflammatory disorder, and infection.

[0128] In one embodiment, the inhibition of kinase activity is irreversible. In another embodiment, the inhibition of kinase activity is reversible.

[0129] The compounds described in this invention are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical field and contain at least one of the compounds of this invention. The pharmaceutical compositions of this invention contain one or more of the compounds described herein and one or more pharmaceutically acceptable excipients. Typically, pharmaceutically acceptable excipients are approved by regulatory authorities or are generally considered safe for use in humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, lubricants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, thickeners, and solvents.

[0130] Pharmaceutical compositions can be administered orally, parenterally, or by inhalation. Examples of parenteral administration include administration by injection, transdermal, transmucosal, transnasal, and transpulmonary artery.

[0131] Suitable carriers include, but are not limited to, water, saline solution, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl esters of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylenes.

[0132] The pharmaceutical composition may also contain one or more pharmaceutically acceptable auxiliaries, humectants, anti-precipitation agents, preservatives, buffers, sweeteners, flavoring agents, colorants, or any combination thereof.

[0133] The pharmaceutical composition may be in conventional forms, such as tablets, capsules, solutions, suspensions, injections, or products for topical application. Furthermore, the pharmaceutical composition of the present invention may be formulated to provide a desired release profile.

[0134] The compounds of the present invention, in their pure form or in suitable pharmaceutical compositions, may be administered using any of the qualified routes of administration of the pharmaceutical composition. The route of administration may be any method that effectively moves the active compounds of the present invention to a suitable or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, cutaneous, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, or topical administration.

[0135] Examples of solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), sugar-coated tablets (in powder or pellet form containing the active ingredient), lozenges, and tablets.

[0136] Examples of liquid formulations include, but are not limited to, sterile injectable liquids such as syrups, emulsions, suspensions, or solutions.

[0137] Topical administration forms of the compound include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, and impregnated bandages, and may contain appropriate conventional additives such as preservatives and solvents that aid in drug penetration.

[0138] The pharmaceutical composition of the present invention can be prepared by prior art known in the literature.

[0139] Suitable doses of the fumarate compound of formula (I) described herein for use in the treatment of the diseases or disorders described herein can be determined by those skilled in the art. Therapeutic doses are generally identified by human dose-range studies based on preliminary evidence derived from animal studies. The dose must be sufficient to produce the desired therapeutic effect without causing unnecessary side effects. Methods of administration, drug formulations, and suitable pharmaceutical excipients can also be readily used and modified by those skilled in the art. Any changes and modifications are assumed to be within the scope of the present invention.

[0140] In one embodiment, the fumarate compound of formula (I) disclosed in the present invention is formulated for pharmaceutical administration.

[0141] Yet another embodiment of the present invention provides the use of a fumarate compound of formula (I) disclosed herein in the treatment and prevention of diseases and / or disorders associated with abnormal activity of selective transcription CDKs, wherein the selective transcription CDK is CDK7, CDK9, CDK12, CDK13, or CDK18, and more specifically CDK7.

[0142] Yet another embodiment of the present invention provides the use of a fumarate compound of formula (I) in the treatment and / or prevention of diseases whose symptoms are treated, improved, reduced and / or prevented by inhibition of a selective transcription CDK, wherein the selective transcription CDK is CDK7, CDK9, CDK12, CDK13, or CDK18, and more specifically CDK7.

[0143] In yet another embodiment, the disorder and / or disease or condition mediated by a selective transcription CDK is a proliferative disorder or disorder or condition.

[0144] In yet another embodiment, the disease and / or disorder mediated by the selective transcription CDK is selected from, but is not limited to, cancer, inflammatory disorders, autoinflammatory disorders, or infections.

[0145] In other embodiments, proliferative disorders that can be treated or prevented with a fumarate compound of formula (I) are typically associated with abnormal activity of CDK, more specifically, CDK7, CDK9, CDK12, CDK13, or CDK18. Abnormal activity of CDK7, CDK9, CDK12, CDK13, or CDK18 may be increased activity and / or inappropriate (e.g., abnormal) activity of CDK7, CDK9, CDK12, CDK13, or CDK18. In one embodiment, CDK7, CDK9, CDK12, CDK13, or CDK18 are not overexpressed, and their activity is increased and / or inappropriate. In certain other embodiments, CDK7, CDK9, CDK12, CDK13, or CDK18 are overexpressed, increasing their activity and / or being unsuitable.

[0146] In yet another embodiment, the fumarate compound of formula (I) is expected to be useful in the treatment of proliferative disorders such as viral diseases, mycoses, neurological / neurodegenerative diseases, autoimmune diseases, inflammatory diseases, arthritis, antiproliferative (e.g., retinal) diseases, neuronal diseases, alopecia, and cardiovascular diseases.

[0147] In yet another embodiment, the fumarate compound of formula (I) includes cancers including breast cancer, liver cancer, lung cancer, colon cancer, kidney cancer, bladder cancer (including small cell lung cancer), non-small cell lung cancer, head and neck cancer, thyroid cancer, esophageal cancer, gastric cancer, pancreatic cancer, ovarian cancer, gallbladder cancer, cervical cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, B-cell lymphoma, T-cell lymphoma, pilocytic cell lymphoma, myeloma, mantle cell lymphoma, and Burkitt lymphoma. It is useful in the treatment of various cancers, including, but not limited to, hematopoietic neoplasms of the lymphatic lineage; hematopoietic neoplasms of the bone marrow lineage, including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; mesenchymal tumors, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous systems, including astrocytoma, neuroblastoma, glioma, and schwannoma; and other tumors, including seminomas, melanoma, osteosarcoma, teratoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi's sarcoma.

