Deuterated analogues of pyrrole inhibitors of ERK, and synthesis and intermediates thereof

Abstract

The present disclosure provides, inter alia, deuterated analogs of optitinib, and pharmaceutically acceptable salts thereof, which are potent inhibitors of ERK protein kinase and have surprisingly improved pharmacokinetics and metabolite formation properties. The present disclosure also provides, inter alia, methods of making and using the same. Kits of compounds and pharmaceutical compositions containing such deuterated analogs are also provided.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 323,221, filed on March 24, 2022, which is incorporated herein by reference in its entirety.

[0003] background

[0004] The absorption, distribution, metabolism and excretion (ADME) performance of drugs is a crucial feature, which can mean the difference between safe / effective drugs and clinical and commercial failures. The latest progress in drug formulation technology (and drug conjugates or prodrugs) has provided some ability to improve ADME performance in limited cases, but potential ADME problems remain the main reason for drug failure in clinical trials. A common ADME problem of currently approved drugs and drug candidates is rapid metabolism. A drug candidate that is otherwise very effective in vitro and preclinical trials can be metabolized too quickly and cleared from the body, thereby producing very little pharmacological effect or no pharmacological effect. The strategy to overcome rapid metabolism includes administration at very high levels or very frequently, but both strategies have obvious disadvantages, including increasing the side effects of the drug, increasing exposure to toxic metabolites and reducing patient compliance due to frequency.

[0005] In some cases, metabolic inhibitors have been used to improve the characteristics of specific drugs (see Kempf, D. et al. Antimicrobial Agents and Chemotherapy, 41 (3), p. 654 (1997); Wang, L. et al. Clinical Pharmacology and Therapeutics, 56 (6 Pt. 1), p. 659 (1994). However, this strategy has not been widely used because it can lead to serious undesirable side effects and undesirable drug-drug interactions. The optimization of drug structure often involves an iterative process of structural modifications to improve biological activity and / or metabolic properties. However, better metabolic characteristics often come at the expense of bioefficacy and potency because significant modifications to the desired pharmacophore structure are required to stop or slow the biodegradation process.

[0006] One possible strategy to improve the metabolic profile of a drug without substantially altering its biopotency and efficacy is to replace one or more hydrogen atoms with deuterium to slow down the metabolism of cytochrome P. 450 Metabolism mediated by cytochrome P 450Enzyme is a class of enzymes that can catalyze the oxidation and reduction biotransformation of most drugs, and is the main source of variability in drug pharmacokinetics and patient responses to treatment. Deuterium is an isotope of hydrogen that contains an extra neutron in its nucleus, and is safe, stable and non-radioactive. Because the mass of deuterium increases relative to hydrogen, the bond between carbon and deuterium requires greater energy than the bond between hydrogen and carbon to break, which can reduce the metabolic reaction rate. Specifically, the activation energy required for the transition state of carbon-deuterium bond to reach bond rupture is larger than carbon-hydrogen bond, and therefore the reaction rate is slower. The metabolic reaction rate reduced can have a favorable effect on the ADME performance of molecules, thereby providing improved effectiveness, safety and tolerability. Other physical characteristics of deuterium are substantially the same as hydrogen, and it is expected that the molecules with deuterium replacement will not produce biologically relevant effects.

[0007] A few drugs that use deuterium replacement to improve metabolism have been tested (see Blake, M. et al. J. Pharm. Sci., 64, p. 367 (1975); Foster, A. Adv. Drug Res., 14, p. 1 (1985); Kushner, D. et al. Can. J. Physiol. Pharmacol., p. 79 (1999); Fisher M. et al. Curt. Opin. Drug Discov. Devel., 9, p. 101 (2006)). However, the effect of deuterium replacement of hydrogen on metabolic rate has proven to be unpredictable and has led to variable results. In some cases, deuterated compounds have reduced in vivo metabolic clearance, while for other cases, there is no change in metabolic clearance, and yet other cases unexpectedly show an increase in metabolic clearance. This unpredictability of ADME poses a significant challenge to deuterium substitution as a strategic drug design modification to reduce metabolic rate (see Foster and Fisher, supra).

[0008] Even if the site and position of metabolism are known, deuterium replacement does not have a predictable effect on metabolic rate. Only by preparing a specific deuterium-substituted drug (candidate) and testing it can the extent of the change in metabolic rate be determined. See Fukuto, J. et al. J. Med. Chem., 34 (9), p. 2871 (1991). Many (if not most) drug candidates have multiple sites that may be metabolized, and the metabolic site characteristics of each drug molecule are unique. Therefore, deuterium replacement requires new research on the metabolic effects of each drug candidate. See Harbeson, L. and Tung. R. Medchem News, 2, p. 8 (2014) and references therein. There are several examples of drug candidates in which deuterium replacement of hydrogen has led to enhanced metabolic rate and / or metabolic conversion, or even after the metabolism is slowed down, the metabolic characteristics of the molecule have not changed in vivo. Harbeson et al. revealed that selective deuteration of paroxetine at predicted metabolically unstable positions actually produced analogs that exhibited increased metabolism in vivo (Scott L. Harbeson and Roger D. Tung, Deuterium in Drug Discovery and Development, 46 annual report in medicinal chemistry, 403-417 (2011)). In addition, Miwa reported that deuteration of metabolically unstable sites may lead to the enhancement (or conversion) of alternative metabolic pathways, resulting in uncertain consequences (Miwa. G., Lu, A., Kinetic Isotope Effects and `Metabolic Switching` in Cytochrome P450-Catalyzed Reactions, 7 Bioassays, 215-19 (1987)). For example, phentermine has been deuterated to reduce its metabolic rate, but replacement of the N,N-dimethyl hydrogen with deuterium did not produce observable changes (Allan B. Foster, "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design", Advances in Drug Research, (14), 1-40 (1985)).Similarly, deuteration of the metabolically active site of tramadol does not result in an increase in duration of effect (Shao et al., “Derivatives of Tramadol for Increased Duration of Effect”, Bioorganic and Medicinal Chemistry Letters, (16), 691-94 (2006)).

[0009] Ulixinib (BVD-523) was originally disclosed by Martinez-Botella et al. in U.S. Pat. No. 7,354,939 (which is incorporated by reference in its entirety), and has been shown to be, for example, a potent inhibitor of ERK1 / 2, making it a promising therapeutic agent for the treatment of cancer and other diseases. However, when administered in vivo, ulixertinib can be metabolized to result in the formation of at least six metabolites, some of which may be undesirable and easily cleared (see, Bin Yu et al., "Pharmacokinetics and metabolism of ulixertinib in rat by liquid chromatography combined with electrospray ionization tandem massspectrometry," Separation Science, Vol. 43, No. 7, pp. 1275-1283 (2020)). Therefore, analogs of ulixertinib are needed to reduce or slow the formation of metabolites and reduce systemic clearance and pre-systemic clearance. The present disclosure is intended to meet these and other needs.

[0010] Summary of the Disclosure

[0011] According to certain aspects, the present disclosure provides novel compounds as derivatives of uritinib, and pharmaceutically acceptable salts thereof, which are effective as inhibitors of ERK protein kinase. In certain embodiments, these compounds have the general formula 1:

[0012]

[0013] Including pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein each X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 aliphatic, and wherein each of Ring A, R1, R2 and m are defined as disclosed herein.

[0014] In certain aspects, the disclosure also provides compositions comprising the compounds disclosed herein and the use of such compounds in methods for treating or lessening the severity of various disorders, including proliferative disorders such as cancer.

[0015] In certain embodiments, the selective replacement of hydrogen atoms with deuterium in the compounds disclosed herein provides the unique benefit of positively affecting the metabolic fate of the parent compound while retaining the physicochemical properties and pharmacological properties of the parent compound by reducing or slowing the formation of undesirable metabolites, reducing the systemic clearance of the compound, thereby increasing its half-life, and reducing systemic premetabolism, thereby increasing the bioavailability of the unmetabolized compound, which in principle can improve the safety, efficacy and / or tolerability of the compound. In addition, in certain embodiments, deuterium replacement in the compounds disclosed herein also reduces the inhibition and / or induction of at least one cytochrome P450 metabolizing enzyme compared to non-isotopically enriched compounds, which thereby reduces the risk of drug-drug interactions.

[0016] According to certain aspects, the present disclosure provides compounds of Formula 1:

[0017]

[0018] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen, deuterium and C 1-4 aliphatic, and wherein: R1 is hydrogen, C 1-3 aliphatic, fluoro or chloro; Ring A is an optionally substituted group selected from the following: phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRS02R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

[0019] According to certain embodiments, the present disclosure provides compounds of the formula:

[0020]

[0021] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 Aliphatic; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; m is 0, 1 or 2; and A, B, C, D, E and F are independently selected from carbon or nitrogen.

[0022] According to certain embodiments, the present disclosure provides compounds according to any one of the following formulae

[0023]

[0024] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

[0025] According to certain embodiments, the present disclosure provides compounds according to Formula 4:

[0026]

[0027] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 Aliphatic.

[0028] In certain embodiments, the compounds disclosed herein are selected from:

[0029] 4-(5-chloro-2-((propan-2-yl-d7)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0030] 4-(5-chloro-2-((propan-2-yl-1,1,1,3,3,3-d6)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0031] 4-(5-chloro-2-((propan-2-yl-1,1,1,2,3-d5)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0032] 4-(5-chloro-2-((propan-2-yl-1,1,1,2-d4)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0033] 4-(5-chloro-2-((propan-2-yl-1,1,2-d3)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0034] 4-(5-chloro-2-((propan-2-yl-1,2-d2)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0035] 4-(5-chloro-2-((propan-2-yl-2-d1)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0036] In certain embodiments, the compound is a substantially pure enantiomer of an S- or R-euritinib analog. In certain embodiments, the compound is a substantially pure enantiomer of a 1S-euritinib analog. In certain embodiments, the compound is a substantially pure enantiomer of a 1R-euritinib analog. In certain embodiments, the compound is an enantiomeric mixture of S- or R-euritinib analogs. In certain embodiments, the compound is primarily (i.e., greater than 50%) an S-euritinib analog. In certain embodiments, the compound is primarily (i.e., greater than 50%) an R-euritinib analog. In certain embodiments, the compound is an enantiomeric mixture of equal parts of S- and R-euritinib analogs.

[0037] In certain embodiments, any atom not designated as deuterium is present at its natural isotopic abundance. In certain embodiments, each of the positions having deuterium has a deuterium enrichment of at least 1%.

[0038] According to certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier, excipient or vehicle.

[0039] According to certain aspects, the present disclosure provides a method of treating a disease, disorder or condition, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, wherein the disease, disorder or condition comprises one or more of cancer, autoimmune disorders, neurodegenerative disorders and neurological disorders, schizophrenia, bone-related disorders, liver disease and cardiac disorders. In certain embodiments, after administration of a therapeutically effective amount of the compound, the compound is enriched by at least one polymorphically expressed cytochrome P compared to the corresponding non-isotopically enriched compound per dosage unit. 450 Isomorph (cytochrome P 450 In certain embodiments, the cytochrome P 450 The isoform is selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6 and CYP2E1. In certain embodiments, the compound has an increased activity per dosage unit of at least one cytochrome P compared to the non-isotopically enriched compound. 450 In certain embodiments, the cytochrome P 450 Selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 , CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, C YP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46 and CYP51.

[0040] According to certain aspects, the present disclosure provides a compound or pharmaceutical composition disclosed herein for use as a medicament. In certain embodiments, the medicament is for preventing or treating a disorder that is ameliorated by inhibition of ERK protein kinase.

[0041] According to certain aspects, the compounds or pharmaceutical compositions disclosed herein with deuterium have at least 1% deuterium incorporation. In certain embodiments, at least one of X1, X2, X3, X4, X5, X6 and X7 is deuterium. In certain embodiments, at least two of X1, X2, X3, X4, X5, X6 and X7 are deuterium. In certain embodiments, at least three of X1, X2, X3, X4, X5, X6 and X7 are deuterium. In certain embodiments, at least four of X1, X2, X3, X4, X5, X6 and X7 are deuterium. In certain embodiments, at least five of X1, X2, X3, X4, X5, X6 and X7 are deuterium. In certain embodiments, at least six of X1, X2, X3, X4, X5, X6 and X7 are deuterium. In certain embodiments, each of X1, X2, X3, X4, X5, X6 and X7 is deuterium. In certain embodiments, each of X2, X3, X4, X5, X6 and X7 is deuterium, and X1 is hydrogen. In certain embodiments, each of X2, X3, X4, X5, X6 and X7 is hydrogen, and X1 is deuterium.

[0042] According to certain aspects, the present disclosure provides a method of inhibiting ERK1 / 2 in a cell, the method comprising the step of contacting the cell with a compound or pharmaceutical composition disclosed herein.

