Deuterated analogs of pyrrole inhibitors of ERK, their synthesis and intermediates

Abstract

The present disclosure provides, inter alia, deuterated analogs of ulixertinib and their pharmacologic acceptable salts, which are effective 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 containing such deuterated analog compounds and pharmaceutical compositions are also provided.In some aspects, the present disclosure also provides compositions comprising the compounds disclosed herein, and the use of such compounds in methods for treating or reducing the severity of various disorders, including proliferative disorders, such as cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 323,221, filed March 24, 2022, which is incorporated by reference herein in its entirety. [Background technology]

[0002] background The absorption, distribution, metabolism and excretion (ADME) properties of a drug are very important characteristics that can mean the difference between a safe / effective drug and clinical and commercial failure. Although recent advances in drug formulation technology (and drug conjugates or prodrugs) have offered some ability to improve ADME properties in limited cases, underlying ADME problems remain the major cause of drug failure in clinical trials. A common ADME problem with currently approved drugs and drug candidates is rapid metabolism. Drug candidates that are otherwise highly effective in vitro and in preclinical trials may be metabolized and cleared from the body too rapidly to provide little or no pharmacological effect. Strategies to overcome rapid metabolism include administering at very high levels or administering very frequently, but both of these strategies have significant drawbacks, including increased side effects of the drug, increased exposure to toxic metabolites, and reduced patient compliance with dosing due to frequency.

[0003] In some cases, metabolic inhibitors have been used to improve the characteristics of certain 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 is not widely used because it may result in unnecessary severe side effects and undesirable drug-drug interactions. Optimization of drug structure usually involves an iterative process of structural modifications to improve biological activity and / or metabolic properties. However, a better metabolic profile often comes at the expense of biological potency and efficacy, since significant modifications of the desired pharmacophore structure are required to stop or slow down the biological degradation process.

[0004] One strategy that may improve the metabolic profile of a drug without substantially altering its biological potency and efficacy is to replace one or more hydrogen atoms with deuterium to form the cytochrome P 450 The aim of this study was to slow down mediated metabolism. Cytochrome P 450Enzymes are a family of enzymes that can catalyze the oxidative and reductive biotransformation of most drugs, and are the main cause of variation in drug pharmacokinetics and patient response to treatment. Deuterium is an isotope of hydrogen that contains an additional neutron in its nucleus, and is safe, stable, and non-radioactive. Due to the increased mass of deuterium compared to hydrogen, the bond between carbon and deuterium requires more energy to break compared to the bond between hydrogen and carbon, which can lead to a slower metabolic reaction rate. In particular, the activation energy required to reach the transition state for bond breakage is greater for carbon-deuterium bonds compared to carbon-hydrogen bonds, and therefore the reaction rate is slower. The slower metabolic reaction rate can favorably affect the ADME properties of molecules, resulting in improved efficacy, safety, and tolerability. The other physical characteristics of deuterium are essentially identical to hydrogen, and it can be predicted that there will be no biologically relevant effects on molecules due to deuterium substitution.

[0005] A small number of drugs have been tested that use deuterium substitution to improve metabolism (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 substitution for hydrogen on metabolic rate has proven unpredictable and variable. In some cases, deuterated compounds have reduced metabolic clearance in vivo, in other cases have not altered metabolic clearance, and in still other cases have unexpectedly increased metabolic clearance. This unpredictability of ADME poses a significant challenge for deuterium substitution as a strategic drug design modification to reduce metabolic rate (see Foster and Fisher, supra).