[0148] In yet another embodiment, the subjects are mammals, including humans.

[0149] In yet another embodiment, the present invention provides a fumarate compound of formula (I) for use as a pharmaceutical agent.

[0150] In yet another embodiment, the present invention provides the use of a fumarate compound of formula (I) in the manufacture of a pharmaceutical product.

[0151] In yet another embodiment, the present invention provides a fumarate compound of formula (I) for use in the treatment of cancer.

[0152] In yet another embodiment, the present invention provides the use of a fumarate compound of formula (I) in the manufacture of a drug for treating diseases and / or disorders associated with abnormal activity of selective transcription CDKs.

[0153] In yet another embodiment, the present invention provides the use of a fumarate compound of formula (I) in the manufacture of a drug for the treatment of cancer.

[0154] In yet another embodiment, the present invention provides a fumarate compound of formula (I) for use as a pharmacopoeia for treating subjects suffering from diseases and / or disorders associated with abnormal activity of selective transcriptional CDKs.

[0155] In yet another embodiment, the present invention includes administering a therapeutically effective amount of a fumarate compound of formula (I) to a subject in need, together with one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics.

[0156] The present invention provides a therapeutic method(s) comprising administering a safe and effective amount of a fumarate compound of formula (I) to a subject (particularly a human) in need.

[0157] In one embodiment, the present invention provides a compound which is (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide, or a pharmaceutically acceptable salt thereof.

[0158] In one embodiment, the present invention provides a pharmaceutical composition comprising (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide and a pharmaceutically acceptable carrier or excipient.

[0159] Combination therapy In certain embodiments, the present invention provides methods for combination therapy of a fumarate compound of formula (I) or its cocrystals with a chemotherapeutic agent, a therapeutic antibody, and / or radiotherapy, which provide a synergistic or additive therapeutic effect in the treatment of diseases, disorders, and conditions such as cancer. In certain embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, bioresponse modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0160] For example, further therapeutic agents may include alkylating agents such as chlorambucil, cyclophosphamide, and cisplatin; mitotic inhibitors such as docetaxel or paclitaxel; antimetabolites such as 5-fluorouracil, cytarabine, methotrexate, or pemetrexed; antitumor antibiotics such as daunorubicin or doxorubicin; corticosteroids such as prednisone or methylprednisolone; BCL-2 inhibitors such as venetoclax; or immunotherapeutic compounds such as nivolumab, pembrolizumab, pidylizumab, avelumab, BMS 936559, or MPDL3280A, or combinations thereof. In one embodiment, the immunotherapeutic compound includes chimeric antigen receptor T cells (CAR T cells).

[0161] In certain embodiments, a further therapeutic agent is docetaxel. Docetaxel is a type of chemotherapeutic agent known as an anti-microtubule inhibitor. Docetaxel is used to treat various cancers, such as metastatic prostate cancer. Docetaxel therapy is often administered intravenously and often includes premedication with corticosteroids such as prednisone. In certain embodiments, a further therapeutic agent is venetoclax, a BCL-2 inhibitor that can induce apoptosis in cancer cells. Venetoclax is usually administered orally.

[0162] In some embodiments, the fumarate compound of formula (I) or its cocrystals is used in erlotinib, bortezomib, disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (gerdanamycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant, sunitinib, letrozole, imatinib mesylate, fumasnate, oxaliplatin, 5-FET (5-fluorouracil), leucovorin, rapamycin, lapatinib, ronafarnib, sorafenib, gefitinib, antimetabolites (such as methotrexate and 5-fluorouracil (5-FU)); taxoids (e.g., paclitaxel), ABRAXANE® (cremophore-free), and albumin-recombinant nanoparticle formulations of paclitaxel (American Pharmaceuticals). It can be used in combination with one or more chemotherapeutic agents, such as Partners, Schaumberg, Ill., and docetaxel / doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; retinoids such as retinoic acid; and any pharmaceutically acceptable salts, acids, and derivatives of the above.

[0163] In some embodiments, the fumarate compound of formula (I) or its cocrystals can be used in combination with one or more additional agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, immunotumor agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies for treating diseases, disorders, or conditions such as cancer.

[0164] In some embodiments, the fumarate compound of formula (I) disclosed herein or its cocrystals can be used in combination therapy with one or more kinase inhibitors for cancer treatment. Exemplary kinase inhibitors include imatinib, baricitinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinib, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, and ninteda. Examples include Nib, palbociclib, lenvatinib, cobimetinib, abemaciclib, acalabrutinib, alectinib, binimetinib, brigatinib, encorafenib, erdafitinib, everolimus, fostamatinib, gilter, lalotrectinib, lorlatinib, netalusdil, osimertinib, pexidartinib, ribociclib, ribociclib, temsirolimus, XL-092, XL-147, XL-765, XL-499, and XL-880.

[0165] In some embodiments, the fumarate compound of formula (I) or its cocrystals can be used in combination with HSP90 inhibitors (e.g., XL888), liver X receptor (LXR) modulators, retinoid-associated orphan receptor gamma (RORγ) modulators, checkpoint inhibitors such as CK1 inhibitors or CK1α inhibitors, Wnt pathway inhibitors (e.g., SST-215), or mineralocorticoid receptor inhibitors (e.g., esaxerenone), XL-888, or poly-ADP-ribose polymerase (PARP) inhibitors (such as olaparib, lucaprib-niraparib, or tarzoparib for cancer treatment).