[0043] In certain embodiments, the compound or pharmaceutical composition effectively reduces at least one polymorphically expressed cytochrome P compared to the corresponding non-isotopically enriched compound. 450 In certain embodiments, the cytochrome P 450 Isoforms selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYP5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F 2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51. In certain embodiments, the cytochrome P 450The isoform is selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6, and CYP2E1. In certain embodiments, the reduction in metabolism is greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, or greater than about 55% compared to the non-isotopically enriched compound. In certain embodiments, the compound or pharmaceutical composition reduces the expression of at least one polymorphically expressed cytochrome P in human cells compared to the corresponding non-isotopically enriched compound. 450 The isoform effectively reduces metabolism of the compound by greater than about 10%, greater than about 20%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 50%, greater than about 55%, or greater than about 60%.

[0044] According to certain aspects, the present disclosure provides a method for synthesizing a deuterated compound according to Formula I:

[0045]

[0046] The method comprises the following steps: (i) making a compound of formula 5:

[0047]

[0048] (ii) reacting a compound of formula 7 with a compound of formula 8:

[0049]

[0050] To produce a compound of formula 9:

[0051]

[0052] (iii) reacting the compound of formula 9 with LiOH to produce a compound of formula 10:

[0053]

[0054] (iv) reacting a compound of formula 10 with a compound of formula 11:

[0055]

[0056] To produce a compound of formula 1:

[0057]

[0058] wherein each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen, deuterium and C 1-4 aliphatic, and wherein:

[0059] R1 is hydrogen, C 1-3 aliphatic, fluoro or chloro; A is an optionally substituted group selected from: phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R 2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2; wherein each R is independently hydrogen or C 1-4 Aliphatic.

[0060] m is 0, 1 or 2, PG is a protecting group; and L1 and L2 are independently selected leaving groups.

[0061] According to certain aspects, the present disclosure provides a method for synthesizing a deuterated compound according to Formula 1:

[0062]

[0063] The method comprises the following steps: (i) making a compound of formula 12:

[0064]

[0065] Reaction with the compound of formula 8:

[0066]

[0067] To produce a compound of formula 13:

[0068]

[0069] (ii) reacting a compound of formula 13 with LiOH to produce a compound of formula 14:

[0070]

[0071] (iii) reacting a compound of formula 14 with Reaction to produce a compound of formula 15:

[0072]

[0073] (iv) deprotecting the compound of formula 15 to produce a compound of formula 16:

[0074]

[0075] (v) reacting a compound of Formula 16 with a compound of Formula 17:

[0076]

[0077] To produce a compound of formula 1:

[0078]

[0079] wherein each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen, deuterium and C 1-4 aliphatic, and wherein:

[0080] R1 is hydrogen, C 1-3 aliphatic, fluorine or chlorine; A is an optionally substituted group selected from the following: phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2; wherein each R is independently hydrogen or C 1-4 aliphatic, m is 0, 1 or 2, PG is a protecting group; and L2 is a leaving group.

[0081] According to certain embodiments, the above general method can be used to prepare any of Formulas 18, 19, or 21 disclosed herein.

[0082] According to certain aspects, the present disclosure provides a method for synthesizing deuterated uritinib of Formula 18 or a pharmaceutically acceptable salt thereof:

[0083]

[0084] The method comprises the following steps:

[0085] (i) making a compound of formula 7A:

[0086]

[0087] Reaction with a compound of formula 8A:

[0088]

[0089] To provide a compound of Formula 9A:

[0090]

[0091] (ii) reacting the compound of formula 9A with LiOH to produce a compound of formula 10A:

[0092] and

[0093] (iii) reacting a compound of formula 10A with a compound of formula 8B:

[0094]

[0095] To produce a compound of formula 18:

[0096]

[0097] According to certain aspects, the present disclosure provides a method for synthesizing the HCl salt form of a deuterated uritinib analog, the method comprising treating a compound of Formula 18:

[0098]

[0099] Steps for reaction with HCl to produce a compound of formula 18A:

[0100]

[0101] According to certain aspects, the present disclosure provides a method for synthesizing deuterated uritinib of Formula 19 or a pharmaceutically acceptable salt thereof:

[0102]

[0103] The method comprises the following steps:

[0104] (i) making a compound of formula 12A:

[0105]

[0106] Reaction with a compound of formula 8A:

[0107]

[0108] To produce a compound of formula 13A:

[0109]

[0110] (ii) reacting a compound of formula 13A with LiOH to produce a compound of formula 14A:

[0111] (iii) reacting a compound of formula 14A with a compound of formula 8B:

[0112]

[0113] To produce a compound of formula 15A:

[0114]

[0115] (iv) reacting a compound of Formula 15A with TFA to produce a compound of Formula 16A:

[0116] and (v) reacting a compound of formula 16A with Reaction to produce a compound of formula 19:

[0117]

[0118] According to certain aspects, the present disclosure provides a method for synthesizing the HCl salt form of a deuterated uritinib analog, the method comprising making a compound of formula 19:

[0119]

[0120] Steps for reaction with HCl to produce a compound of formula 19A:

[0121]

[0122] According to certain aspects, the present disclosure provides a method for synthesizing deuterated uritinib of Formula 21 or a pharmaceutically acceptable salt thereof:

[0123]

[0124] The method comprises the following steps:

[0125] (i) making a compound of formula 7B:

[0126]

[0127] Reaction with a compound of formula 8A:

[0128]

[0129] To produce a compound of formula 9B:

[0130]

[0131] (ii) reacting the compound of formula 9B with LiOH to produce a compound of formula 10B:

[0132]

[0133] and (iii) reacting a compound of formula 10B with a compound of formula 8B:

[0134]

[0135] To produce a compound of formula 21:

[0136]

[0137] According to certain aspects, the present disclosure provides a method for synthesizing a deuterated uritinib analog, the method comprising making a compound of formula 21:

[0138]

[0139] Steps for reaction with HCl to produce a compound of formula 21A:

[0140]

[0141] According to certain aspects, the present disclosure provides a compound selected from the group consisting of:

[0142]

[0143]

[0144]

[0145]

[0146] and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0147] According to certain aspects, the present disclosure provides a compound selected from the group consisting of:

[0148]

[0149] In certain aspects, the present disclosure provides a kit for treating or ameliorating the effects of a disease in a subject, the kit comprising a compound or pharmaceutical composition as disclosed herein packaged with instructions for use. In certain embodiments, the compound or pharmaceutical composition in the kit is effective in reducing at least one polymorphically expressed cytochrome P compared to the corresponding non-isotopically enriched compound. 450 Metabolism of the compound or pharmaceutical composition by the isoform.

[0150] Detailed Description

[0151] According to certain aspects, the present disclosure provides deuterated analogs of Uritinib of Formula I, solvates, prodrugs and pharmaceutically acceptable salts thereof, as well as methods for making and using the same, and pharmaceutical compositions thereof.

[0152] In certain embodiments, the deuterated analogs of Uritinib disclosed herein are compounds represented by the general structure in Formula 1:

[0153]

[0154] Including pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein each X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 aliphatic, and wherein each of Ring A, R1, R2 and m is as defined herein. In certain embodiments:

[0155] R1 is hydrogen, C 1-3 aliphatic, fluorine or chlorine;

[0156] Ring A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0157] R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRS02R or N(R)2; and

[0158] m is 0, 1 or 2.

[0159] According to certain embodiments, the compounds include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein.

[0160] definition

[0161] Unless otherwise indicated, the following definitions shall apply. As used herein, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0162] The term "prodrug" used herein means a derivative of a parent drug molecule that requires conversion in vivo to release the active drug, and that has improved physical and / or delivery properties compared to the parent drug molecule. Prodrugs are designed to enhance the pharmacy and / or pharmacokinetic properties associated with the parent drug molecule. The advantage of a prodrug is its physical properties, such as enhanced water solubility at physiological pH compared to the parent drug for parenteral administration, or it enhances absorption from the digestive tract, or it can enhance the stability of the drug for long-term storage. It is known in the art to use esters as prodrug types for drugs containing carboxyl or hydroxyl functional groups, such as described in "The Organic Chemistry of Drug Design and Drug Interaction" by Richard Silverman, published by Academic Press (1992).

[0163] As used herein, "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., a compound of Formula 1 or a salt or prodrug thereof) and a solvent. Such solvents for the purposes of the present disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol, and acetic acid. Typically, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Typically, the solvent used is water.

[0164] As described herein, the compounds disclosed herein may be optionally substituted with one or more substituents, such as generally described above, or as exemplified by specific classes, subclasses, and species disclosed herein. It should be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether or not preceded by the term "optionally", means replacing a hydrogen residue in a given structure with a residue of a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified set, the substituent at each position may be the same or different.

[0165] Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not substantially change when placed under conditions that allow their production, detection, and preferably their recovery, purification, and use for one or more purposes disclosed herein. In certain embodiments, a stable compound or chemically feasible compound is one that does not substantially change when stored at 40° C. or less for at least one week in the absence of moisture or other chemically reactive conditions.

[0166] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl"), having a single point of attachment to the rest of the molecule. In certain embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In certain embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0167] As used herein, the term "unsaturated" refers to a moiety having one or more units of unsaturation.

[0168] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an alkyl, alkenyl or alkoxy group, as appropriate, substituted with one or more halogen atoms. The term "halogen" refers to F, Cl, Br or I.

[0169] The term "aryl", used alone or as part of a larger moiety (such as in "aralkyl", "aralkyloxy" or "aryloxyalkyl"), refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3-7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring".

[0170] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds are within the scope of the present disclosure. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to the replacement of a hydrogen by a deuterium or tritium or a carbon by an isotopically enriched 13 C or 14 Compounds having the present structures other than substitution of the carbons at C are within the scope of the present disclosure.

[0171] It should be recognized that some variation in natural isotopic abundance will occur in the synthesized compounds, depending on the source of the chemical materials used in the synthesis. Therefore, preparations of the compounds disclosed herein will inherently contain small amounts of deuterated isotopologues. The term "isotopologue" refers to a species that differs only in its isotopic composition from a particular compound disclosed herein. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and unimportant compared to the degree of stable isotope substitution of the compounds of the present disclosure. See, e.g., Wada, E et al., Seikagaku, 1994, 66: 15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

[0172] In the compounds disclosed herein, any atom that is not explicitly designated as a specific isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. In addition, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", the position is understood to have a deuterium abundance of at least 66 times the natural deuterium abundance of 0.015% (i.e., at least 1% deuterium incorporation).

[0173] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. In certain embodiments, the compounds disclosed herein have an isotopic enrichment factor of at least 66 (1% incorporation at each designated deuterium atom), at least 1666 (25% deuterium incorporation), at least 3333 (50% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6533 (98% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0174] When representing the compounds disclosed herein, the term "compound" means a collection of molecules with the same chemical structure except that isotopic variants may exist between the component atoms of the molecule. Thus, it will be apparent to those skilled in the art that the compound represented by the specific chemical structure containing the indicated deuterium atom will also contain a smaller amount of isotopologues with hydrogen atoms at one or more specified deuterium positions in the structure. The relative amount of such isotopologues in the compounds disclosed herein will depend on many factors, including the isotopic purity of the deuterated reagent used to make the compound and the incorporation efficiency of deuterium in each synthesis step for preparing the compound. However, as described above, the relative amount of such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1% or less than 0.5 / 0 of the compound.

[0175] Compounds disclosed herein (including compounds of Formula 1) may contain asymmetric carbon atoms, for example, due to deuterium substitution or other reasons. Therefore, compounds disclosed herein may exist as each enantiomer or a mixture of enantiomers. Therefore, compounds disclosed herein may exist as a racemic mixture or a scalemic mixture, or as a separate corresponding stereoisomer, and the stereoisomer is substantially free of other possible stereoisomers. The term "substantially free of other stereoisomers" or "substantially pure enantiomers" used herein refers to the presence of less than 25% of other stereoisomers, less than 10% of other stereoisomers, less than 5% of other stereoisomers and less than 2% of other stereoisomers or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, including end values). The method of obtaining or synthesizing each enantiomer of a given compound is known in the art and can be applied to the final compound or starting material or intermediate where practicable.

[0176] The term "racemate" or "racemic mixture" refers to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. The term "enantiomeric enrichment" as used herein refers to an increase in the amount of one enantiomer relative to the other.