[0006] Even when the site and location of metabolism are known, deuterium substitution has unpredictable effects on metabolic rate. Only by preparation and testing of a specific deuterium-substituted drug (candidate) can the extent of 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 of potential metabolism, and the profile of metabolic sites is unique to each drug molecule. Thus, deuterium substitution requires a new study for each drug candidate for metabolic effects. See Harbeson, L. and Tung. R. Medchem News, 2, p. 8 (2014) and references therein. There are several examples of drug candidates where deuterium substitution for hydrogen resulted in enhanced metabolic rate and / or metabolic switching, or where there was no change in the metabolic profile of the molecule in vivo even after metabolism slowed down. Harbeson et al. showed that selective deuteration of paroxetine at predicted metabolically unstable positions did indeed produce analogs that demonstrated 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)). Furthermore, Miwa reported that deuteration of metabolically labile sites could result in enhancement (or switching) of alternative metabolic pathways, but the results were inconclusive (Miwa. G., Lu, A., Kinetic Isotope Effects and `Metabolic Switching` in Cytochrome P450-Catalyzed Reactions, 7 Bioassays, 215-19 (1987)).For example, phentermine was deuterated to reduce its metabolic rate, but no change was observed upon replacement of the N,N-dimethyl hydrogen with deuterium (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 did not increase the duration of effect (Shao et. al., “Derivatives of Tramadol for Increased Duration of Effect”, Bioorganic and Medicinal Chemistry Letters, (16), 691-94 (2006)). Urixertinib (BVD-523), originally disclosed by Martinez-Botella et al. in U.S. Pat. No. 7,354,939 (incorporated by reference in its entirety), has been shown to be a potent inhibitor of, for example, ERK1 / 2 and a promising therapeutic agent for the treatment of cancer and other diseases. However, when administered in vivo, ulixertinib can be metabolized to form at least six metabolites, some of which may be undesirable, and are also easily removed. (See Bin Yu et al., “Pharmacokinetics and metabolism of ulixertinib in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry,” Separation Science, vol. 43, issue 7, pages 1275-1283 (2020).) Thus, there is a need for analogs of ulixertinib that reduce or slow the formation of metabolites and reduce systemic and pre-systemic clearance. The present disclosure is directed to meeting these and other needs.

Prior technical literature

Non-licensed literature

[0007] [Non-licensed document 1] Kempf, D. et al. Antimicrobial Agents and Chemotherapy, 41(3), p. 654 (1997)

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed Document 8

Non-licensed literature 9

[0008] Disclosure Summary According to some aspects, the present disclosure provides novel compounds that are ulixertinib derivatives and pharma- ceutically acceptable salts thereof that are effective as inhibitors of ERK protein kinase. In some embodiments, these compounds have the general formula 1: [ka] (including pharma- ceutically acceptable salts, solvates, and prodrugs thereof), wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently hydrogen and deuterium or C 1~4 aliphatic, wherein each of rings A, R1, R2, and m are as defined as disclosed herein.

[0009] In some aspects, the disclosure also provides compositions comprising the compounds disclosed herein, and uses of such compounds in methods for treating or lessening the severity of various disorders, including proliferative disorders, e.g., cancer.

[0010] In some embodiments, the selective replacement of hydrogen atoms with deuterium in the compounds disclosed herein, while retaining the physicochemical properties and pharmacological profile of the parent compound, positively affects its metabolic fate by reducing or slowing the formation of undesired metabolites, lowering the systemic clearance of the compound, thus extending its half-life, and reducing metabolism prior to the systemic circulation, thereby providing the unique benefit of increasing the bioavailability of the unmetabolized compound, which in principle can improve the safety, efficacy, and / or tolerability of the compound. Furthermore, in some embodiments, deuterium substitution in the compounds disclosed herein also reduces the inhibition and / or induction of at least one cytochrome P450 metabolic enzyme compared to non-isotopically enriched compounds, thereby resulting in a lower risk of drug-drug interactions.

[0011] According to some embodiments, the present disclosure provides a compound of formula 1: [ka] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently hydrogen, deuterium, or C 1~4 aliphatic, R1 is selected from the group consisting of hydrogen, C 1~3 aliphatic, fluoro, or chloro; 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; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or N(R)2; each R is independently hydrogen or C; 1~4 aliphatic and m is 0, 1, or 2.

[0012] According to some embodiments, the present disclosure provides a compound of the formula: [ka] Compound

[0013] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently hydrogen and deuterium or C 1~4 aliphatic, R 2 are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SOR, -C(O)R, -COR, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or N(R)2, where each R is independently hydrogen or 1~4aliphatic, m is 0, 1, or 2, and A, B, C, D, E, and F are independently selected from carbon or nitrogen.

[0014] According to some embodiments, the present disclosure provides a compound of formula [ka]

[0015] [ka] or

[0016] [ka] Compounds conforming to any of the following:

[0017] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R)2, -NR(O)R, -NR(O)N(R)2, -NRSO2R, or N(R)2, and each R is independently hydrogen or C 1~4 aliphatic and m is 0, 1, or 2.

[0018] According to some embodiments, the present disclosure provides a compound represented by formula 4: [ka] Compounds according to

[0019] or a pharma- ceutically acceptable salt, solvate, or prodrug thereof, wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently hydrogen and deuterium or C 1~4 aliphatic].