[0166] In some embodiments, the fumarate compound of formula (I) disclosed herein or its cocrystals is used for the treatment of cancer, such as an immune checkpoint inhibitor, e.g., a PD-1 inhibitor or a PD-L1 inhibitor, e.g., an anti-PD-1 monoclonal antibody or an anti-PD-L1 monoclonal antibody, e.g., nivolumab (Opdivo), pembrolizumab (Keytruda, MK-3475), atezolizumab, avelam It can be used in combination with semiprimab, spartalizumab, camrelizumab, cetrerimab, tripalimab, cintilimab, AB122, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, and TSR-042, AMP-224, AMP-514, PDR001, durvalumab, pidilizumab (Imfinzi®, CT-011), CK-301, BMS 936559, and MPDL3280A. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, pidilizumab, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD1 antibody is nivolumab.

[0167] In some embodiments, the fumarate compounds of formula (I) disclosed herein or their cocrystals can be used in combination with PD-L1 inhibitors for the treatment of cancer. Examples of antibodies that bind to human PD-L1 include atezolizumab, avelumab, durvalumab, tislerizumab, BMS-935559, MEDI4736, FAZ053, KN035, CS1001, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, KN035, AUNP12, CA-170, BMS-986189, and LY3300054. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A, or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, or durvalumab.

[0168] In some embodiments, the fumarate compound of formula (I) or its cocrystals disclosed herein can be used in combination with other anticancer agents such as CTLA-4 inhibitors, e.g., anti-CTLA-4 antibodies, e.g., ipilimumab (Yervoy), tremelimumab, and AGEN1884; phosphatidylserine inhibitors, e.g., bavituximab (PGN401); antibodies against cytokines (IL-10, TGF-β, etc.); and semiprimab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1 and CTLA-4, e.g., an anti-PD-L1 / CTLA-4 bispecific antibody or an anti-PD-1 / CTLA-4 bispecific antibody. An example of a bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0169] In certain embodiments, the present invention provides compositions comprising a fumarate compound of formula (I) or its cocrystals together with other therapeutic agents and pharmaceutically acceptable carriers. The fumarate compound of formula (I) or its cocrystals can be administered in combination with one or more other therapeutic agents (preferably one or two, more preferably one) to (1) complement and / or enhance the prophylactic and / or therapeutic effects of the compound of the present invention, (2) modulate pharmacodynamics, improve absorption, or reduce dose reduction of the prophylactic and / or therapeutic compound of the present invention, and / or (3) reduce or mitigate the side effects of the prophylactic and / or therapeutic compound of the present invention. As used herein, the term “co-administration” means any form of administration of two or more different therapeutic compounds such that a second compound is administered while a previously administered therapeutic compound is still present in the body (for example, the two compounds may be simultaneously effective in the patient and may include a synergistic effect of the two compounds).

[0170] For example, different therapeutic compounds can be administered in the same formulation, or in separate formulations, either simultaneously or sequentially. In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week from each other. Thus, individuals receiving such treatment can benefit from the combined effects of different therapeutic compounds. Corresponding compounds can be administered by the same or different routes and by the same or different methods. In certain embodiments, other therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week before or after administration of the fumarate compound of formula (I) or its co-crystal. In certain embodiments, other therapeutic compounds can be administered within 0.5 hours to 24 hours before or after administration of the fumarate compound of formula (I) or its co-crystal. In certain embodiments, other therapeutic compounds can be administered within 0.5 hours to 72 hours before or after administration of the fumarate compound of formula (I) or its co-crystal. In certain embodiments, other therapeutic compounds may be administered within 2 hours before or after administration of the fumarate compound of formula (I) or its co-crystal.

[0171] A combination drug comprising the compound of the present invention and other agents may be administered as a combination preparation in which both components are contained in a single formulation, or as separate formulations. Administration by separate formulations may include simultaneous administration of the formulations and / or administration separated by several time intervals. In the case of administration with several time intervals, the compound of the present invention may be administered first followed by the other agent, or the other agent may be administered first followed by the compound of the present invention, as long as the two compounds become simultaneously active in the patient for at least some of the time between the combination therapy. The administration of each agent may be by the same or different routes and by the same or different methods.

[0172] The dosage of other drugs can be appropriately selected based on clinically used dosages, or it can be a reduced dose that is effective when administered in combination with the compound of the present invention. The mixing ratio of the compound of the present invention with other drugs can be appropriately selected according to the age and weight of the recipient, the method of administration, the time of administration, the disorder or symptoms being treated, and combinations thereof. For example, other drugs can be used in an amount of about 0.01 to about 100 parts by mass per 1 part by mass of the compound of the present invention. Other drugs can be any combination of two or more drugs in an appropriate ratio. Other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compound of the present invention include not only drugs that have already been discovered, but also drugs that may be discovered in the future based on the above mechanism.

[0173] In certain embodiments, the fumarate compound of formula (I) or its co-crystals may be administered in combination with non-chemical methods for cancer treatment. In certain embodiments, the fumarate compound of formula (I) or its co-crystals may be administered in combination with non-chemical methods for cancer treatment. In certain embodiments, the fumarate compound of formula (I) or its co-crystals may be administered in combination with radiotherapy. In certain embodiments, the fumarate compound of formula (I) or its co-crystals may be administered in combination with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0174] experiment The present invention provides a method for preparing fumarate compounds of formula (I) using appropriate materials and following the procedures of the following examples. Those skilled in the art will understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation procedures. Furthermore, by utilizing the procedures detailed below, those skilled in the art can prepare further compounds of the present invention.

[0175] Analysis method X-ray powder diffraction: X-ray powder diffraction patterns were collected using CuKa radiation (45kV, 40mA) with an X'Pert3 PRO MPD diffractometer.