[0177] It should be understood that compounds of the invention having chiral centers can exist and be separated in optically active forms and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, diastereomeric, polymorphic or stereoisomeric forms or mixtures thereof of compounds of the invention having the useful properties described herein, and it is well known in the art how to prepare optically active forms (e.g., by resolving racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

[0178] The method of obtaining an enriched or pure enantiomer comprises at least the following:

[0179] i) Physical separation of crystals - a technique used to manually separate macroscopic crystals of each enantiomer. This technique can be used if crystals of individual enantiomers are present, i.e. the material is an aggregate, and the crystals are visible to the naked eye;

[0180] ii) simultaneous crystallization - a technique for separately crystallizing each enantiomer from a solution of the racemate, which is only possible if the racemate is an aggregate in the solid state;

[0181] iii) Enzymatic resolution - a technique that partially or completely separates racemates by taking advantage of the different reaction rates of enantiomers with enzymes;

[0182] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one synthetic step uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

[0183] v) chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which conditions can be achieved using chiral catalysts or chiral auxiliaries as disclosed in more detail herein;

[0184] vi) Diastereoisomeric separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) which converts each enantiomer into a diastereomer. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

[0185] vii) first and second order asymmetric transformations - a technique whereby the diastereomers are equilibrated relative to the racemate so that the diastereomer predominates over the desired enantiomer in solution, or where preferential crystallization of the diastereomer relative to the desired enantiomer disturbs the equilibrium so that ultimately substantially all of the material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then liberated from the diastereomers;

[0186] viii) Kinetic resolution - This technique refers to the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by exploiting the different reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions;

[0187] ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from achiral starting materials and in which the stereochemical integrity is not destroyed or only slightly destroyed during the synthesis;

[0188] x) Chiral liquid chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase by exploiting the different interactions of the enantiomers with the stationary phase. The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions;

[0189] xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the enantiomers are separated by exploiting their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;

[0190] xii) Extraction with chiral solvents - a technique in which the enantiomers are separated by taking advantage of the preferential solubility of one enantiomer in a specific chiral solvent;

[0191] xiii) Transport across chiral membranes - a technique in which a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force (such as a concentration or pressure difference) causes preferential transport across the membrane barrier. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0192] Stereoisomers can also be separated by conventional techniques known to those skilled in the art, including fractional crystallization of a base or its salt or chromatographic techniques such as LC or flash chromatography. The (+) enantiomer is separated from the (-) enantiomer using techniques and procedures well known in the art, such as those described in J. Jacques, et al., antiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. For example, chiral chromatography using a suitable organic solvent (such as ethanol / acetonitrile) and Chiralpak AD packing (20 microns) can also be used to achieve separation of enantiomers.

[0193] Both "D" and "d" stand for deuterium.

[0194] The term "optionally substituted with deuterium" means that one or more hydrogen atoms in the mentioned moiety may be replaced by a corresponding number of deuterium atoms.

[0195] The present disclosure provides a prodrug of a compound of formula 1 above. In general, such a prodrug will be a functional derivative of a compound of formula 1, which is easily converted into a desired compound of formula 1 in vivo. Conventional procedures for selecting and preparing suitable prodrug derivatives are described in, for example, Design of Prodrugs, H.Bundgaard, ed. Elsevier, 1985. Such prodrugs include, but are not limited to, ester prodrugs of alcohols and acids and phosphate prodrugs of alcohols. Prodrugs can be formulated to achieve the goals of improving chemical stability, improving patient acceptance and compliance, improving bioavailability, extending duration of action, improving organ selectivity, improving formulations (including increasing water solubility) and / or reducing side effects (including toxicity).

[0196] The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of the deuterated compounds disclosed herein.

[0197] Therapeutic compounds

[0198] In certain embodiments, the present disclosure provides deuterated pyridyl pyrrole carboxamide analogs according to Formula 1:

[0199]

[0200] Wherein Ring A, the number and type of substituents, and the substitution pattern on the ring are variable.

[0201] In one aspect, the present disclosure provides compounds of Formula 2B-1 and 2B-2:

[0202]

[0203] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

[0204] Each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium.

[0205] In certain embodiments, X1, X2, X3, X4, X5, X6 and X7 are deuterium, such that the deuterated analogs of Uritinib are compounds having the structures of Formula 3C-1 and 3C-2:

[0206]

[0207] and pharmaceutically acceptable salts, solvates and prodrugs thereof.

[0208] In certain embodiments, the compounds of Formula 2B-1 and 2B-2 have X2, X3, X4, X5, X6 and X7 as hydrogen, such that the deuterated analogs of Uritinib are compounds having the structures of Formula 3A-11 and 3A-12:

[0209]

[0210] In certain embodiments, the compounds of Formula 2B-1 and 2B-2 have X1 as hydrogen, and X2, X3, X4, X5, X6 and X7 are deuterium, such that the deuterated analog of Uritinib is

[0211] Compounds of the structures of formula 3B-1 and 3B-2:

[0212]

[0213] In yet other embodiments, compounds according to Formula 2B-1 and 2B-2 having one of the following structures are provided:

[0214]

[0215]

[0216]

[0217] Other non-limiting exemplary embodiments of compounds of Formula 1 include:

[0218]

[0219]

[0220]

[0221]

[0222]

[0223] General Methods for Preparing Compounds

[0224] In certain embodiments, the compounds disclosed herein are prepared or isolated generally by synthetic methods of analogous compounds known to those skilled in the art, and as illustrated in the following General Scheme IV and the subsequent Preparative Examples.

[0225] Option I:

[0226]

[0227] Scheme 1 above depicts a general method for preparing compounds disclosed herein. The pyrrole compound of formula 22 is iodinated and esterified to form a compound of formula 23. The pyrrole moiety is optionally protected at -NH- with a suitable amino protecting group to form a compound of formula 25. Amino protecting groups are well known in the art and are described in detail in Greene's Protective Groups in Organic Synthesis, 55th edition, 2014, Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, the entire contents of which are hereby incorporated by reference. The iodinated portion of formula 25 is replaced by an appropriate boronic acid or ester to provide formula 8.

[0228] Option II:

[0229]

[0230] Scheme II depicts a general synthetic route for preparing compounds disclosed herein. Because the compounds of the present invention involve a polysubstituted pyridine moiety, the reaction sequence is considered, and the method of activating the position on the pyridine is used to guide the regiochemistry. In the first step, the leaving group L2 is installed on the pyridine ring in a regioselective manner. In the second step, the leaving group L1 can be replaced by alcohol, thiol or amine as needed. Various L1 leaving groups are suitable for the reaction. Examples of such groups include, but are not limited to halogen, activated ether and activated ester. After the reaction, the second leaving group L2 is replaced by a metal-catalyzed cross-coupling reaction or a nucleophilic aromatic substitution reaction to form an intermediate of formula 9. Various L2 leaving groups are suitable for the reaction. Examples of such groups include, but are not limited to halogen and activated ether, activated ester, boric acid, boric ester or phosphonium salt. The protecting group on the pyrrole is then removed by a method suitable for removing the amino protecting group. Depending on which amino protecting group is used, conditions suitable for removing it may simultaneously saponify or otherwise provide a carboxylate functional group, as shown in the compound of formula 10. If the conditions suitable for removing the amino protecting group are not suitable for providing a carboxylate of formula 10, another chemical transformation step may be used. Compounds of formula 1 may be prepared from formula 10 by coupling the resulting carboxylic acid group with a desired amine. A variety of amide bond coupling conditions may be used for the reaction, and may include a step of activating the carboxylic acid of the compound of formula 10 prior to or simultaneously with treatment with the desired amine. Such conditions include, but are not limited to, the conditions described in detail in the Examples section below.

[0231] The compound according to the intermediate of formula 5 is commercially available, or can be synthesized by the following scheme. In the following scheme, the acetone starting material (e.g., D6-acetone) can be obtained from a commercial supplier and can be used to prepare, for example, D6- and D7-isopropylamine. The intermediate of formula 5 produced can be separated into maleate (described in detail below in the Examples section).

[0232] Scheme III :

[0233]

[0234] Scheme III depicts a general synthetic route for preparing intermediates of Formula 5. In the first step, acetone is oximated with hydroxylamine using appropriate conditions to provide an intermediate of Formula 27. In the second step, the oxime in the intermediate of Formula 5 is reduced to an amine functional group using an appropriate reducing agent. This scheme can be used to prepare D1-isopropylamine (X1=D), D6-isopropylamine (X 2-7 =D) and D7-isopropylamine (X 1-7 =D).

[0235] Scheme IV :

[0236]

[0237] Scheme IV depicts another general synthetic route for preparing compounds according to the intermediates of Formula 5. The method according to this scheme is disclosed in Journal of Labelled Compounds and Radiopharmaceuticals, 2016, 59: 552-556 (which is incorporated by reference in its entirety) for the preparation of D6-isopropylamine, but can be extended to the preparation of D7-isopropylamine in particular:

[0238] Option V:

[0239]

[0240] Scheme V above depicts an alternative route to prepare the compounds disclosed herein. The L1 group of the intermediate of Formula 6 is replaced with the desired amine H2N-PG to provide an intermediate of Formula 31. Formula 31 can then be used to prepare an intermediate of Formula 32 according to conditions including, but not limited to, those described in Scheme II, conditions described in the following synthetic examples, and methods known to those of ordinary skill in the art. The protecting group on the aminopyridine moiety is removed by a method suitable for deprotecting the amino protecting group used. The compounds disclosed herein can be prepared by reductive amination of the intermediate of Formula 33 with a ketone in the presence of a suitable reducing agent.

[0241] Other suitable amino protecting groups are well known in the art and are included in those described in detail in Protecting Groups in Organic Synthesis, Theodora W.Greene and Peter GM Wuts, 1991 (published by John Wiley and Sons). In certain embodiments, the PG group is an alkyl or aryl sulfonyl moiety. Examples of such groups include mesyl, toluenesulfonyl, p-nitrobenzenesulfonyl, p-bromobenzenesulfonyl and 2,4,6-trimethylbenzenesulfonyl ("Mts"). Other such groups include Bn, PMB, Ms, Ts, SiR3, MOM, BOM, Tr, Ac, CO2R, CHOCH2CH2Si(CH3)3.

[0242] Suitable leaving groups are chemical groups that are easily replaced by the desired new chemical moiety. Therefore, the selection of specific suitable leaving groups depends on its ability to be easily replaced by the new chemical moiety. Suitable leaving groups are well known in the art, for example, referring to " Advanced Organic Chemistry, " Jerry March, the 5th edition, pages 351-357, John Wiley and Sons, NY. Such leaving groups include, but are not limited to halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl, optionally substituted arylsulfonyl and diazo moieties. The example of suitable leaving groups includes chlorine, iodine, bromine, fluorine, mesyl (methylsulfonyl), tosyl, trifluoromethyl sulfonate, nitro-benzenesulfonyl (p-nitrobenzenesulfonyl) and bromo-benzenesulfonyl (p-bromobenzenesulfonyl).

[0243] Metabolites of Uritinib

[0244] According to certain embodiments, the compositions disclosed herein have an altered metabolite profile relative to a non-isotopically enriched compound. Certain metabolites of ulixertinib have previously been described by Bin Yu et al., "Pharmacokinetics andmetabolism of ulixertinib in rat by liquid chromatography combined withelectrospray ionization tandem mass spectrometry," Separation Science, Vol. 43, No. 7, pp. 1275-1283 (2020), which is incorporated by reference in its entirety. In short, the metabolites of ulixertinib include:

[0245]

[0246]

[0247] In certain embodiments, the metabolites of Uritinib comprise

[0248] In certain embodiments, a metabolite of Uritinib comprises

[0249] In certain embodiments, a metabolite of Uritinib comprises

[0250] In certain embodiments, a metabolite of Uritinib comprises

[0251]

[0252] The steady-state exposure levels of non-isotopically enriched parent uritinib and related metabolites in rats (Day 5) and human subjects (Day 15) are provided in Table 1 below:

[0253] Table 1

[0254]

[0255] In certain embodiments, the deuterated compounds disclosed herein have reduced formation of one or more metabolites compared to the non-isotopically enriched compound. In certain embodiments, the deuterated analogs of uritinib are effective in reducing the formation of N-dealkyl metabolites of Formula 34. In certain embodiments, one or more of Formula 21, Formula 19, and Formula 18 are effective in reducing the formation of N-dealkyl metabolites of Formula 34. See, e.g., Tables 6 (HLM) and 8 (rat plasma). In certain embodiments, the deuterated analogs of uritinib are effective in reducing the formation of isopropylhydroxy metabolites of Formula 35. In certain embodiments, one or more of BVD-523-D1, BVD-523-D6, and BVD-523-D7 are effective in reducing the formation of isopropylhydroxy metabolites of Formula 35. See, e.g., Tables 6 (HLM) and 8 (rat plasma). In certain embodiments, one or more of Formula 21, Formula 19, and Formula 18 are effective in reducing the formation of carboxylic acid metabolites of Formula 36. See, e.g., Table 6 (HLM).

[0256] In certain embodiments, the deuterated compounds disclosed herein have increased formation, decreased formation, or the same formation of one or more metabolites compared to the non-isotopically enriched compound. In certain embodiments, the deuterated analogs of Uritinib are effective to increase the formation, decrease its formation, or maintain the same formation of the N-oxide metabolite of Formula 37. See, e.g., Tables 6 (HLM) and 8 (rat plasma).