[0020] In some embodiments, the compounds disclosed herein are

[0021] 4-(5-chloro-2-((propan-2-yl-d7)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0022] 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,

[0023] 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,

[0024] 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,

[0025] 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,

[0026] 4-(5-chloro-2-((propan-2-yl-1,2-d2)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide,

[0027] 4-(5-chloro-2-((propan-2-yl-2-d1)amino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, and pharma- ceutically acceptable salts, solvates, and prodrugs thereof.

[0028] In some embodiments, the compound is a substantially pure enantiomer of an S- or R-ulixertinib analog. In some embodiments, the compound is a substantially pure enantiomer of a 1S-ulixertinib analog. In some embodiments, the compound is a substantially pure enantiomer of a 1R-ulixertinib analog. In some embodiments, the compound is an enantiomeric mixture of an S- or R-ulixertinib analog. In some embodiments, the compound is predominantly (i.e., greater than 50%) an S-ulixertinib analog. In some embodiments, the compound is predominantly (i.e., greater than 50%) an R-ulixertinib analog. In some embodiments, the compound is an enantiomeric mixture of equal amounts of S- and R-ulixertinib analogs.

[0029] In some embodiments, any atom not designated as deuterium is present at its natural isotopic abundance, hi some embodiments, each of said deuterium-bearing positions has a deuterium enrichment of at least 1%.

[0030] According to some aspects, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable carrier, excipient, or vehicle.

[0031] According to some aspects, the present disclosure provides a method of treating a disease, disorder, or condition, comprising administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof, wherein the disease, disorder, or condition comprises one or more of cancer, autoimmune disorder, neurodegenerative and neurological disorder, schizophrenia, bone-related disorder, liver disease, and cardiac disorder. In some embodiments, after administration of a therapeutically effective amount of the compound, the amount of at least one polymorphically expressed cytochrome P is increased per dosage unit compared to the corresponding non-isotopically enriched compound. 450 There is a reduced rate of metabolism of the compound by the isoform. In some embodiments, cytochrome P 450The isoforms are selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6, and CYP2E1. In some embodiments, the compound has at least one cytochrome P per dosage unit compared to a non-isotopically enriched compound. 450 In some embodiments, the cytochrome P 450 are: CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP 2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, Selected from the group consisting of 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.

[0032] According to some aspects, the present disclosure provides a compound or pharmaceutical composition disclosed herein for use as a medicament. In some embodiments, the medicament is for the prevention or treatment of a disorder that is ameliorated by the inhibition of ERK protein kinase.

[0033] According to some aspects, the compound or pharmaceutical composition having deuterium disclosed herein has a deuterium incorporation rate of at least 1%. In some embodiments, at least one of X1, X2, X3, X4, X5, X6, and X7 is deuterium. In some embodiments, at least two of X1, X2, X3, X4, X5, X6, and X7 are deuterium. In some embodiments, at least three of X1, X2, X3, X4, X5, X6, and X7 are deuterium. In some embodiments, at least four of X1, X2, X3, X4, X5, X6, and X7 are deuterium. In some embodiments, at least five of X1, X2, X3, X4, X5, X6, and X7 are deuterium. In some embodiments, at least six of X1, X2, X3, X4, X5, X6, and X7 are deuterium. In some embodiments, each of X1, X2, X3, X4, X5, X6, and X7 is deuterium. In some embodiments, each of X2, X3, X4, X5, X6, and X7 is deuterium, and X1 is hydrogen. In some embodiments, each of X2, X3, X4, X5, X6, and X7 is hydrogen, and X1 is deuterium.

[0034] According to some aspects, the disclosure provides a method of inhibiting ERK1 / 2 in a cell, comprising contacting the cell with a compound or pharmaceutical composition disclosed herein.

[0035] In some embodiments, the compound or pharmaceutical composition has an increased activity against at least one polymorphically expressed cytochrome P compared to a corresponding non-isotopically enriched compound. 450 In some embodiments, the cytochrome P isoform is effective in decreasing the metabolism of the compound. 450The isoforms are CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4 F3, 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. 450 The isoform is selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6, and CYP2E1. In some 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 some embodiments, the compound or pharmaceutical composition comprises at least one polymorphically expressed cytochrome P. 450 It is effective to reduce metabolism of the compound in human cells by an isoform by more than about 10%, more than about 20%, more than about 30%, more than about 35%, more than about 40%, more than about 50%, more than about 55%, or more than about 60% as compared to the corresponding non-isotopically enriched compound.