[0176] Details of the data collection are summarized below: [Table 2]

[0177] HPLC: Purity analysis was performed using Chemstation software vB.04.03 on an Agilent HP1100 series system equipped with a diode array detector, using the method detailed below. [Table 3]

[0178] Thermogravimetric analysis and differential scanning calorimetry: Thermogravimetric analysis (TGA) data were collected using a TA Instruments Q5000 TGA. Differential scanning calorimetry (DSC) was performed using a TA Instruments TA Q2000 DSC. The method parameters are described below. [Table 4]

[0179] The compound of formula (I) was found to be amorphous. In the preparation of compound (I), the final purification required redundant column chromatography operations, which resulted in impurities eluting nearby and necessitated the purification of multiple impurity fractions, making it extremely difficult to obtain the desired yield of the compound.

[0180] To obtain better yields and to avoid redundant column purification in the final step of preparing the compound of formula (I), the inventors attempted several times to crystallize / precipitate the final compound of formula (I) using various solvent systems, but none of these methods were successful. Even salt screening methods using various acids (e.g., citric acid, succinic acid, tartaric acid, etc.) along with different solvent systems (e.g., ethanol, methanol, IPA, DMSO, DMF, etc.) and temperature ranges did not yield any promising yields with better purity. Subsequently, it was surprisingly discovered that the fumarate compound of formula (I) is naturally crystalline with excellent purity.

[0181] Furthermore, the fumarate compound of formula (I) is unexpectedly advantageous compared to other salts / cocrystals of the compound of formula (I) in various desired properties such as filterability, hygroscopicity, purity, and stability. Also, the fumarate compound of formula (I) exhibited only a crystalline form. Such crystalline materials were not obtained with other acid addition salts / cocrystals.

[0182] Example 1: Preparation of the fumarate compound of formula (I) [ka]

[0183] Step 1: Synthesis of 2-(3-bromophenyl)-3-methylbutyrate 2M LDA (698 mL, 1.38 mol) was added to a solution of 2-(3-bromophenyl)acetic acid (150 g, 0.69 mol) in THF (700 mL) over 30 minutes at -78°C. The reaction mixture was stirred at -78°C for 2 hours, after which isopropyl bromide (255 g, 2.07 mol) was added dropwise over 30 minutes at -78°C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 1N HCl (pH 2), and the product was extracted in ethyl acetate (500 mL x 3). The combined organic layer was washed with water, followed by brine, dried, and concentrated under reduced pressure to obtain the crude compound. This was purified by silica column chromatography by elution with a 0-10% ethyl acetate-hexane system to obtain the title compound 2 (150 g, yield 83%). LCMS: m / z = 254.80 (M-2H) -

[0184] Step 2: Synthesis of tert-butyl=3-(2-(3-bromophenyl)-3-methylbutanamide)-5-cyclopropyl-1H-pyrazole-1-carboxylate 2-(3-bromophenyl)-3-methylbutyrate (70 g, 0.0.27 mol) was dissolved in anhydrous DCM (500 mL), and oxalyl chloride (68 mL, 0.78 mol) was added dropwise at 0°C. Subsequently, a catalytic amount of DMF (0.8 mL) was added, and the reaction mixture was maintained at the same temperature for 30 minutes. The reaction mixture was brought to room temperature and stirred for 4 hours. The solvent and excess oxalyl chloride were removed under vacuum by distillation. The resulting residue was redissolved in DCM (250 mL) and slowly added at 0°C for 30 minutes to a solution of tert-butyl=3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate (compound 3, 49 g, 0.218 mol) and TEA (55 mL, 0.546 mol) in chilled THF (250 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction mass was then concentrated under reduced pressure, and the residue was dissolved in DCM and washed with saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography by elution with 15% ethyl acetate-hexane to obtain the title compound 4 (90 g, 71%). LCMS: m / z = 363.80 (M-Boc +2 ).

[0185] Step 3: Synthesis of tert-butyl=5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanamide)-1H-pyrazole-1-carboxylate To a degassed solution of tert-butyl=3-(2-(3-bromophenyl)-3-methylbutanamide)-5-cyclopropyl-1H-pyrazole-1-carboxylate (90 g, 0.193 mol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (62 g, 0.251 mol) in 1,4-dioxane (500 mL), potassium acetate (37.80 g, 0.386 mol) was added. The reaction mixture was stirred at room temperature for 10 minutes while degassing, and PdCl2(dppf).DCM complex (12.5 g, 0.015 mol) was added. The reaction mixture was heated at 100 °C for 3 to 4 hours. The reaction mixture was cooled to room temperature, filtered through a Celite® bed, and the filtrate was evaporated to obtain a dark brown liquid. The crude compound was purified by silica column chromatography by elution with hexane containing 20% ​​ethyl acetate to obtain compound 5 (90 g, 86%). LC-MS: m / z = 410 (M-Boc+1) + .

[0186] Step 4: Synthesis of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide To a degassed solution of tert-butyl=5-cyclopropyl-3-(3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanamide)-1H-pyrazole-1-carboxylate (10 g, 0.019 mol) and (E)-N-(5-bromopyridine-2-yl)-4-morpholinbuta-2-enamide (7.7 g, 0.023 mol) in 1,4-dioxane (100 mL) and water (40 mL), Cs2CO3 (14.5 g, 0.045 mol) was added. The reaction mixture was stirred for 10 minutes while degassing, and Pd(PPh3)4 (1.1 g, 0.00095 mol) was added. The reaction mixture was heated in a sealed tube at 100°C for 4 hours. Then the reaction mixture was cooled and diluted with brine solution. The resulting aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layer was evaporated to dryness, and the crude material was purified by silica column chromatography by elution with 10-15% methanol-containing DCM to obtain pure compound 8 (4.5 g, 44%). LCMS: m / z = 529.15 (M + H) +; HPLC: 95.17%, retention time: 6.34 min.