[0257] In certain embodiments, the polymorphically expressed cytochrome P 450 Inhibition and / or induction of metabolic enzymes, altering the metabolism of the deuterated compounds disclosed herein compared to non-isotopically enriched compounds. In certain embodiments, the deuterated compounds disclosed herein effectively induce and / or inhibit CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYP3A5P2, CYP3A7, CYP4A11, CYP4A5P2, CYP4A5P3, CYP4A7, CYP4A12, CYP4A13, CYP4A14, CYP4A15, CYP4A16, CYP4A17, CYP4A18, CYP4A19, CYP4A19, CYP4A19, CYP4A11, CYP4A19, CYP4A12, CYP4A13, CYP4A14, CYP4A15 In some embodiments, the deuterated compounds disclosed herein are effective in inducing and / or inhibiting one or more of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6, and CYP2E1. In certain embodiments, the deuterated compounds disclosed herein are effective in reducing the metabolism of the deuterated compounds by inhibiting one or more of the cytochrome P450 enzymes disclosed herein. In certain embodiments, the deuterated compounds disclosed herein are effective in inhibiting the metabolism of a concomitantly administered drug.

[0258] Use, preparation and administration

[0259] As discussed above, the present disclosure provides compounds that are protein kinase inhibitors, and thus the compounds of the present invention can be used to treat diseases, disorders and conditions, including, but not limited to cancer, autoimmune disorders, neurodegenerative disorders and neurological disorders, schizophrenia, bone-related disorders, liver disease and cardiac disorders. Therefore, in another aspect of the present disclosure, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0260] It should also be understood that certain compounds of the present disclosure may exist in free form for therapeutic use or, where appropriate, as pharmaceutically acceptable derivatives thereof. Pharmaceutically acceptable derivatives, according to the present disclosure, include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other addition compounds or derivatives that, upon administration to a patient in need thereof, are capable of providing, directly or indirectly, a compound described elsewhere herein, or a metabolite or residue thereof.

[0261] The term "pharmaceutically acceptable salt" as used herein refers to salts that are suitable for contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to any non-toxic salt or ester salt of a compound disclosed herein, which, after administration to a recipient, is capable of directly or indirectly providing a compound disclosed herein or an inhibitory metabolite or residue thereof. The term "an inhibitory metabolite or residue thereof" as used herein means that a metabolite or residue thereof is also an inhibitor of ERK2 protein kinase.

[0262] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds disclosed herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+ (C 1-4 The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. By such quaternization, water or oil-soluble or dispersible products can be obtained. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0263] As described above, the pharmaceutically acceptable compositions disclosed herein additionally include pharmaceutically acceptable carriers, adjuvants or vehicles, which, as used herein, include any or all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. suitable for a specific expected dosage form, as long as they are suitable for the desired specific dosage form. Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for preparing pharmaceutically acceptable compositions and known techniques for preparing them. Unless any conventional carrier medium is incompatible with the compounds disclosed herein, such as producing any undesirable biological effects or otherwise interacting with any other components of the pharmaceutically acceptable composition in a harmful manner, its use is considered within the scope of the present disclosure. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl Cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffered solutions, and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, all according to the judgment of the formulator.

[0264] Uses of compounds and pharmaceutically acceptable compositions

[0265] In yet another aspect, a method for treating or alleviating the severity of cancer, autoimmune disorders, neurodegeneration or neurological disorders, liver disease or cardiac disorders is provided, the method comprising administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable composition comprising a compound disclosed herein to a subject in need thereof. In certain embodiments of the present disclosure, the "effective amount" of the compound or pharmaceutically acceptable composition is an amount of the severity of a disease, illness or disorder selected from cancer, autoimmune disorders, neurodegeneration or neurological disorders, schizophrenia, bone-related disorders, liver disease or cardiac disorders. According to the methods disclosed herein, any amount and any route of administration of the severity of cancer, autoimmune disorders, neurodegeneration or neurological disorders, schizophrenia, bone-related disorders, liver disease or cardiac disorders can be used to administer the compound and composition. The exact amount required will vary between subjects, depending on the species, age and overall condition of the subject, the severity of the infection, a specific agent, its mode of administration, etc. For ease of administration and uniform dosage, the compound disclosed herein is preferably formulated into a dosage unit form. As used herein, the expression "dosage unit form" refers to physically discrete dosage units suitable for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions disclosed herein will be decided by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of the treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical arts. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0266] The pharmaceutically acceptable compositions disclosed herein can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneal, topically (e.g., by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection to be treated. In certain embodiments, the compounds disclosed herein can be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg and preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, once or more per day to obtain the desired therapeutic effect.

[0267] Liquid dosage forms for oral administration include, but are not limited to: pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain an inert diluent commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics.

[0268] According to known techniques, injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (U.S. Pharmacopeia) and isotonic sodium chloride solutions. In addition, sterile fixed oils are generally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0269] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0270] In order to prolong the effect of the compounds disclosed herein, it is often necessary to slow down the absorption of the compounds injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable preparations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0271] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound disclosed herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0272] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0273] Solid compositions of similar type can also be used as fillers in soft or hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They can optionally contain opacifiers and can also be compositions that release the active ingredient only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of similar type can also be used as fillers in soft or hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0274] The active compound can also form a microencapsulated form with one or more excipients as described above. With coating agents and shells such as enteric coating agents, controlled release coating agents and other coating agents well-known in the field of pharmaceutical formulation, solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. According to conventional practice, such dosage forms can also include additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. They can optionally contain an opacifier, and can also be a composition that only or preferentially releases the active ingredient in a delayed manner in a specific part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

[0275] The dosage form for topical or transdermal administration of the compounds disclosed herein includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under aseptic conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer that may be needed. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present disclosure. In addition, the present disclosure provides the use of transdermal patches, which have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0276] As generally described above, the compounds disclosed herein can be used as inhibitors of ERK protein kinases. In one embodiment, the compounds and compositions disclosed herein are inhibitors of one or both of ERK1 and ERK2 protein kinases, and therefore, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of a disease, disorder, or disorder, wherein the activation of one or both of ERK1 and ERK2 protein kinases is associated with the disease, disorder, or disorder. When the activation of ERK1 and / or ERK2 protein kinases is associated with a particular disease, disorder, or disorder, the disease, disorder, or disorder may also be referred to as an "ERK1 or ERK2-mediated" disease, disorder, or disease symptom. Therefore, in another aspect, the present disclosure provides a method for treating or reducing the severity of a disease, disorder, or disorder, wherein the activation of one or both of ERK1 and ERK2 protein kinases is associated with the disease, disorder, or disorder.

[0277] The activity of inhibitors of ERK1 and / or ERK2 protein kinases can be determined in vitro, in vivo or in cell lines. In vitro assays include assays that determine the phosphorylation activity of activated ERK1 or ERK2 protein kinases or the inhibition of ATPase activity. Alternative in vitro assays can quantify the ability of the inhibitor to bind to ERK1 or ERK2 protein kinases. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, separating the inhibitor / ERK1 or inhibitor / ERK2 complex and determining the amount of radiolabeled binding. Alternatively, inhibitor binding can be determined by running a competition experiment in which a new inhibitor is incubated with an ERK1 or ERK2 protein kinase that binds a known radioligand.

[0278] As used herein, the term "measurably inhibits" refers to a measurable change in ERK1 or ERK2 protein kinase activity between a sample comprising the composition and ERK1 or ERK2 protein kinase and an equivalent sample comprising ERK1 or ERK2 protein kinase but without the composition. Such measurements of protein kinase activity are known to those of ordinary skill in the art and include those methods described below.

[0279] According to another embodiment, the present disclosure provides a method of inhibiting ERK1 or ERK2 protein kinase activity in a patient, the method comprising the step of administering to the patient a compound disclosed herein or a composition comprising the compound.

[0280] As used herein, the term "ERK-mediated condition" or "disease" refers to any disease or other deleterious condition in which ERK is known to play a role. The term "ERK-mediated condition" or "disease" also refers to those diseases or conditions that are alleviated by treatment with ERK inhibitors. Such conditions include, but are not limited to, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease (including cardiac hypertrophy, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis), psoriasis, allergic disorders (including asthma), inflammation, neurological disorders, and hormone-related diseases. The term "cancer" includes, but is not limited to, the following cancers: breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell cancer, oral cavity and throat cancer (oral cancer), lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, and leukemia.

[0281] Therefore, according to another embodiment, the present disclosure provides a method for treating or reducing the severity of one or more diseases in which ERK is known to play a role. Specifically, the present disclosure provides a method for treating or reducing the severity of a disease or condition selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease (including cardiac hypertrophy), Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders (including asthma), inflammation, neurological disorders and hormone-related diseases, wherein the method comprises administering a composition according to the method disclosed herein to a patient in need thereof.

[0282] According to another embodiment, the present disclosure provides a method of treating a cancer selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, myeloid disorders, lymphoid disorders, Hodgkin's disease, hairy cell cancer, oral cavity and throat cancer (oral cancer), lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, and leukemia.

[0283] Another embodiment is directed to a method of treating melanoma, breast cancer, colon cancer, or pancreatic cancer in a patient in need thereof.

[0284] It should also be understood that the compounds disclosed herein and pharmaceutically acceptable compositions can be used in conjoint therapy, that is, the compounds and pharmaceutically acceptable compositions can be used in parallel with one or more other desired therapeutic agents or medical operations, before or after them. The specific combination of treatment (therapy or operation) adopted in the conjoint scheme will consider the compatibility of the desired therapy and / or operation with the desired therapeutic effect to be achieved. It should also be understood that the therapy adopted can achieve the expected effect on the same obstacle (for example, the compounds disclosed herein can be used in parallel with another agent for treating the same obstacle), or they can achieve different effects (for example, control any adverse effects). As used herein, the other therapeutic agents that are usually applied to treat or prevent a specific disease or condition are referred to as "suitable for the disease or condition treated".

[0285] For example, chemotherapeutic agents or other anti-proliferative agents can be combined with the compounds disclosed herein to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, for example, other therapies or anti-cancer agents that can be used in combination with the anti-cancer agents disclosed herein include surgery, radiation therapy (gamma-irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes, to name a few), endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), to name a few), hyperthermia and cryotherapy, agents for attenuating any adverse effects (e.g., antiemetics), and other approved chemotherapeutic drugs, including, but not limited to, alkylating drugs ( dichloromethane, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabile, gemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (carmustine, lomustine), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase) and hormones (tamoxifen, leuprolide, flutamide and megestrol), Gleevec TM , doxorubicin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of the latest cancer therapies, see, http: / / www.nci.nih.gov / , the FDA-approved oncology drug list at http: / / www.fda.gov / cder / cancer / druglistframe.htm, and The Merck Manual, Seventeenth Edition. 1999, the entire contents of which are hereby incorporated by reference.

[0286] Other examples of agents with which the inhibitors may also be combined include, but are not limited to, therapeutic agents for Alzheimer's disease such as and Therapeutic agents for Parkinson's disease such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents used to treat multiple sclerosis (MS) such as beta interferon (e.g., and ), and mitoxantrone; asthma treatments such as Agents used to treat schizophrenia such as Zyprexa, Risperdal, Seroquel, and Haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anti Convulsants, ion channel blockers, riluzole, and anti-Parkinson agents; agents for the treatment of cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for the treatment of liver disease such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for the treatment of blood disorders such as corticosteroids, anti-leukemia agents, and growth factors; and agents for the treatment of immunodeficiency disorders such as gamma globulin.

[0287] The amount of additional therapeutic agent present in the compositions disclosed herein will not exceed the amount normally administered in a composition comprising the therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein ranges from about 50% to 100% of the amount normally present in a composition comprising the agent as the only therapeutically active agent.

[0288] In an alternative embodiment, the method utilizing the composition not containing additional therapeutic agent disclosed herein comprises the additional step of administering additional therapeutic agent separately to the patient.When these additional therapeutic agents are administered separately, they can be administered to the patient before, in sequence with, or after administering the composition disclosed herein.

[0289] Compounds disclosed herein or pharmaceutically acceptable compositions thereof can also be incorporated into compositions for coating implantable medical devices (such as prostheses, artificial valves, vascular grafts, stents and catheters). Therefore, the present disclosure provides compositions for coating implantable devices in another aspect, comprising compounds generally described above and in the categories and subcategories herein, and carriers suitable for coating the implantable devices. In yet another aspect, the present disclosure provides implantable devices coated with compositions, comprising compounds generally described above and in the categories and subcategories herein, and carriers suitable for coating the implantable devices.

[0290] For example, vascular stents have been used to overcome restenosis (restenosis of the vascular wall after injury). However, patients using stents or other implantable devices may have the risk of clot formation or platelet activation. By pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor, these undesirable effects can be prevented or mitigated. The general preparation of suitable coatings and coated implantable devices is described in U.S. Patents 6,099,562, 5,886,026 and 5,304,121. The coating is typically a biocompatible polymeric material such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene-vinyl acetate, and mixtures thereof. The coating may optionally be further covered with a suitable outer coating of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or a combination thereof to impart controlled release characteristics to the composition.

[0291] Another aspect of the present disclosure relates to inhibiting ERK1 or ERK2 protein kinase activity in a biological sample or a patient, the method comprising administering to the patient a compound disclosed herein or a composition comprising the compound, or contacting the biological sample with a compound disclosed herein or a composition comprising the compound. The term "biological sample" as used herein includes, but is not limited to, cell culture or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0292] Inhibition of ERK1 or ERK2 protein kinase activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and bioassays.