[0036] According to some aspects, the present disclosure provides a compound according to formula I:

[0037] [ka] A method for synthesizing a deuterated compound according to

[0038] (i) A compound of formula 5:

[0039] [ka]

[0040] with a compound of formula 6:

[0041] [ka]

[0042] to produce a compound of formula 7:

[0043] [ka] generating

[0044] (ii) reacting a compound of formula 7 with a compound of formula 8:

[0045] [ka]

[0046] to produce a compound of formula 9:

[0047] [ka] generating

[0048] (iii) reacting a compound of formula 9 with LiOH to give a compound of formula 10:

[0049] [ka] generating

[0050] (iv) reacting a compound of formula 10 with a compound of formula 11:

[0051] [ka]

[0052] to produce a compound of formula 1:

[0053] [ka] and generating

[0054] [In the formula, each of X1, X2, X3, X4, X5, X6, and X7 is independently hydrogen, deuterium, or C 1~4 aliphatic,

[0055] 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 are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SOR, -C(O)R, -COR, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or N(R)2, where each R is independently hydrogen or 1~4 It is aliphatic,

[0056] m is 0, 1, or 2; PG is a protecting group; and L1 and L2 are independently selected leaving groups. to provide.

[0057] According to some embodiments, the present disclosure provides a compound represented by formula 1:

[0058] [ka] A method for synthesizing a deuterated compound according to

[0059] (i) A compound of formula 12:

[0060] [ka]

[0061] with a compound of formula 8:

[0062] [ka]

[0063] to produce a compound of formula 13:

[0064] [ka] generating a

[0065] (ii) reacting a compound of formula 13 with LiOH to give a compound of formula 14:

[0066] [ka] generating a

[0067] (iii) reacting a compound of formula 14 with [ka] to produce a compound of formula 15:

[0068] [ka] generating a

[0069] (iv) deprotecting the compound of formula 15 to give a compound of formula 16:

[0070] [ka] generating a

[0071] (v) reacting a compound of formula 16 with a compound of formula 17:

[0072] [ka]

[0073] to produce a compound of formula 1:

[0074] [ka] and generating

[0075] [In the formula, each of X1, X2, X3, X4, X5, X6, and X7 is independently hydrogen, deuterium, or C 1~4 aliphatic,

[0076] 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; R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or N(R)2; 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. to provide.

[0077] According to some embodiments, the above general process can be used to make any of formulas 18, 19, or 21 disclosed herein.

[0078] According to some aspects, the present disclosure provides a compound represented by formula 18:

[0079] [ka]

[0080] or a pharma- ceutically acceptable salt thereof, comprising:

[0081] (i) A compound of formula 7A:

[0082] [ka]

[0083] with a compound of formula 8A:

[0084] [ka]

[0085] to produce a compound of formula 9A:

[0086] [ka] generating

[0087] (ii) reacting a compound of formula 9A with LiOH to give a compound of formula 10A:

[0088] [ka]

[0089] generating

[0090] (iii) reacting a compound of formula 10A with a compound of formula 8B:

[0091] [ka]

[0092] to produce a compound of formula 18:

[0093] [ka] and generating a

[0094] According to some embodiments, the present disclosure provides a method of synthesizing an HCl salt form of a deuterated ulixertinib analog, comprising:

[0095] [ka]

[0096] with HCl to give a compound of formula 18A:

[0097] [ka] The method includes generating a

[0098] According to some embodiments, the present disclosure provides a deuterated ulixertinib of formula 19, or a pharma- ceutically acceptable salt thereof:

[0099] [ka]

[0100] A method for synthesizing

[0101] (i) A compound of formula 12A:

[0102] [ka]

[0103] with a compound of formula 8A:

[0104] [ka]

[0105] to produce a compound of formula 13A:

[0106] [ka] generating

[0107] (ii) reacting a compound of formula 13A with LiOH to give a compound of formula 14A:

[0108] [ka] generating

[0109] (iii) reacting a compound of formula 14A with

[0110] Compound of formula 8B:

[0111] [ka]

[0112] to produce a compound of formula 15A:

[0113] [ka] generating

[0114] (iv) reacting a compound of formula 15A with TFA to give a compound of formula 16A:

[0115] [ka] generating

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

[0117] [ka] and generating a

[0118] According to some embodiments, the present disclosure provides a method of synthesizing an HCl salt form of a deuterated ulixertinib analog, comprising:

[0119] [ka]

[0120] with HCl to give a compound of formula 19A:

[0121] [ka] The method includes generating a

[0122] According to some embodiments, the present disclosure provides a deuterated ulixertinib of formula 21, or a pharma- ceutically acceptable salt thereof:

[0123] [ka]

[0124] A method for synthesizing

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

[0126] [ka]

[0127] with a compound of formula 8A:

[0128] [ka]

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

[0130] [ka] generating a

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

[0132] [ka] generating a

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

[0134] [ka]

[0135] to produce a compound of formula 21:

[0136] [ka] and generating a

[0137] According to some embodiments, the present disclosure provides a method of synthesizing a deuterated ulixertinib analog, comprising:

[0138] [ka]

[0139] with HCl to give a compound of formula 21A:

[0140] [ka] The method includes the step of generating:

[0141] According to some aspects, the present disclosure provides a method for producing a method for treating a cancer cell comprising:

[0142] [ka]

[0143] [ka]

[0144] [ka]

[0145] [ka]

[0146] [ka]

[0147] [ka]

[0148] [ka]

[0149] [ka]

[0150] [ka]

[0151]

change

[0152]

change

[0153]

change

[0154]

change

[0155]

change

[0156]

change

[0157]

change

[0158]

change

[0159]

change

[0160]

change

[0161]

change

[0162] [ka]

[0163] [ka]

[0164] and pharma- ceutically acceptable salts, solvates, and prodrugs thereof.

[0165] According to some aspects, the present disclosure provides a method for producing a method for treating a cancer cell comprising: [ka] The present invention provides a compound selected from the group consisting of:

[0166] In some aspects, the present disclosure provides a kit for treating or ameliorating the effects of a disease in a subject, comprising a compound or pharmaceutical composition disclosed herein packaged together with instructions for use thereof. In some embodiments, the compound or pharmaceutical composition in the kit is capable of inhibiting at least one polymorphically expressed cytochrome P, as compared to a corresponding non-isotopically enriched compound. 450 It is effective to reduce the metabolism of a compound or pharmaceutical composition by an isoform. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0167] Detailed Description According to some aspects, the present disclosure provides deuterated analogs of ulixertinib of formula I, solvates, prodrugs, and pharma- ceutically acceptable salts thereof, as well as methods for their preparation and use, and pharmaceutical compositions thereof.

[0168] In some embodiments, the deuterated analog of ulixertinib disclosed herein has Formula 1: [ka] (including pharma- ceutically acceptable salts, solvates, and prodrugs thereof) represented by the general structure found in 1~4 aliphatic, and each of rings A, R, R, and m is as defined herein.

[0169] R1 is hydrogen, C 1~3 aliphatic, fluoro, or chloro;

[0170] Ring A is an optionally substituted group selected from a 5-6 membered monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from phenyl, 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;

[0171] R2 is independently -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or N(R);

[0172] m is 0, 1, or 2.

[0173] According to some embodiments, the compounds include those generally described above, further illustrated by classes, subclasses, and species disclosed herein. definition

[0174] The following definitions apply unless otherwise specified: As used herein, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference herein.

[0175] As used herein, the term "prodrug" refers to a derivative of a parent drug molecule that must be transformed in the body to release the active drug and has improved physical and / or delivery properties than the parent drug molecule. Prodrugs are designed to enhance the pharmaceutical and / or pharmacokinetic-based properties associated with the parent drug molecule. The advantage of a prodrug is that it may have enhanced physical properties, such as water solubility for parenteral administration at physiological pH, or may enhance absorption from the digestive tract, or enhance the stability of the drug for long-term storage, compared to the parent drug. The use of esters as a class of prodrugs for drugs containing carboxyl or hydroxyl functional groups is known in the art, for example, as described in "The Organic Chemistry of Drug Design and Drug Interaction" Richard Silverman (1992), published by Academic Press.

[0176] 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 a solvent for the purposes of the present invention does not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol, and acetic acid. In general, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. In general, the solvent used is water.