[0187] Step 5: Chiral Separation The compound (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide was separated into chiral preparative HPLC columns (Method: Column: Chiral Pak IA (20mm X) The samples were separated using a 250 mm, 5 micrometer (250 mm, 5 micrometer) elution method (isocratic (50:50), A=ACN, B=MeOH, flow rate: 20 mL / min) to obtain pure S and R isomers, respectively: (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbutan-2-enamide and (R,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbutan-2-enamide.

[0188] S isomer: (S,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide (compound of formula (I)) 1 HNMR(DMSO-d6,400MHz):δ 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.05 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.49 (d, 1H), 6.13 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.41-2.32 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.59 (m, 2H);LCMS:m / z=529.15(M+H) + ;HPLC: 96.72%, retention time: 6.39 minutes; Chiral HPLC: 97.68%, retention time: 14.47.

[0189] R isomer: (R,E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazole-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridine-2-yl)-4-morpholinbuta-2-enamide 1HNMR(DMSO-d6,400MHz):δ 12.02 (s, 1H), 10.78 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.28 (d, 1H), 8.07-8.04 (m, 1H), 7.68 (s, 1H), 7.57 (d, 1H), 7.41-7.37 (m, 2H), 6.81-6.78 (m, 1H), 6.50 (d, 1H), 6.14 (s, 1H), 3.61-3.58 (m, 4H), 3.36-3.34 (m, 1H), 3.12 (d, 2H), 2.40-2.39 (m, 5H), 1.82-1.76 (m, 1H), 0.97 (d, 3H), 0.88-0.85 (m, 2H), 0.67 (d, 3H), 0.62-0.60 (m, 2H);LCMS:m / z=529.15(M+H) + ;HPLC: 96.24%, retention time: 6.39 minutes; Chiral HPLC: 97.92%, retention time: 8.80.

[0190] Step 6: Preparation of the fumarate compound of formula (I) The compound of formula (I) was dissolved in methanol (4 volumes), the solution was heated to 60-65°C, and fumaric acid solution was added (1.1, for example, fumaric acid was dissolved in approximately 6 volumes of methanol relative to the amount of compound of formula (I) added). The reaction mixture was stirred at 60-65°C for 4 hours and then cooled to room temperature. The resulting suspension was stirred at room temperature for 16 hours. The solid was filtered, washed with 2 volumes of methanol, and dried by vacuum for 3 hours. The substance was further dried at 45-50°C under vacuum for 4 hours to obtain the title compound as a white solid. Yield: 85%.

[0191] Example 2: Polymorphic Screening Method A. Crystallization from methanol / acetone mixture At room temperature, 200 mg of the fumarate compound of formula (I) was dissolved in a mixture of methanol and acetone (15 mL:15 mL) in a glass tube. The solution was slowly evaporated at room temperature, and after 10 days, crystals were observed to obtain the fumarate compound of formula (I) in solid form.

[0192] B. Solution crystallization 15 mg of the fumarate compound of formula (I) was dissolved in a conical flask in 15 mL of solvent (acetone, ethanol, acetonitrile, isobutylene acetate, isopropyl acetate, n-butyl acetate, n-hexane). The solvent was heated near its boiling point until a clear solution was formed. The solution was slowly evaporated at room temperature. After 10 days, crystals were obtained, yielding the fumarate compound of formula (I) in crystalline form.

[0193] C. Crystallization in poor solvents 10 mg of the fumarate compound of formula (I) was dissolved in 10 mL of solvent (methyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, isobutyl acetate, 1-butanol, and acetonitrile) near its boiling point in a conical flask. Once a clear solution was formed, one of the corresponding poor solvents (1 mL) (1,2-dichloroethane, n-hexane, and methylcyclohexane) was added to the clear solution. The solution was slowly evaporated at room temperature, and after 10 days, crystals were obtained, yielding the fumarate compound of formula (I) in the desired solid form.

[0194] D. Cooling crystallization 10 mL of the fumarate compound of formula (I) was dissolved in 10 mL of solvent (methyl acetate, n-propyl acetate, 1-pentanol, methanol, and methylcyclohexane) in a conical flask at near the boiling point of the corresponding solvent until a clear solution was formed. The solution was transferred to an ice bath maintained at 2–8°C, and crystals were then grown. The solution was then filtered to obtain the fumarate compound of formula (I) in solid form.

[0195] E. Slurry crystallization At room temperature, 20 mg of the fumarate compound of formula (I) was added in a glass bottle to 5 mL of organic solvent (1,2-dichloroethane, methyl acetate, n-propyl acetate, acetonitrile, isobutanol, 1-butanol, 2-butanol, 1-propanol, n-butyl acetate, isobutyl acetate, isopropyl acetate, n-hexane). The resulting slurry was stirred at 200 rpm for 24 hours. After 24 hours, the slurry was filtered to obtain the fumarate compound of formula (I) in the required solid form.

[0196] Characterization of the fumarate compound of formula (I) The solids prepared as described herein were confirmed to be crystalline fumarate compounds of formula (I) by X-ray powder diffraction (XPRD), differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), dynamic water vapor adsorption (DVS), and single-crystal structure analysis.

[0197] i. Single-crystal X-ray crystal structure analysis Single crystals of the fumarate compound of formula (I) were selected under polarizing microscope. The selected crystals were used for data acquisition using a Bruker Kappa Apex2 CCD diffractometer at 100K. The X-ray generator was operated at 40kV and 30mA using Cu Kα (λ=1.5418Å) radiation. Data were acquired with an ω scan width of 1.0 degree. Data reduction after empirical absorption correction was adapted to various modules within the Apex2 software suite. The structure was analyzed directly using the SHELXTL package and refined using the full matrix least squares method in F2 from the same package. All non-hydrogen atoms were anisotropically purified, and hydrogen atoms were refined using a riding model. The structure was depicted using Mercury 3.1 and Pymol.