[0293] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0294] The following examples are provided to further illustrate the methods of the present disclosure. These examples are merely exemplary and are not intended to limit the scope of the present disclosure in any way. Example

[0295] Example 1

[0296] D7-Uritinib was prepared as follows:

[0297]

[0298] Preparation of intermediate formula 7A

[0299]

[0300] DMSO (128 mL, 6V), formula 38 (21.37 g, 1.0 eq.), d7-isopropylamine hydrochloride (12.72 g, 1.5 eq.) and K2CO3 (25.84 g, 2.25 eq.) were added to the flask at ambient temperature. The temperature of the mixture was raised to 80 to 85°C and stirred until the reaction was completed. The temperature of the mixture was lowered to 20 to 25°C and water (770 mL, 36V) was added to the mixture. The mixture was extracted with EtOAc (427 mL, 20V x 3) and the organic phases were combined. The EtOAc solution was washed with water (427 mL, 20V x 2) and brine (213 mL, 10V x 1). The solution solvent was then exchanged into n-heptane (214 mL, 10V x 2) to a final volume of 6. The temperature of the n-heptane mixture was lowered to 0 to 10°C. The slurry was filtered and the separated solid was dried to produce 16 g of the product (Formula 7A) as an off-white solid. Yield: 77.8%, HPLC purity: 89.2% (215 nm); LC-MS: m / z 304.0 (M+1); 1 H-NMR (400MHz, CDCl3): δ8.01 (s, 1H), 6.88 (s, 1H).

[0301] Preparation of Intermediate Formula 9A

[0302]

[0303] To a solution of formula 7A (1.0 g, 3.29 mmol, 1 eq) and formula 8A (1.28 g, 3.95 mmol, 1.2 eq) in DME (15 mL, 15 V) and water (1 mL, 1 V) was added palladium acetate (0.01 g, 0.45 mmol, 0.14 eq), tricyclohexylphosphonium tetrafluoroborate (0.01 g, 0.45 mmol, 0.14 eq) and sodium carbonate (0.52 g, 4.9 mmol, 1.5 eq) under nitrogen. The temperature of the mixture was raised to 75 to 85 ° C and stirred for 12 hours. The reactants were cooled to 20-25 ° C and the mixture was filtered. The filtrate was collected and concentrated to produce a residue, which was re-slurried with 2.8 mL of methanol. The methanol slurry was filtered and the filter cake was washed with methanol (1 mL x 2). The solid was dried under nitrogen to produce 1.1 g of the product (Formula 9A) as an off-white solid. Yield: 79.0%, HPLC purity: 99.6% (215 nm); LC-MS: m / z 455.1 (M+1); 1H-NMR (400MHz, DMSO-d6): δ8.35(s,1H),8.31(s,1H),8.13-8.16(d,2H),7.49-7.52(m,3H),6.57(s,1H),4.56(s,1H),3.92(s,3H),2.61(s,3H).

[0304] Preparation of Intermediate Formula 10A

[0305]

[0306] An aqueous solution of LiOH (5.0 eq., 7 wt. %) and diethylamine (7.26 g, 2.0 eq.) was added to a solution of Formula 9A (22 g, 1.0 eq.) in THF (4V) at 15 to 30°C. The temperature of the mixture was raised to 60 to 70°C until the reaction was complete. The temperature of the reactants was lowered to 20 to 25°C. The solution was concentrated under vacuum and the pH was adjusted to 6-7 with 1N HCl. The solid was collected by filtration and dried under vacuum to produce 7.2 g of the product (Formula 10A) as an off-white solid. Yield: 64.9%, HPLC purity: 98.9% (215 nm); LC-MS: m / z 287.1 (M+1); 1 H-NMR (400MHz, DMSO-d6): δ12.17(s,1H),7.98(s,1H),7.96(s,1H),7.46(s,1H),7.18(s,1H),6.59(s,1H),5.76(s,1H).

[0307] Preparation of compounds of formula 18

[0308]

[0309] HOBt (1.2 eq., 5.21 g) was added to a solution of Formula 10A (1.0 eq., 8 g) in DMF (1.5 V, 12 mL) at -10 to -20 °C, followed by EDCI (1.1 eq., 5.94 g). The temperature of the mixture was lowered to -20 to -30 °C and Formula 19 (1.2 eq., 5.84 g) and DIPEA (1.2 eq. 0.31 g) were added to the reaction mixture. The mixture was stirred at 0 to 10 °C until the reaction was complete. Ethyl acetate (10 V, 80 mL) and water (4 V, 32 mL) were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with ethyl acetate (10 V x 3, 80 mL). The combined organic phases were washed with water (4 V x 2, 32 mL each), 5% acetic acid aqueous solution (7 V x 2), Na2CO3 aqueous solution (7 V x 2, 17 wt %) and brine (10 V x 2) in sequence. Silica gel (1 g / g, 8 g) was added to the organic solution and the silica gel slurry was stirred for 2 to 4 hours and filtered. The filter cake was rinsed with ethyl acetate (4.5 g / g, 36 mL). The combined filtrate was concentrated to 1 to 2 V under vacuum and then MTBE (1.48 g / g, 11.8 g) was added. The temperature of the mixture was lowered to 0°C and stirred for 2 hours. The solid was collected by filtration and dried to produce 9.1 g (Formula 18) as an off-white solid. Yield: 69.7%, HPLC purity: 99.0% (215 nm); HPLC chiral purity (ee): 100.0% (254 nm); LC-MS: m / z 440.1 (M+1); 1 H-NMR (400MHz, CD3OD): δ7.99(s,1H),7.48-7.52(m,3H),7.39(s,1H),7.2 7-7.31(m,2H),7.23-7.26(m,2H),6.55(s,1H),5.15(q,1H),3.85(m,2H).

[0310] The compound of formula 18 is further reacted with HCl to produce the HCl salt of formula 18A. At 15 to 25 ° C, the filtered absolute ethanol (0.26V), the filtered methanol (0.02V) and the filtered isopropanol (0.02V) are loaded into a glass flask and stirred for 20 to 30min. Then, hydrogen chloride gas is bubbled in the mixture at 10 to 25 ° C under stirring. After 2 hours, the mixture is sampled and analyzed every 2 to 4 hours until the content of hydrogen chloride reaches ≥35% by weight. While the temperature is maintained at 15 to 25 ° C, the filtered absolute ethanol (9V), the filtered methanol (0.5V) and the filtered isopropanol (0.5V) are loaded into a separate reactor by an in-line fluid filter and stirred for 20 to 30min. Then add formula 18 (1.0 equivalent). The temperature of the mixture is raised to 70 to 75 ° C at a rate of 15 to 25 ° C / hour and stirred until the solid is completely dissolved. At 70 to 75 ° C, seed crystals (0.1 wt %) are added to the mixture, and then anhydrous HCl solution is added. The mixture is maintained at 70 to 75 ° C for 1 to 2 hours under stirring. The temperature of the mixture is reduced to 15 to 25 ° C at a rate of 5 to 15 ° C / hour and then maintained at 15 to 25 ° C for 4 to 6 hours under stirring. The mixture is filtered and the filter cake is rinsed with filtered MTBE. The filter cake is dried at 40 to 50 ° C under nitrogen for 24 hours to provide 8.29g of product (Formula 18A) as a white solid. Yield: 84.5%, HPLC purity: 99.4% (215nm); HPLC chiral purity (ee): 100.0% (254nm); HPLC determination purity: 99% (215nm); chloride content: 7.31%; isotopic purity: 99.7% (CD3), 100% (CD); LC-MS: m / z 440.2 (M+1); 1 H-NMR (400MHz, CD3OD): δ7.99(s,1H),7.75(s,1H),7.48(s,1H),7.42(s,1 H),7.39(s,1H),7.27-7.31(m,2H),7.08(s,1H),5.11(q,1H),3.88(m,2H).

[0311] Example 2

[0312] Formula 19 is prepared as follows:

[0313]

[0314] Preparation of Formula 12A

[0315]

[0316] Formula 38 (200 g, 777 mmol, 1 eq.), p-methoxybenzylamine (320 g, 2.33 mol, 3 eq.) and DMSO (2500 mL) were added to a flask. The temperature of the mixture was raised to 80°C and stirred for 12 hours. The temperature of the reaction mixture was lowered to 20 to 25°C. The reactants were distributed between water (4 L) and DCM (4 L). Water (4.5 L) was added to the organic layer, and the pH was adjusted to pH 3 to 4 under stirring. Stirring was stopped and the aqueous layer was separated and discarded. Water (4.5 L) was added to the DCM layer and the pH was adjusted to 9. The mixture was stirred for 5 min. Stirring was stopped and the aqueous layer was separated and discarded. The organic layer was dried and concentrated under reduced pressure to provide 240 g of the product (Formula 12A) as a white solid. Yield: 82.5%, HPLC purity: 97.3% (254 nm); LC-MS: m / z 375.0 (M+1); 1 H-NMR (400MHz, DMSO-d6): δ7.99(s,1H),7.28-7.31(t,1H),7.21-7.23(d,2H),7.11(s,1H),6.85-6.88(d,2H),4.35-4.36(d,2H),3.73(s,3H).

[0317] Preparation of Formula 13A

[0318]

[0319] Formula 12A (143 g, 380 mmol, 1 eq), Formula 8A (123 g, 380 mmol, 1.0 eq), Pd(OAc)2 (2.56 g, 11.4 mmol, 0.03 eq), PCy3.HBF4 (5.60 g, 15.2 mmol, 0.04 eq), sodium carbonate (60.42 g, 570 mmol, 1.5 eq), DME (1500 mL, 10 V) and water (150 mL, 1 V). The temperature of the reaction mixture was raised to 80°C under nitrogen and stirred at 80°C for 23 hours. An additional amount of Formula 8A (32 g) was added to the flask and the reaction mixture was stirred overnight. The mixture was filtered on a celite pad and the filtrate was collected and concentrated under reduced pressure. Methanol (750 ml) was added to the residue and the slurry was stirred for 2 hours and filtered to provide 180 g of the product (Formula 13A) as an off-white solid. Yield: 89.6%, HPLC purity: 90.5% (254 nm); LC-MS: m / z 526.0 (M+1); 1H-NMR (400MHz, DMSO-d6): δ8.22(d,1H),8.05(s,1H),7.95-7.97(d,2H),7.48-7.50(d,2H),7.24-7.26( d,2H),7.14-7.17(t,1H),6.86-6.88(d,2H),6.76(s,1H),4.41-4.42(d,2H),3.69(s,6H),2.42(s,3H).

[0320] Preparation of Formula 14A

[0321]

[0322] Formula 13A (170 g, 323 mmol, 1 eq.), lithium hydroxide monohydrate (67.8 g, 1616 mmol, 5 eq.), THF (1700 mL, 10 V) and water (1500 mL, 8.8 V) were added to a flask. The temperature of the mixture was raised to 60 to 80 °C and stirred at this temperature for about 60 hours. The temperature of the reaction mixture was lowered to 20-25 °C. The pH of the mixture was adjusted to 3. The organic layer was separated and the solvent was concentrated to about 0.33 V under reduced pressure. The slurry was filtered and dried to produce 196 g of the product (Formula 14A) as a light yellow solid. The solid was used in the next step without further purification. HPLC purity: 82.5% (254 nm); LC-MS: m / z 358.1 (M+1); 1 H-NMR (400MHz, DMSO-d6): δ12.44(s,1H),8.11(s,1H),7.62(s,1H),7.46-7.48(d,2H),7.26-7.28 (d,2H),7.19(s,1H),7.09-7.11(d,2H),7.01(s,1H),6.90-6.92(d,2H),4.50(s,2H),2.23(s,3H).

[0323] Preparation of Formula 15A

[0324]

[0325] EDCI HCl (132g, 690mmol, 1.3 equivalents), HOBt (107g, 795mmol, 1.5 equivalents) and DIEA (103g, 795mmol, 1.5 equivalents) were added to a solution of formula 14A (190g, 530mmol, 1 equivalent) in dry DMF (1330mL) at -10 to -20°C. The mixture was stirred for 20min, and then a compound of formula 8B (109g, 640mmol, 1.2 equivalents) was added to the mixture. The temperature of the reaction mixture was raised to 20 to 25°C and stirred for 16 hours. The mixture was distributed between EtOAc (1L) and water (1L). The aqueous phase was extracted twice with EtOAc (3L). The combined organic layer was washed with water (2L), brine (2L), and dried over magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to provide 173 g of the product (Formula 15A) as a yellow solid. Yield (2 steps): 100%; HPLC purity: 97% (254 nm); LC-MS: m / z 511.1 (M+1); 1 H-NMR (400MHz, DMSO-d6): δ11.86(s,1H),8.47(d,1H),7.91(s,1H),7.45(s,1H),7.38-7.30(m,5H),7.24-7.26(m,2H ), 7.08-7.10(m,1H), 6.86-6.88(m,2H),6.62(s,1H),5.02(m,2H),4.40-4.41(m,2H), 3.71(m,3H), 3.66-3.69(m,2H);

[0326] Preparation of Formula 16A

[0327]

[0328] Anisole (25.4 g, 235 mmol) was added to a solution of Formula 15A (80 g, 156 mmol) in TFA (480 mL) at 20 to 25 °C. The mixture was stirred at 50 °C for 14 hours and then the temperature was reduced to 20 to 25 °C. The solution was concentrated under reduced pressure. The residue was dissolved in water, and the solution was adjusted to pH 8 with saturated NaHCO3 aqueous solution, EtOAc (800 ml, 10 volumes) was added to the aqueous solution and the mixture was stirred. The solid was filtered and recrystallized with EtOAc (50 volumes) to provide 38 g of the product (Formula 16A) as a white solid. Yield: 61.5%, HPLC purity: 96.9% (254 nm): HPLC chiral purity (ee) 99.9%, LC-MS m / z 391.0 (M+1); 1H-NMR (400MHz, DMSO-d6): δ11.86(s,1H),8.47(d,1H),7.91(s,1H),7.45(s, 1H),7.38-7.30(m,5H),6.62(s,1H),6.01(s,2H),5.02(m,2H),3.67(m,2H).