[0177] As described herein, the compounds disclosed herein may be optionally substituted with one or more substituents, for example, as generally shown above or as exemplified by the specific classes, subclasses, and species disclosed herein. It will be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen radical in a given structure with the radical of a specific substituent. Unless otherwise specified, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specific group, the substituents can be the same or different at each position.

[0178] The combination of substituents envisioned by this disclosure is preferably a combination that results in the formation of a stable or chemically feasible compound.The term "stable" as used herein refers to a compound that is substantially unchanged when subjected to conditions that allow their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.In some embodiments, a stable or chemically feasible compound is a compound that is substantially unchanged when maintained at or below 40°C for at least one week in the absence of moisture or other conditions of high chemical reactivity.

[0179] The term "aliphatic" or "aliphatic group," as used herein, refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"), and has a single point of attachment to the rest of the molecule. In certain embodiments, an aliphatic group contains 1-6 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has 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.

[0180] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0181] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I.

[0182] The term "aryl" used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic ring systems in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members, having a total of 5 to 14 ring members. The term "aryl" may be used interchangeably with the term "aryl ring."

[0183] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the invention are within the scope of the disclosure. Unless otherwise stated, all tautomers of the compounds are within the scope of the disclosure. In addition, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0184] It will be recognized that in synthesized compounds, there will be some natural variation in isotopic abundance depending on the origin of the chemical materials used in synthesis. Thus, preparations of compounds disclosed herein will inherently contain small amounts of deuterated isotopologues. The term "isotopologue" refers to a species that differs from a specific compound disclosed herein only in its isotopic composition. The concentration of naturally abundant stable hydrogen and carbon isotopes is small and insignificant compared to the stable isotopic substitution degree of compounds disclosed herein, despite this variation. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0185] In the compounds disclosed herein, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that 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. Also, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", the position is understood to have deuterium at an abundance at least 66 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 1% deuterium incorporation).

[0186] The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. In some embodiments, the compounds disclosed herein have an isotopic enrichment factor of at least 66 (1% incorporation per 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 6000 (80% deuterium incorporation), at least 7000 (90% deuterium incorporation), at least 8000 (100% deuterium incorporation), at least 9000 (120% deuterium incorporation), at least 10000 (140% deuterium incorporation), at least 10000 (160% deuterium incorporation), at least 10000 (18 ... or at least 6533 (98% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0187] The term "compound", when referring to a compound disclosed herein, refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations in the constituent atoms of the molecule. Thus, it will be clear to one skilled in the art that a compound represented by a particular chemical structure containing a designated deuterium atom will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amount of such isotopologues in the compounds disclosed herein will depend on several factors, including the isotopic purity of the deuteration reagent used to make the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound. However, as mentioned above, the relative amount of such isotopologues will total less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues will total 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.

[0188] The compounds disclosed herein (including the compound of formula 1) may contain asymmetric carbon atoms, for example, as a result of deuterium substitution or otherwise. Thus, the compounds disclosed herein can exist as either individual enantiomers or mixtures of enantiomers. Thus, the compounds disclosed herein can exist as racemic or scalemic mixtures, or as individual respective stereoisomers substantially free of other possible stereoisomers. The term "substantially free of other stereoisomers" or "substantially pure enantiomer," as used herein, means that 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 (X being a number between 0 and 100, inclusive) are present. Methods for obtaining or synthesizing individual enantiomers of a given compound are known in the art and may be applied practicably to final compounds, or to starting materials or intermediates.

[0189] The term "racemate" or "racemic mixture" refers to a mixture of equal proportions of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. The term "enantiomerically enriched," as used herein, refers to an increase in the amount of one enantiomer relative to the other enantiomer.

[0190] It is understood that the compounds of the present invention that have chiral centers can exist and be isolated in optically active and racemic forms.Some compounds may show polymorphism.It should be understood that the present invention encompasses any racemic, optically active, diastereomeric, polymorphic or stereoisomeric form of the compounds of the present invention, or mixtures thereof, that have the useful properties described herein, and how to prepare optically active forms is well known in the art (for example, 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).