[0198] Single crystals of the fumarate compound of formula (I) diffracted X-rays well with a resolution of 1.5 Å or higher, and a series of diffraction data with good statistics (Table 2) were collected at room temperature. The structure was analyzed by direct methods and refined to a good shape. The study successfully measured the complete three-dimensional structure of the compound of formula (I), and an absolute configuration was assigned to the sole chiral center present in the compound. Fumarate connects two molecules of the compound by contacting the pyridine ring and its adjacent amide-NH group with an H bond. Similarly, fumarate also forms an H bond with the N atom of the pyrazole ring and its adjacent amide-NH group, establishing a bridging contact between two adjacent molecular rings of the compound. [Table 5]

[0199] Single-crystal X-ray analysis revealed the structure of the fumarate compound of formula (I). This investigation confirmed that the fumarate molecule is related to the compound of formula (I) as a cocrystal, and also revealed that one molecule of the compound of formula (I) and one molecule of fumarate are present in the asymmetric unit (molar ratio 1:1). The hydrogen bond distance between the fumarate atom and the nitrogen atom of the compound of formula (I) was measured to be 2.6–2.9 Å, which is a distance typically observed for cocrystals. Figure 1.

[0200] ii. X-ray powder diffraction investigation In one embodiment, the compound-fumaric acid cocrystal of formula (I) showed characteristic Bragg peaks at 2θ values ​​of 5.02, 9.99, 10.52, 11.93, 14.98, 18.71, 22.08, 22.51, and 24.03. The X-ray powder diffraction scans are shown in Figure 2. The peaks obtained from the X-ray powder diffraction are shown in Table 1.

[0201] iii. Differential scanning calorimetry Differential scanning calorimetry (DSC) of the compound (I)-fumaric acid cocrystal showed endothermic activity at 203.9°C (peak temperature) before melting / decomposition began at 200.2°C (Figure 3).

[0202] iv. Thermogravimetric analysis (TGA) TGA analysis of the compound-fumaric acid cocrystal of formula (I) was performed using a Q5000 TA TGA instrument. Accurately weighed samples (5–15 mg) were placed in a platinum pan and heated at a rate of 10°C / min in the temperature range of 30–300°C under a nitrogen purge of 50 mL / min. The TGA thermogram showed the start of weight loss after 175°C. This indicates that there was no solvent / water adsorption. Figure 4.

[0203] Optical and polarized light microscopy The powder samples were examined at 100x magnification using optical and polarized light microscopes (Nikon ECLIPSE, LV100POL with Linkam THMSE 600:TMS94 hot stage). Microscopic images were acquired using a Media Cybernetics video camera and Qcapture software. Optical microscopy revealed that the compound (I)-fumaric acid cocrystal exhibited an irregular shape / plate-like crystal habit (Figure 5A), while polarized light microscopy of the compound (I)-fumaric acid cocrystal showed the presence of a birefringence pattern, thus confirming the properties of the crystal (Figure 5B).

[0204] Example 4: Stability of compound (I)-fumaric acid cocrystal Temperature-Variable X-ray Diffraction (VT-XRD) XRPD patterns were collected in situ as a function of humidity using a temperature-humidity chamber (THC) manufactured by Anton Paar. Humidity was generated with an RH-200 manufactured by VTI Inc. and carried by a nitrogen gas stream. Inside the THC, humidity and temperature were monitored by a HygroClip sensor manufactured by Rotronic, placed next to the specimen. XRPD patterns were collected in a symmetric Bragg-Brentano mirror configuration with a PANalytical X’Pert PRO MPD diffractometer. Isothermal conditions were maintained for 60 minutes at a given temperature. The heating rate was maintained at 10 °C / min. A sample of approximately 200 mg was used for VT-XRD analysis. Cu Kα radiation was generated using a long fine-focus tube source operating at 45 kV and 40 mA. The incident beam was conditioned using a nickel filter, a Soller slit of 0.02 rad, a fixed incident beam mask of 11.6 mm, a fixed 1 / 2° scattered radiation removal slit, and a fixed 1 / 4° divergence slit. The diffracted beam was conditioned using a 5 mm scattered radiation removal slit and a Soller slit of 0.04 rad. A scanning position-sensitive detector (X′Celerator) located 240 mm from the sample was used to collect the diffraction pattern. Data were collected and analyzed using Data Collector software v.5.5.

[0205] Exposing the fumaric acid compound of formula (I) to various temperatures revealed that it was physically stable. It was confirmed by VT-XRD analysis that the compound-fumaric acid co-crystal of formula (I) remained stable and no solid form transformation / phase change occurred even under higher temperature conditions. From this observation, it was found that the fumaric acid compound of formula (I) was physically stable under various temperature conditions. See Figure 6A.

[0206] Variable Humidity X-ray Diffraction (VH-XRD) XRPD patterns were collected in situ as a function of temperature using an Anton Paar TTK 450 stage. The sample was heated with a resistance heater placed directly beneath the sample holder, and the temperature was monitored with a platinum-100 resistance sensor located inside the sample holder. The heater was driven and data was collected by an Anton Paar TCU 100 interfaced with a data collector. Approximately 200 mg of sample was used for VH-XRD analysis.