[0329] Preparation of Compound 118217 (BVD-523-D6)

[0330]

[0331] A mixture of formula 16A (20 g, 52.1 mmol) and acetone-d6 (80 mL) in a buffer solution (2000 mL, NaOAc: 48 g, AcOH: 68 mL, MeOH: 2000 mL) was stirred at 20 to 25 ° C for 1 hour. NaBH3(CN) (48.3 g, 768 mmol) was then added to the solution. The mixture was stirred at 55 ° C for 18 hours and then lowered to 20 to 25 ° C. Buffer solution (400 mL) and acetone-d6 (30 mL) were added. The mixture was stirred at 20 to 25 ° C for 1 hour, and then additional NaBH3(CN) (16 g) was added. The temperature of the mixture was raised to 55 ° C and stirred for another 14 hours. The temperature of the mixture was lowered to 20 to 25 ° C, and washed with a saturated NaHCO3 aqueous solution. The mixture was concentrated under reduced pressure and diluted with 2-MeTHF (1500 mL, 75 volumes). The solution was washed with a saturated NaHCO3 aqueous solution and brine. The organic solution was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, and the crude solid was recrystallized (MeOH:H2O=2.4:1, 96ml:40ml) to provide 14.14g of the final product (Formula 19) as a white solid. Yield: 63%, HPLC purity: 98.2% (254nm); HPLC chiral purity (ee): 99.9%; LC-MS: m / z 439.1 (M+1); 1 H-NMR: (400MHz, DMSO-d6): δ11.87(s,1H),8.45(d,1H),7.98(s,1H),7.44-7.29(m,6H ),6.59(s,1H),6.40-6.39(m,1H),5.10-5.04(m,2H),3.92(s,1H),3.69-3.67(m,2H).

[0332] The compound of formula 19 is further reacted with HCl to produce the HCl salt form of formula 19A. At 15 to 25 ° C, filtered anhydrous ethanol (145g, 0.26V), filtered methanol (8.1g, 0.02V) and filtered isopropanol (8.1g, 0.02V) are loaded into a 20L glass flask and stirred for 20 to 30min. Then, hydrogen chloride gas is bubbled in the mixture at 10 to 25 ° C under stirring. After 2 hours, the mixture is sampled and analyzed every 2 to 4 hours until the content of hydrogen chloride reaches ≥35% by weight. While maintaining the temperature at 15 to 25 ° C, filtered anhydrous ethanol (4292g, 9V), filtered methanol (232g, 0.5V) and filtered isopropanol (232g, 0.5V) are loaded into a separate 20L reactor through an in-line fluid filter and stirred for 20 to 30min. Then add formula 19 (580g, 1.0 equivalent). The temperature of the mixture is raised to 70 and 75°C at a rate of 15 to 25°C / hour and stirred until the solid is completely dissolved. At 70 to 75°C, seed crystals (0.58g, 0.1 wt%) are added to the mixture, and then anhydrous HCl solution (141g) is added. The mixture is maintained at 70 to 75°C for 1 to 2 hours under stirring. The temperature of the mixture is reduced to 15 to 25°C at a rate of 5 to 15°C / hour and then maintained at 15 to 25°C for 4 to 6 hours under stirring. The mixture is filtered and the filter cake is rinsed with filtered MTBE for 20 to 30min. The filter cake is dried at 40 to 50°C under nitrogen for 24 hours to provide 12.9g of product (Formula 19A) as a white solid. Yield: 84.5%, HPLC purity: 99.4% (215nm); HPLC chiral purity (ee): 100.0% (254nm); HPLC determination purity: 98.3% (215nm); chloride content: 7.2%; isotopic purity: 97.9%; LC-MS: m / z 439.2 (M+1); 1 H-NMR (400MHz, DMSO-d6): δ8.10(s,1H),7.65(s,1H),7.56(s,1H),7.46(s,1H),7. 36(m,2H),7.32(m,1H),7.10(s,1H),5.05(q,1H),3.97(s,1H),3.73-3.69(m,2H).

[0333] Example 3

[0334] Formula 21 was prepared as follows:

[0335]

[0336] Preparation of Formula 39:

[0337]

[0338] A solution of propane-2-one oxime (1.0 equiv.) in THF was added to a suspension of LiAlD4 (1.5 equiv.) in THF (16.7 V) at 50 to 55 ° C. The mixture was stirred at 60-65 ° C for 12 hours. The temperature was reduced to 0 to 10 ° C and quenched by the addition of sodium sulfate (0.5 equiv.). The mixture was stirred for 1 hour and filtered. The filter cake was rinsed with THF (5 V). The filtrate was transferred to a flask and maleic acid (1.0 equiv.) was added at 15 to 30 ° C. The mixture was stirred at 20 to 25 ° C for 2 hours and stirred for another 2 hours at a temperature of 0 to 10 ° C. The slurry was filtered and the filter cake was washed with THF (1 V). The solid was dried under nitrogen to provide 1.95 kg of the product (Formula 39) as an off-white solid. Yield: 39.0%, chemical purity: 98.2%; isotopic purity: 99%; 1 H-NMR (400MHz, D2O): δ6.22(s,2H),1.18(s,6H).

[0339] Preparation of Formula 7B:

[0340]

[0341] Formula 39 (3.0 equivalents) and K2CO3 (4.5 equivalents) are added to the suspension of formula 38 (1.0 equivalent) in DMSO (20V) at 15 to 30°C. The temperature of the mixture is raised to 75 to 85°C and stirred for 24 hours. The temperature of the mixture is reduced to 15-25°C and water (36V) is added. The product is extracted with EtOAc (6V x 3) and organic phases are combined. The organic phases combined are washed with water (10V x2) and NaCl aqueous solution (10Vx 1). The solution is concentrated to 2V under reduced pressure and normal heptane (5V) is added to the mixture. The heptane mixture is concentrated to 2V under reduced pressure and the process is repeated 2 times. (N-Heptane (IV) was added to the concentrated residue and stirred at 15 to 25°C for 4 hours. The mixture was filtered and the filter cake was dried at 20 to 30°C under nitrogen for 12 hours to produce 640 g of the product (Formula 7B) as an off-white solid. Yield: 69.0%, HPLC purity: 98.9% (215 nm); HPLC assay purity: 97.3% (215 nm); isotopic purity: 98%; 1 H-NMR (400MHz, CDCl3): δ8.01(s,1H), 6.88(s,1H), 1.22(s,6H).

[0342] Preparation of Formula 9B:

[0343]

[0344] Purified water (1V) and anhydrous sodium carbonate (1.5 equivalents) were added to a solution of formula 7B (1.0 equivalents) and formula 8A (1.1 equivalents) in ethylene glycol dimethyl ether (8V) at 20 to 30°C. The mixture was degassed with nitrogen for 30 min. Pd(OAc)2 (0.02 equivalents) and P(cy)3HBF4 (0.05 equivalents) were added to the mixture under nitrogen protection. After the addition, the mixture was evacuated and filled with nitrogen. The process was repeated 10 times. The temperature of the mixture was raised to 75 to 85°C and stirred for 4 hours. The temperature of the reaction mixture was lowered to 25-35°C and filtered. The filter cake was rinsed with THF (1.3V x 2). The filtrates were combined and concentrated to 1V under reduced pressure. MeOH (1.3 volumes) was added to the mixture at 15 to 25°C and stirred for 2 hours at 15 to 25°C. The slurry was filtered and the filter cake was rinsed with methanol (1V x 2). The solid was reslurried in a mixture of EtOAc: hexane (1:6.5, 5.6V) at 15 to 25°C for 2 hours. The slurry was filtered and the filter cake was rinsed with hexane (1V) and dried under nitrogen for 8 hours to produce 351 g of the product (Formula 9B) as a light yellow solid. Yield: 85.0%, HPLC purity: 96.5% (215nm); HPLC assay purity: 95.1% (215nm); Isotopic purity: 98%; 1 H-NMR (400MHz, CDCl3): δ8.15(s,1H),8.10(s,1H),7.93-7.95(m,2H),7.34-7.36(m,3H),6.40(s,1H),3.77(s,3H),2.44(s,3H),1.24(s,6H).

[0345] Preparation of Formula 10B:

[0346]

[0347] An aqueous solution of LiOH (5.0 eq., 7 wt%) was added to a solution of Formula 9B (1.0 eq.) in THF (5V) at 15 to 30°C. Et2NH (2.0 eq.) was then added to the mixture and the mixture was stirred at 60 to 70°C for 30 hours. The temperature of the mixture was lowered to 20 to 25°C. MTBE (5V) was added to the mixture at 15 to 25°C and stirred for 30 min. The phases were separated and the organic phase was discarded. The pH of the aqueous phase was adjusted between 1 and 2 with 6N HCl. At 15 to 25°C, an aqueous solution of sodium carbonate was added to the mixture to adjust the pH between 9 and 10 to dissolve the solid. The pH of the solution was adjusted to 6.2 with 6N HCl. The mixture was filtered and the filter cake was re-slurried in water (10V) and stirred for 2 hours. The slurry was filtered and dried at 55 to 65°C for 40 hours. The solid was slurried with MTBE (6V) at 20 to 25°C for 2 hours and filtered. The filter cake was dried to produce 138 g of the product (Formula 10B) as an off-white solid. Yield: 65.0%, HPLC purity: 98.3% (215 nm); HPLC assay purity: 89.4% (215 nm); Isotopic purity: 99%; 1 H-NMR (400MHz, DMSO-d6): δ7.97(s,1H),7.49(s,1H),7.13(s,1H),6.62(s,1H),1.13(s,6H).

[0348] Preparation of Formula 21

[0349]

[0350] HOBt (1.2 equivalents) and EDCI (1.1 equivalents) were added to a solution of formula 10B (1.0 equivalents) in DMF (10V) at -10 to -20°C. The temperature of the mixture was lowered to -20 to -30°C. Formula 8B (1.05 equivalents) and DIPEA (1.2 equivalents) were then added. The mixture was stirred at 0 to 10°C for 8 hours. The reaction mixture was diluted with ethyl acetate (9V) and water (4V). Each phase was separated, and the aqueous phase was extracted with ethyl acetate (9V x 3). The organic phases were combined and washed with water (4V x 2), 5% HOAc (7V x 2), Na2CO3 aqueous solution (7V x 2, 17 wt%) and brine (10V x 2) in sequence. Silica gel (1g / g) was added to the organic phase and stirred at 15 to 30°C for 4 hours, then filtered. The filter cake was rinsed with ethyl acetate (4.5V). The combined filtrate was concentrated to 2V under reduced pressure. MTBE (2V) was added to the mixture. The mixture was cooled to 0°C to 10°C and stirred for 1 hour. The mixture was filtered and the solid was dried to produce 181 g of the product (Formula 21) as a yellow solid. Yield: 69.0%, HPLC purity: 99.6% (215nm); HPLC chiral purity (ee): 100.0% (254nm); HPLC assay purity: 99.0% (215nm); isotopic purity: 99%; 1 H-NMR (400MHz, DMSO-d6): δ7.98(s,1H),7.45(s,1H),7.38(m,4H),7.31(m,1H),6.61(s,1H),5.08(q,1H),3.69(m,2H),1.13(s,6H).