[0191] Methods for obtaining enriched or pure enantiomers include at least the following:

[0192] i) Physical separation of crystals - a technique in which macroscopic crystals of the individual enantiomers are manually separated. This technique can be used when crystals of separate enantiomers exist, i.e. the material is a conglomerate and the crystals are visually distinguishable,

[0193] ii) Simultaneous crystallization - a technique in which the individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the latter are conglomerates in the solid state;

[0194] iii) Enzymatic resolution - a technique in which the racemate is partially or completely separated by the different rates of reaction of the enantiomers with an enzyme;

[0195] iv) enzymatic asymmetric synthesis - a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enriched synthetic precursor of a desired enantiomer;

[0196] v) Chemical Asymmetric Synthesis - a synthetic technique in which a desired enantiomer is synthesized from an achiral precursor under conditions that result in asymmetry (i.e., chirality) in the product, which may be accomplished using chiral catalysts or chiral auxiliaries as disclosed in more detail herein;

[0197] vi) Diastereomeric separation - a technique in which a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more clearly defined structural differences, and later removal of the chiral auxiliary gives the desired enantiomer.

[0198] vii) Primary and secondary asymmetric transformation - techniques in which either the diastereomers from the racemate equilibrate so that the diastereomer from the desired enantiomer predominates in solution, or preferential crystallization of the diastereomer from the desired enantiomer disrupts the equilibrium, so that ultimately in principle all of the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer,

[0199] viii) Kinetic resolution - this technique refers to the partial or complete resolution of a racemate (or further resolution of a partially resolved compound) achieved by the unequal reaction rates of enantiomers with a chiral non-racemic reagent or catalyst under kinetic conditions;

[0200] ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from non-chiral starting materials and the stereochemical integrity is not or only minimally compromised over the course of the synthesis;

[0201] x) Chiral Liquid Chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase by their different interactions with the stationary phase. The stationary phase can be made of a chiral material or the mobile phase can contain additional chiral material to induce the different interactions.

[0202] xi) Chiral Gas Chromatography - a technique in which the racemate is volatilized and the enantiomers are separated by virtue of their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;

[0203] xii) Chiral solvent extraction - a technique for separating enantiomers by preferentially dissolving one enantiomer in a particular chiral solvent;

[0204] xiii) Transport across chiral membranes - a technique in which a racemate is contacted with a thin membrane barrier. The barrier typically separates two miscible fluids, one of which contains the racemate, and a driving force such as a concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0205] Stereoisomers may also be separated by conventional techniques known to those skilled in the art, including fractional crystallization of bases or their salts, or chromatographic techniques, such as LC or flash chromatography. The (+) enantiomer may be separated from the (-) enantiomer using techniques and procedures well known in the art, such as those described by 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 micron, may also be utilized to effect separation of the enantiomers.

[0206] "D" and "d" both refer to deuterium.

[0207] The term "optionally substituted with deuterium" means that one or more hydrogen atoms in the referenced moiety may be replaced with the corresponding number of deuterium atoms.

[0208] The present disclosure provides prodrugs of the compounds of formula 1 above. In general, such prodrugs are functional derivatives of the compounds of formula 1 that can be easily converted in vivo to the required compounds of formula 1. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard. Elsevier, 1985. Such prodrugs include, but are not limited to, ester prodrugs derived from alcohols and acids, and phosphate prodrugs of alcohols. Prodrugs can be formulated to achieve the goals of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, extended duration of action, improved organ selectivity, improved formulation (including increased hydrosolubility), and / or reduced side effects (including toxicity).

[0209] The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weights are based on the total weight of the deuterated compounds disclosed herein. therapeutic compounds

[0210] In some embodiments, the present disclosure provides a compound represented by Formula 1: [ka] Deuterated pyridinyl pyrrole carboxamide analogs according to

[0211] wherein ring A, the number and type of substituents, and the substitution pattern on the ring are varied. to provide.

[0212] In one aspect, the disclosure provides compounds of formula 2B-1 and 2B-2: [ka]

[0213] or pharma- ceutically acceptable salts, solvates, and prodrugs thereof,

[0214] Each of X1, X2, X3, X4, X5, X6, and X7 is independently selected from hydrogen and deuterium. to provide.

[0215] In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are selected from the group consisting of a deuterated analog of ulixertinib having the structures of formulas 3C-1 and 3C-2: [ka]

[0216] and pharma- ceutically acceptable salts, solvates, and prodrugs thereof.