[0207] The compound of the present invention was exposed to various humidity conditions. The sample, i.e., the fumarate compound of formula (I), was exposed to desorption cycles from 40% RH to 85% RH, followed by desorption cycles from 85% to 40% RH. The sample was allowed to equilibrate at each RH level (both adsorption and desorption) for 1 hour. The PXRD patterns collected during this adsorption-desorption cycle showed no change as a function of relative humidity exposure. From these observations, it can be confirmed that the fumarate compound of formula (I) remained physically stable under various relative humidity conditions. See Figure 6B.

[0208] When the fumarate compound of formula (I) was subjected to conditions of 25°C / 60% relative humidity (RH) and 40°C / 75% RH for 6 months, it was observed that the fumarate compound of formula (I) remained unchanged in terms of solid form and particle morphology even after 6 months under the above conditions. See Figure 7.

[0209] Dynamic water vapor adsorption (DVS) The moisture absorption of the compound of the present invention was investigated at 25°C using a DVS apparatus (Q5000SA, TA instruments, New Castle, Delaware, USA) to examine the physical stability of the compound to humidity, or its tendency to absorb moisture. The apparatus consisted of a microbalance housed in a temperature-controlled chamber. Humidity was controlled by switching a valve that regulates the flow of dry gas (nitrogen) during the humidification stage. The apparatus was programmed using equilibrium conditions for moisture absorption conditions of 40-90% RH in a 10% RH process at 25±0.1°C. The equilibrium conditions were set so that the total mass change was less than 0.01% during residence times of 10 minutes or less and a maximum of 60 minutes, followed by desorption in the 90% RH to 10% RH process. The equilibrium conditions for desorption were set so that the total mass change was less than 0.01% during residence times of 10 minutes or less and a maximum of 60 minutes.

[0210] As humidity increased, the weight gain / moisture absorption by the fumarate compound of formula (I) increased, showing a typical "S" curve. At 90% RH, approximately 0.646% w / w of weight / moisture was obtained by the fumarate compound of formula (I). The DVS adsorption-desorption isotherm (25°C) of the fumarate compound cocrystal of formula (I) is shown in Figure 8.

[0211] Example 5: Solubility of fumarate compounds of formula (I) The equilibrium stability of the free base compound of formula (I) and the fumarate compound of formula (I) was measured in various media. Excess amounts of the compound of formula (I) and the fumarate compound of formula (I) were added to glass bottles containing various media. These bottles were maintained at 200 rpm and appropriate temperatures (25°C for water and 37°C for buffer) for shaking in a shaking water bath. The resulting preparations were filtered and analyzed by HPLC. The results are shown below. [Table 6]

[0212] Reference All publications and patents described herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In the event of any conflict, the present application, including any definitions herein, shall prevail.

[0213] Equal parts While specific embodiments of the invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon consideration of this specification and the claims below. The full scope of the invention should be determined by referring to the claims, together with the full scope of their equivalents, and the specification together with such variations.

Claims

1. Compounds of formula (I): 【Chemistry 2】 and co-crystal with fumaric acid.

2. 2. The co-crystal of claim 1, wherein the molar ratio of the compound of formula (I) to fumaric acid is 1:

1. (a) at least one peak at a 2θ angle of about 15.0±0.2; (b) at least one peak at a 2θ angle selected from about: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2; (c) at least two peaks at 2θ angles selected from about: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2; (d) at least three peaks at 2θ angles selected from about: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2; (e) peaks at 2θ angles of about: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2; (f) at least four peaks at 2θ angles selected from about: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 22.0±0.2, and 22.5±0.2; (g) peaks at 2θ angles of about: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 22.0±0.2, and 22.5±0.2; or (h) Peaks at 2θ angles of about 5.0±0.2, 10.0±0.2, 10.5±0.2, 12.0±0.2, 14.8±0.2, 15.0±0.2, 15.6±0.2, 17.6±0.2, 18.7±0.2, 19.8±0.2, 20.0±0.2, 20.1±0.2, 21.2±0.2, 22.0±0.2, 22.5±0.2, 23.4±0.2, 24.0±0.2, 25.0±0.2, 26.1±0.2, 26.8±0.2, 27.4±0.2, and 36.6±0.2 2. The co-crystal of claim 1, characterized by an X-ray powder diffraction pattern comprising: (a) an endothermic transition at about 195° C. to about 210° C. as measured by differential scanning calorimetry; (b) an endothermic transition selected from about 195° C. to about 205° C., about 198° C. to about 205° C., and about 199° C. to about 204° C., as measured by differential scanning calorimetry; (c) an endothermic transition at 203° C.±3° C. as measured by differential scanning calorimetry; (d) weight loss after 175°C as measured by thermogravimetric analysis; and / or (e) Weight / moisture gain of approximately 0.646% w / w at 90% RH as measured by dynamic water vapor sorption.

2. The co-crystal of claim 1, having the formula:

5. A process for preparing a fumaric acid compound of formula (I), comprising the steps of: a) reacting fumaric acid with a compound of formula (I): 【Chemistry 3】 and a solvent; b) obtaining said fumaric acid compound of formula (I) from said mixture; and The method comprising:

6. The method of claim 5 , wherein the mixture comprises a solution of the compound of formula (I).

7. The method of claim 6 , wherein the fumaric acid is dissolved in a solvent.

8. 6. The method of claim 5, wherein the solvent is methanol, acetonitrile, acetone, anisole, dichloromethane, dichloroethane, ethanol, methyl acetate, n-propyl acetate, isopropyl alcohol, isopropyl acetate, propanol, butanol, pentanol, n-butyl acetate, isobutyl acetate, isobutylene, acetate, methylcyclohexane, methyl tert-butyl ether, n-hexane, n-heptane, tetrahydrofuran, or water, or a mixture of any of these.