[0351] Preparation of Formula 21A

[0352]

[0353] At 15 to 25°C, filtered anhydrous ethanol (145 g, 0.26 V), filtered methanol (8.1 g, 0.02 V) and filtered isopropanol (8.1 g, 0.02 V) were charged into a flask and stirred for 20 to 30 min. Hydrogen chloride gas was then bubbled through the mixture at 10 to 25°C under stirring. After 2 hours, the mixture was sampled and analyzed every 2 to 4 hours until the content of hydrogen chloride reached ≥ 35% by weight. While maintaining the temperature at 15 to 25°C, filtered anhydrous ethanol (4292 g, 9 V), filtered methanol (232 g, 0.5 V) and filtered isopropanol (232 g, 0.5 V) were charged into a separate 20 L reactor through an in-line fluid filter and stirred for 20 to 30 min. Formula 21 (580 g, 1.0 equivalent) was then added. The temperature of the mixture is raised to 70 and 75°C at a rate of 15 to 25°C / hour and stirred until the solid is completely dissolved. At 70 to 75°C, seed crystals (0.58g, 0.1% by weight) are added to the mixture, and then anhydrous HCl solution (141g) is added. The mixture is maintained at 70 to 75°C for 1 to 2 hours under stirring. The temperature of the mixture is reduced to 15 to 25°C at a rate of 5 to 15°C / hour and then maintained at 15 to 25°C for 4 to 6 hours under stirring. The mixture is filtered and the filter cake is rinsed with filtered MTBE for 20 to 30min. The filter cake is dried at 40 to 50°C under nitrogen for 24 hours to provide 580g of product (Formula 21A) as a white solid. Yield: 92.0%, HPLC purity: 99.9% (215nm); HPLC chiral purity (ee): 100.0% (254nm); HPLC determination purity: 99% (215nm); chloride content: 7.6%; isotopic purity: 99%; 1 H-NMR (400MHz, DMSO-d6): δ12.32(s,1H),8.78(d,1H),8.50(s,1H),8.11(s,1H),7.64(s,1H),7.57 (s,1H),7.46(s,1H),7.37(m,2H),7.31(m,1H),7.11(s,1H),5.05(q,1H),3.70(m,2H),1.22(s,6H).

[0354] Example 4

[0355] Characterization data of deuterated analogs of Uritinib

[0356] Mechanism of Action (MOA) Cellular Assay - A375 Cell Proliferation, pERK / ERK and pRSK / RSK Analysis:

[0357] Results of A375 proliferation assay:

[0358] Table 2

[0359]

[0360]

[0361] In brief, A375 cells were plated in three 96-well plates at 10,000 cells / well. The plates were incubated overnight at 37°C and allowed to recover. The cells were washed with 150 μL of DPBS and 90 μL of fresh culture medium was added to each well. The cells were then treated with a dose response of the selected compound. The compound was diluted from a stock concentration (10 mM in DMSO). Serial dilutions were prepared in DMSO, with a total of 8 different concentrations for each compound. When the compound was added, a control plate was analyzed using CellTiterGlo to set a proliferation baseline. Compound-treated cells were allowed to grow for 72 hours at 37°C / 5% CO2 and then analyzed using Cell TiterGlo according to the kit protocol.

[0362] A375 pERK / ERK dose response study:

[0363] Table 3

[0364]

[0365] In brief, A375 cells were plated at 30,000 cells / well in 2x 96-well plates, allowed to recover overnight, washed and fed with fresh medium the next day, and then treated with the dose response of the selected compound. After a determined pretreatment time with the compound at 37°C / 5% CO2, the culture medium was aspirated and the cells were lysed with cold complete MESO Scale Discovery (MSD) lysis buffer. pERK and total ERK1 / 2 levels were measured using the MESO Scale Discovery Phospho (Thr202 / Tyr204; Thr185 / Tyr187) / Total ERK1 / 2 kit. The protocol and all reagents were provided in the kit. All wells were blocked for one hour with 150 μl of blocking solution. 25 ml of cell lysate and 25 ml of lysis buffer were added to each well and incubated overnight at 4°C. After overnight incubation, the wells were washed three times with Tris wash buffer, and then 25 ml of 1X detection antibody was added to each well and incubated for one hour at room temperature with vigorous shaking. All wells were then washed three times with Tris wash buffer, and then 150 μl of 1X read buffer was added to each well and the plate was read using an MSD Sector Imager. Data were calculated as the ratio of phosphorylated ERK1 / 2 to total ERK1 / 2 in order to normalize the samples.

[0366] A375 pRSK / RSK dose response study

[0367] Table 4

[0368]

[0369] Briefly, A375 cells were plated at 30,000 cells / well in 2x 96-well plates, allowed to recover overnight, washed and fed with fresh media the next day, and then treated with dose responses of selected compounds. After a defined pretreatment with compounds at 37°C / 5% CO2, media was aspirated and cells were lysed with cold complete MSD lysis buffer. pRSK and total RSK were analyzed using CST / PathScan pRSK and total RSK ELISAS according to the respective kit protocols. All samples were analyzed according to the kit protocol, with 90% of the remaining samples in pRSK and 10% of the remaining samples in the total RSK ELISA.

[0370] Determination of the half-life of Uritinib, Formula 18, Formula 19 and Formula 21 in human liver microsomes (HLM):

[0371] Table 5

[0372]

[0373] Human microsomes from a panel of 10 donors were obtained from a commercial source. Microsomes prepared in potassium phosphate buffer were spiked with 100 mg / ml of 1 μM each, in replicates of 6, to a final concentration of 1 μM. Experiments were initiated using NADPH; controls minus NADPH (minus cofactors) were also run in parallel to examine human liver microsomal stability. After spiking the test substances, the microsomes were placed in a 37°C incubator in replicates for the following time courses: 0, 5, 10, 15, 20, 30, 45, and 60 minutes. Samples were extracted with a protein precipitation quencher consisting of ice-cold acetonitrile containing an internal standard (tolbutamide). Samples were analyzed for 100 mg / ml of 1 μM. The half-life of Uritinib, Formula 18, Formula 19 and Formula 21 was characterized by the natural log of the slope of the line from the % remaining vs time and using the formula described below.

[0374]

[0375] ke (clearance rate): the slope of ln (percent remaining) vs time (in minutes)

[0376] The formation of N-dealkyl, isopropyl hydroxy, aldehyde, pyridine N-oxide and carboxylic acid metabolites was monitored simultaneously with each parent test substance. Percent metabolite formation values ​​were calculated for N-dealkyl (M2), isopropyl hydroxy (M3), N-oxide (M6) and carboxylic acid (M7) metabolites based on the peak areas of the metabolites formed and the peak areas of the test substance at the same time point.

[0377] % formation = [(PA 代谢物 ) / (PA p0 )]x100

[0378] PA 代谢物 :Peak area ratio of metabolites at a given time point

[0379] PA p0 : Peak area ratio of the test substance at time zero

[0380] Table 5 shows that Formula 21 has a half-life in the assay that is 30% longer than uritinib, Formula 18 has a half-life that is 21% longer than uritinib, and Formula 19 has a half-life that is 7% shorter than uritinib.

[0381] Observed mean percentages of metabolites formed after incubation with human liver microsomes:

[0382] Table 6

[0383]

[0384]

[0385] Table 6 shows that in the assay, Formula 21 (D1) reduced the formation of M2 by 53%, reduced the formation of M3 by 25%, reduced the formation of M6 by 8%, and increased the formation of M7 by 26% compared to uritinib. In the assay, Formula 19 (D6) reduced the formation of M2 by 15%, reduced the formation of M3 by 100%, reduced the formation of M6 by 7%, and reduced the formation of M7 by 100% compared to uritinib. In the assay, Formula 18 reduced the formation of M2 by 69%, reduced the formation of M3 by 100%, increased the formation of M6 by 59%, and reduced the formation of M7 by 100% compared to uritinib.

[0386] Evaluation of the pharmacokinetics and metabolite formation of Example compounds of formula 18, 19 and 21 in rats:

[0387] Rats were administered uritinib, Formula 18A, 19A and 21A by oral gavage (PO) twice a day (12 hours apart, ±30 minutes) for five consecutive days (10 doses / animal). Each compound was administered to 6 rats (3 males / 3 females, N=6 rats / compound) at a dose of 12.5 mg / kg. Each compound was formulated in a 1% (w / v) carboxymethylcellulose (CMC) aqueous solution at a concentration of 1.25 mg / mL. After the second dose (afternoon) on Day 5, blood samples were collected from each rat at approximately 0.5, 1, 2, 4, 6, 8 and 12 hours after administration. The blood samples were centrifuged to obtain plasma. The concentrations of the administered compounds and selected metabolites in the plasma samples were analyzed using an established LC-MS / MS method. The lower limit of quantification for each compound was 1.00 ng / mL. Table 7 shows the rat half-life values ​​for each compound (determined by non-compartmental analysis using WinNonlin software), and Table 8 shows the area under the curve (AUC) for each dosed compound and selected metabolites from time 0 to 12 hours calculated using the linear trapezoidal rule. 0-12 ).

[0388] Table 7

[0389]

[0390]

[0391] a Percent change relative to uritinib

[0392] Table 7 shows that the average half-life of Formula 21A (D1) is 4% longer than that of uritinib, the average half-life of Formula 19A (D6) is 9% longer than that of uritinib, and the average half-life of Formula 18A (D7) is 14% longer than that of uritinib.

[0393] Table 8

[0394]

[0395]

[0396] a Percent change relative to uritinib

[0397] Evaluation of Inhibition and Induction of Cytochrome P450 Metabolizing Enzymes:

[0398] In vitro CYP inhibition studies:

[0399] This study was designed to evaluate the ability of four test substances to inhibit the major CYP enzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5) in human liver microsomes in a direct and time-dependent manner. A mixture of seven prototype CYP substrates was used for incubation to determine the potential of each test substance to inhibit the metabolism of concomitantly administered drugs. A mixed gender pool of 200 human liver microsome samples was used for this study. Incubation was performed at approximately 37°C in 200 μL of an incubation mixture (pH 7.4) containing water, potassium phosphate buffer (50 mM), MgCl2 (3 mM), EDTA (1 mM), NADPH regeneration system (NADP [1 mM], glucose 6-phosphate [5 mM], glucose 6-phosphate dehydrogenase [1 unit / mL]) and probe substrates (i.e., seven substrate mixtures) at final concentrations as shown in Table 9. The reaction was started by adding the NADPH-regenerating system and automatically terminated at about 5 minutes by adding an internal standard mixed in the stop reagent acetonitrile. The samples were centrifuged at 920×g for 10 minutes at 10°C. The supernatant fraction was analyzed by LC-MS / MS. In order to examine its ability as a time-dependent inhibitor of CYP enzymes, each test substance (at the same concentration used to evaluate direct inhibition (i.e., 0, 0.02, 0.06, 0.2, 0.6, 2, 6, 20 μM)) was preincubated with NADPH-fortified human liver microsomes at 37±2°C for about 30 minutes. The preincubation was started by adding the NADPH-regenerating system. After 30 minutes, the probe substrate incubation was started by adding the probe substrate mixture. The incubation was terminated and the samples were analyzed by LC-MS / MS. When inhibition was observed, the data was processed using LIMS using the Levenberg-Marquardt algorithm to determine the IC 50 values ​​to perform data with the following 4-parameter S-shaped-logic IC 50 Nonlinear regression fit of the equation:

[0400]

[0401] When using a percentage of the control value, set the minimum value (Min) to zero and the maximum value (Max) to 100 (or other value, as appropriate). 50 LIMS calculates the IC only if the value is within the concentration range of the inhibitor being studied. 50 Therefore, when IC 50 When the value falls outside the concentration range studied, the IC 50 Values ​​are reported as being greater than the highest concentration of the test substance evaluated.

[0402] Table 9

[0403]

[0404] In vitro CYP induction studies:

[0405] This study was designed to evaluate the ability of four test substances (BVD-523 Uritinib, Formula 18, Formula 21A and Formula 19) to induce mRNA expression of major CYP enzymes (i.e., CYP1A2, CYP2B6 and CYP3A4) in cultured human hepatocytes. Single preparations of characterized cryopreserved human hepatocytes isolated from non-transplantable human livers were treated in this study. Three wells of each culture were treated in 48-well plates with supplemented MCM (37±2°C) containing 0.1% v / v DMSO (solvent control), one of three concentrations of each test substance (1, 10 and 20 μM) or positive control CYP enzyme inducers omeprazole (50 μM), phenobarbital (1000 μM) or rifampicin (20 μM). The cultures were incubated in a humidified culture chamber (37±2°C, 95% relative humidity, 95 / 5% air / CO2). About 24 hours after treatment, the hepatocytes were lysed in a buffer RLT reagent containing β-mercaptoethanol (100:1). The culture medium was aspirated and buffer RLT was added to each well. Cell lysates were prepared by repeated aspiration and shaking. Total RNA was isolated using the RNeasy Mini Kit. RNA quality and concentration were determined by measuring the absorbance at 260 and 280 nm on a plate reader. Single-stranded cDNA was prepared from RNA using RT Master Mix. RTMaster Mix contained 10X RT buffer, 25X deoxyNTP, 10X random primers, RNase inhibitor (20U / μL), MultiScribe reverse transcriptase (50U / μL) and RNase-free water. RT Master Mix was added to each RNA sample to complete the components of the reaction. A template-free control (NTC) was included in the analysis. For the NTC reaction, RNase-free water was added instead of the RNA sample. The prepared cDNA samples were stored at -20±5°C and then analyzed by qRT-PCR. Each PCR was performed in quadruplicate. Prepare primer mixes for each gene expression assay. A typical primer mix contains TaqMan FastAdvanced Master Mix (1X), gene expression assay (1X, 900nM forward primer and reverse primer), and RNase-free water. Prepare the reaction mixture by adding the primer mix to the cDNA. A certain percentage of samples (not less than 10%) includes NAC (no amplification control) samples. NAC samples are RNA samples that have not been reverse transcribed and are used to indicate that mRNA (not genomic DNA) is the source of the fluorescent signal for PCR. Analyze the reaction on a PCR sequence detection system. By ΔΔC tMethod determines the relative amount of target cDNA relative to control cDNA (GAPDH). Relative quantification measures the change in mRNA expression in a test sample relative to the mRNA expression in a control sample (e.g., DMSO). This method assumes that the efficiency of target amplification and the efficiency of endogenous control amplification are roughly equal.