9. Obtaining the fumaric acid compound of formula (I) i. stirring a mixture comprising the compound of formula (I) and fumaric acid; ii. cooling the mixture to ambient temperature to form a suspension; iii. isolating the fumaric acid compound of formula (I) from the suspension; and The method of claim 5 , comprising:

10. 10. The method of claim 9, wherein isolating the fumaric acid compound of formula (I) comprises filtering the fumaric acid compound of formula (I) from the mixture. (a) the fumaric acid compound of formula (I) is in substantially pure form; and / or (b) the purity of the fumaric acid compound of formula (I) is selected from about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, and about 99%.

12. 1. A process for the preparation of a crystalline compound of fumaric acid of formula (I) or a co-crystal of said compound of formula (I) with fumaric acid, comprising the steps of: 【Chemistry 4】 a) optionally heating a mixture comprising the fumaric acid compound of formula (I) and a solvent; b) crystallizing said fumaric acid compound of formula (I) from said mixture; The method comprising:

13. 13. The method of claim 12, wherein the mixture is a solution of the fumaric acid compound of formula (I) dissolved in the solvent.

14. 13. The method of claim 12, wherein the solvent is selected from methanol, ethanol, anisole, isopropanol, butanol, 1,2-dimethoxyethanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, tetrahydrofuran, diethyl ether, 1,4-dioxane, diisopropyl ether, methyl tert-butyl ether, acetone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethyl acetate, isopropyl acetate, chloroform, dichloromethane, acetonitrile, benzene, toluene, and xylene, or any combination thereof.

15. The method of claim 1, wherein (a) crystallizing the fumaric acid compound of formula (I) from the mixture comprises precipitating the co-crystal from solution by evaporating the solvent at ambient temperature; or 14. The method of claim 12 or 13, wherein (b) crystallizing the fumaric acid compound of formula (I) from the mixture comprises cooling the mixture to below ambient temperature to precipitate a co-crystal.

16. 1. A process for the preparation of a crystalline compound of fumaric acid of formula (I) or a co-crystal of said compound of formula (I) with fumaric acid, comprising the steps of: 【Chemistry 5】 a) adding an anti-solvent to a mixture containing the fumaric acid compound of formula (I) and a solvent; b) crystallizing said fumaric acid compound of formula (I) from said mixture; The method comprising:

17. The method of claim 16 , wherein the mixture is heated to form a solution.

18. 17. The method of claim 16, wherein the solvent is acetone, n-propyl acetate, acetonitrile, methanol, isopropyl acetate, isobutanol, 2-butanol, 1-butanol, n-butyl acetate, 1-pentanol, 1-propanol, chloroform, methyl acetate, isobutyl acetate, isobutanol, or ethanol.

19. 19. The method of any one of claims 16 to 18, wherein the mixture comprising the fumaric acid compound of formula (I) is a solution, and the step of crystallizing the fumaric acid compound of formula (I) from the mixture comprises supersaturating the solution, thereby precipitating the fumaric acid compound of formula (I) from the solution.

20. (a) the step of supersaturating the solution comprises adding an anti-solvent; (b) the step of supersaturating the solution comprises cooling the solution to below ambient temperature; or 20. The method of claim 19, wherein (c) supersaturating the solution comprises maintaining a solution temperature above about 20°C.

21. 17. The method of claim 16, wherein the anti-solvent is dichloromethane, dichloroethane, ethanol, methanol, propanol, butanol, pentanol, isobutyl acetate, isobutylene acetate, methylcyclohexane, n-hexane, n-heptane, tetrahydrofuran, and mixtures thereof.

22. The method of claim 21, wherein the anti-solvent is 1,2-dichloroethane, n-hexane, and methylcyclohexane.

23. (A) (a) the mixture containing the fumaric acid compound of formula (I) is a slurry; and / or (b) further comprising isolating said fumaric acid crystalline compound of formula (I), wherein, optionally, said isolating said fumaric acid crystalline compound of formula (I) comprises filtering the crystalline form of the fumaric acid compound of formula (I) from the mixture; and / or (B) the fumaric acid compound of formula (I) is in substantially pure form; and / or (C) The fumaric acid crystalline compound of formula (I) is a crystalline form of the fumaric acid compound of formula (I) according to any one of claims 1 to 4; The method of claim 12.

24. 24. The method of claim 23, wherein isolating the fumaric acid crystalline compound of formula (I) comprises filtering the fumaric acid crystalline compound of formula (I) from the mixture.

25. 24. The method of claim 23, wherein the purity of the fumaric acid crystalline compound of formula (I) is selected from about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, and about 99%.

26. A pharmaceutical composition comprising the fumaric acid compound of formula (I) or the compound of formula (I)-fumaric acid cocrystal according to any one of claims 1 to 4, and one or more pharma- ceutically acceptable excipients.

27. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a disease and / or disorder mediated by an alternative transcription CDK in a subject, comprising: the alternative transcription CDK is CDK7, CDK9, CDK12, CDK13, or CDK18; The use, wherein said disease and / or disorder mediated by alternative transcription CDK is selected from the group consisting of cancer, inflammatory disorders, autoinflammatory disorders, and infectious diseases.

28. Carcinomas, including cancer of the breast, liver, lung, colon, kidney, bladder, small cell lung cancer, non-small cell lung cancer, head and neck, thyroid, esophagus, stomach, pancreas, ovary, gallbladder, cervix, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, B cell lymphoma, T cell lymphoma, hairy cell lymphoma, myeloma, mantle cell lymphoma, and Burkitt's lymphoma; acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannoma; and other tumors, including seminoma, melanoma, osteosarcoma, teratocarcinoma, keratoacanthoma, xeroderma pigmentosum, follicular thyroid carcinoma, and Kaposi's sarcoma.

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