[0406] Treatment with up to 20 μM of uritinib, Formula 18, Formula 21A, and Formula 19 resulted in increases in CYP1A2 mRNA expression of up to 6.63-fold, 7.56-fold, 8.51-fold, and 12.1-fold changes, respectively. Notably, the maximum fold change was observed at 10 μM for uritinib, Formula 21A, and Formula 19, which then decreased to 6.42-fold, 4.00-fold, and 9.52-fold changes, respectively. Treatment with up to 20 μM of uritinib, Formula 18, Formula 21A, and Formula 19 resulted in concentration-dependent increases in CYP2B6 mRNA expression of up to 2.43-fold, 2.54-fold, 2.22-fold, and 2.44-fold changes, respectively. Treatment with up to 20 μM of uritinib, Formula 18, Formula 21A, and Formula 19 resulted in concentration-dependent increases in CYP3A4 mRNA expression, up to 8.26-fold, 7.06-fold, 6.86-fold, and 11.7-fold changes, respectively. The results are summarized in Table 10 below.

[0407] Table 10

[0408]

[0409] Referenced documents:

[0410] Kempf, D. et al. Antimicrobial Agents and Chemotherapy, 41(3), p. 654 (1997);

[0411] Wang, L. et al. Clinical Pharmacology and Therapeutics, 56 (6 Pt. 1), p. 659 (1994);

[0412] Blake, M. et al. J. Pharm. Sci., 64, p. 367 (1975);

[0413] Foster, A. Adv. Drug Res., 14, p. 1 (1985);

[0414] Kushner, D. et al. Can. J. Physiol. Pharmacol., p. 79 (1999);

[0415] Fisher M. et al., Curt. Opin. Drug Discov. Devel., 9, p. 101 (2006);

[0416] Fukuto, J. et al., J. Med. Chem., 34(9), p. 2871 (1991);

[0417] Harbeson, L. and Tung, R., Medchem News, 2, p. 8 (2014);

[0418] Scott L. Harbeson and Roger D. Tung, Deuterium in Drug Discovery and Development, 46 annual report in medicinal chemistry, 403 - 417 (2011);

[0419] Miwa, G., Lu, A., Kinetic Isotope Effects and `Metabolic Switching` in Cytochrome P450 - Catalyzed Reactions, 7 Bioessays, 215 - 19 (1987);

[0420] Allan B. Foster, “Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design”, Advances in Drug Research, (14), 1 - 40 (1985)

[0421] Shao et al., “Derivatives of Tramadol for Increased Duration of Effect”, Bioorganic and Medicinal Chemistry Letters, (16), 691 - 94 (2006);

[0422] Bin Yu et al., “Pharmacokinetics and metabolism of ulixertinib in rat by liquid chromatography combined with electrospray ionization tandem massspectrometry,” Separation Science, Vol. 43, No. 7, pp. 1275-1283 (2020);

[0423] "The Organic Chemistry of Drug Design and Drug Interaction" Richard Silverman, published by Academic Press (1992);

[0424] Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980.

[0425] All documents cited in this application are hereby incorporated by reference as if fully incorporated herein.

[0426] Although exemplary embodiments of the present invention have been described herein, it should be understood that the present invention is not limited to those described, and that various other changes or modifications may be made by one of ordinary skill in the art without departing from the scope or spirit of the present invention.

Claims

1. Compound of formula 1: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen, deuterium and C 1-4 aliphatic, and wherein: R1 is hydrogen, C 1-3 aliphatic, fluorine or chlorine; A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

2. Compounds of formula 2A: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 Aliphatic; R 2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; m is 0, 1 or 2; and A, B, C, D, E and F are independently selected from carbon or nitrogen.

3. Compounds of formula 2B: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 aliphatic; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

4. Compounds of formula 3A: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

5. Compounds of formula 3B: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

6. Compounds of formula 3C: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2, wherein each R is independently hydrogen or C 1-4 aliphatic; and m is 0, 1 or 2.

7. Compounds of formula 4: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen and deuterium or C 1-4 Aliphatic.

8. The compound of claim 1, wherein the compound is selected from: 4-(5-chloro-2-((propan-2-yl-d7)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,1,1,3,3,3-d6)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,1,1,2,3-d5)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,1,1,2-d4)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,1,2-d3)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,2-d2)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-2-d1)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, and pharmaceutically acceptable salts, solvates and prodrugs thereof.

9. The compound of any one of claims 1-8, which is an enantiomerically pure 1S- or 1R-uritinib analog.

10. The compound of any one of claims 1-8, wherein any atom not designated as deuterium is present in its natural isotopic abundance.

11. The compound of any one of claims 1-8, wherein each of the positions having deuterium has a deuterium enrichment of at least 1%.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier, excipient or vehicle.

13. A method of treating a disease, disorder or condition, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 12, wherein the disease, disorder or condition comprises one or more of cancer, autoimmune disorders, neurodegenerative disorders and neurological disorders, schizophrenia, bone-related disorders, liver disease and cardiac disorders.

14. The method of claim 13, wherein after administration of a therapeutically effective amount of the compound or pharmaceutical composition, the compound is enriched by at least one polymorphically expressed cytochrome P per dosage unit compared to the corresponding non-isotopically enriched compound. 450 The metabolism of the xenomorph is reduced.

15. The method of claim 14, wherein the cytochrome P 450 The isoform is selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6 and CYP2E1.

16. The method of claim 12, wherein the compound has an increased activity per dosage unit for at least one cytochrome P compared to the non-isotopically enriched compound. 450 The inhibition is reduced.

17. The method of claim 16, wherein the cytochrome P 450 Selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 , CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, C YP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46 and CYP51.

18. A compound according to claim 1 or a pharmaceutical composition according to claim 12 for use as a medicament.

19. The compound of claim 1 or the pharmaceutical composition of claim 12 for use in the preparation of a medicament for preventing or treating a disorder ameliorated by inhibition of ERK protein kinase.

20. The compound of claims 1 to 8 or the pharmaceutical composition of claim 12, wherein each position having deuterium has at least 1% deuterium incorporation.

21. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein at least one of X1, X2, X3, X4, X5, X6 and X7 is deuterium.

22. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein at least 2 of X1, X2, X3, X4, X5, X6 and X7 are deuterium.

23. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein at least three of X1, X2, X3, X4, X5, X6 and X7 are deuterium.

24. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein at least 4 of X1, X2, X3, X4, X5, X6 and X7 are deuterium.

25. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein at least 5 of X1, X2, X3, X4, X5, X6 and X7 are deuterium.

26. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein at least 6 of X1, X2, X3, X4, X5, X6 and X7 are deuterium.

27. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein each of X1, X2, X3, X4, X5, X6 and X7 is deuterium.

28. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein each of X2, X3, X4, X5, X6 and X7 is deuterium, and X 1 It's hydrogen.

29. The compound of claims 1 to 3 or the pharmaceutical composition of claim 12, wherein each of X2, X3, X4, X5, X6 and X7 is hydrogen, and X 1 It's deuterium.

30. A method for inhibiting ERK1 / 2 in a cell, the method comprising the step of contacting the cell with a compound according to claims 1 to 8 or a pharmaceutical composition according to claim 12.

31. The compound of claims 1 to 8 or the pharmaceutical composition of claim 12, wherein the compound or pharmaceutical composition effectively reduces at least one polymorphically expressed cytochrome P compared to the corresponding non-isotopically enriched compound. 450 Metabolism of the compound or pharmaceutical composition by the isoform.

32. The compound or pharmaceutical composition of claim 31, wherein the cytochrome P 450 Isoforms selected from CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYP5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F 2. CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46 and CYP51.

33. The compound or pharmaceutical composition of claim 32, wherein the cytochrome P 450 The isoform is selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6 and CYP2E1.

34. The compound of claims 1 to 8 or the pharmaceutical composition of claim 12, which, when administered to a subject in need thereof, results in a reduction in metabolism of the compound or pharmaceutical composition compared to the corresponding non-deuterated form of the compound or pharmaceutical composition, the reduction being at least greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, greater than about 50%, greater than about 55%, or greater than about 60% compared to the non-isotopically enriched compound.

35. A method for synthesizing a deuterated compound according to formula 1: The method comprises the following steps: (i) making a compound of formula 5: Reaction with the compound of formula 6: To produce a compound of formula 7: (ii) reacting a compound of formula 7 with a compound of formula 8: To produce a compound of formula 9: (iii) reacting the compound of formula 9 with LiOH to produce a compound of formula 10: (iv) reacting a compound of formula 10 with a compound of formula 11: To produce a compound of formula 1: wherein each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen, deuterium and C 1-4 aliphatic, and wherein: R1 is hydrogen, C 1-3 aliphatic, fluorine or chlorine; A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2; wherein each R is independently hydrogen or C 1-4 aliphatic; m is 0, 1, or 2, PG is a protecting group; and L1 and L2 are independently selected leaving groups.

36. A method for synthesizing a deuterated compound according to formula 1: The method comprises the following steps: (i) making a compound of formula 12: Reaction with the compound of formula 8: To produce a compound of formula 13: (ii) reacting a compound of formula 13 with LiOH to produce a compound of formula 14: (iii) reacting a compound of formula 14 with Reaction to produce a compound of formula 15: (iv) deprotecting the compound of formula 15 to produce a compound of formula 16: (v) reacting a compound of Formula 16 with a compound of Formula 17: To produce a compound of formula 1: wherein each of X1, X2, X3, X4, X5, X6 and X7 is independently selected from hydrogen, deuterium and C 1-4 aliphatic, and wherein: R1 is hydrogen, C 1-3 aliphatic, fluorine or chlorine; A is an optionally substituted group selected from phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R or N(R)2; wherein each R is independently selected from hydrogen or C1'4 aliphatic; m is 0, 1, or 2, PG is a protecting group; and L2 is a leaving group.

37. A method for synthesizing deuterated uritinib of formula 18 or a pharmaceutically acceptable salt thereof: The method comprises the following steps: (i) making a compound of formula 7A: Reaction with a compound of formula 8A: To provide a compound of Formula 9A: (ii) reacting the compound of formula 9A with LiOH to produce a compound of formula 10A: and (iii) reacting a compound of formula 10A with a compound of formula 8B: To produce a compound of formula 18:

38. The method of claim 31, further comprising the step of reacting Formula 18 with HCl to produce a compound of Formula 18A:

39. A method for synthesizing deuterated uritinib of formula 19 or a pharmaceutically acceptable salt thereof: The method comprises the following steps: (i) making a compound of formula 12A: Reaction with a compound of formula 8A: To produce a compound of formula 13A: (ii) reacting a compound of formula 13A with LiOH to produce a compound of formula 14A: (iii) reacting a compound of formula 14A with a compound of formula 8B: To produce a compound of formula 15A: (iv) reacting a compound of Formula 15A with TFA to produce a compound of Formula 16A: and (v) treating a compound of formula 16A with Reaction to produce a compound of formula 19:

40. The method of claim 39, further comprising the step of reacting Formula 19 with HCl to produce a compound of Formula 19A 41. A method for synthesizing deuterated uritinib of formula 21 or a pharmaceutically acceptable salt thereof: The method comprises the following steps: (i) making a compound of formula 7B: Reaction with a compound of formula 8A: To produce a compound of formula 9B: (ii) reacting the compound of formula 9B with LiOH to produce a compound of formula 10B: and (iii) reacting a compound of formula 10B with a compound of formula 8B: To produce a compound of formula 21:

42. A method for synthesizing deuterated uritinib of formula 21A, the method comprising treating a compound of formula 21: Steps for reaction with HCl to produce a compound of formula 21A:

43. A compound selected from the group consisting of: and pharmaceutically acceptable salts, solvates and prodrugs thereof.

44. A kit for treating or ameliorating the effects of a disease in a subject, the kit comprising a compound according to claims 1-8 or a pharmaceutical composition according to claim 12 packaged together with instructions for its use.

45. The kit of claim 44, wherein the compound or pharmaceutical composition is effective in reducing at least one polymorphically expressed cytochrome P compared to the corresponding non-isotopically enriched compound. 450 Metabolism of the compound or pharmaceutical composition by the isoform.

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