[0217] In some embodiments, the compounds of formula 2B-1 and 2B-2 are those in which the deuterated analog of ulixertinib has the structure of formula 3A-11 and 3A-12: [ka] and X2, X3, X4, X5, X6, and X7 as hydrogen so that the compound has the formula:

[0218] In some embodiments, the compounds of formula 2B-1 and 2B-2 include deuterated analogs of ulixertinib having the structures of formulas 3B-1 and 3B-2: [ka] X1 is hydrogen and X2, X3, X4, X5, X6, and X7 are deuterium, so that the compound has the formula:

[0219] In yet other embodiments, compounds according to formulas 2B-1 and 2B-2 are provided, having one of the following structures: [ka] [ka] [ka]

[0220] Further non-limiting exemplary embodiments of compounds of formula 1 include the following: [ka] [ka] [ka]

[0221] [ka]

[0222] [ka]

[0223] [ka]

[0224] [ka]

[0225] [ka]

[0226] [ka]

[0227] [ka]

[0228] [ka]

[0229] [ka]

[0230] [ka]

[0231] [ka]

[0232] [ka]

[0233] [ka] General Methods for Preparing Compounds

[0234] In some embodiments, the compounds disclosed herein may be prepared or isolated generally by synthetic methods known to those of skill in the art for similar compounds, as illustrated by the following general Schemes I-V and the preparative examples that follow.

[0235] Scheme I: [ka]

[0236] Scheme I above illustrates a general method for preparing the compounds disclosed herein. A pyrrole compound of formula 22 is iodized 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 can be found in Greene's Protective Groups in Organic Synthesis, 5, published by John Wiley and Sons. th Ed.5, 2014, Theodora W. Greene and Peter GM Wuts, which is hereby incorporated by reference in its entirety. The iodo moiety of formula 25 is replaced by an appropriate boronic acid or ester to provide formula 8.

[0237] Scheme II: [ka]

[0238] Scheme II illustrates a general synthetic route for preparing the compounds disclosed herein. Since the compounds of the present invention concern polysubstituted pyridine moieties, the reaction sequence is considered and methods for activating positions on the pyridine are utilized to direct the regiochemistry. In the first step, the leaving group L2 is introduced on the pyridine ring in a regioselective manner. In the second step, the leaving group L1 can be replaced by an alcohol, thiol or amine as desired. A variety of L1 leaving groups are acceptable for this reaction. Examples of such groups include, but are not limited to, halogens, activated ethers and activated esters. This reaction is followed by the replacement of the second leaving group L2 by either a metal-catalyzed cross-coupling reaction or a nucleophilic aromatic substitution reaction to form an intermediate of formula 9. A variety of L2 leaving groups are acceptable for this reaction. Examples of such groups include, but are not limited to, halogens and activated ethers, activated esters, boronic acids, boronic esters, or phosphonium salts. The protecting group on the pyrrole is then removed by a method suitable for removing amino protecting groups. Depending on which amino protecting group is used, suitable conditions for removing the amino protecting group can be used to simultaneously saponify or otherwise provide the carboxylate functionality depicted in the compound of formula 10. If the conditions suitable for removing the amino protecting group are not suitable for providing the carboxylate of formula 10, another chemical transformation step can be used. Compounds of formula 1 are prepared from formula 10 by coupling the resulting carboxylic acid group with a desired amine. A variety of amide bond coupling conditions are useful for the reaction, and can 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, those conditions detailed in the Examples section below.

[0239] Compounds according to the intermediate of formula 5 are commercially available or can be synthesized via 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, for example, in the preparation of D6- and D7-isopropylamine. The intermediate of formula 5 produced can be isolated as a maleate salt (described in detail in the Examples section below).

[0240] Scheme III: [ka]

[0241] Scheme III illustrates a general synthetic route for preparing intermediates of formula 5. In the first step, suitable conditions are used to oximate acetone with hydroxylamine to provide intermediates of formula 27. In the second step, reduction of the oxime to the amine functionality in intermediates of formula 5 is accomplished using a suitable reducing agent. This approach can be used with D1-isopropylamine (X1=D), D6-isopropylamine (X 2~7 =D), and D7-isopropylamine (X 1~7 =D).

[0242] Scheme IV: [ka]

[0243] Scheme IV illustrates a further general synthetic route for preparing compounds according to the intermediate of formula 5. The method according to this scheme was published 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, among others.

[0244] Scheme V: [ka]

[0245] Scheme V above illustrates an alternative route for preparing 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, those described in the synthetic examples below, and methods known to those skilled in the art. The protecting group on the aminopyridine moiety is removed by a method suitable for deprotecting the amino protecting group used. Reductive amination of the intermediate of formula 33 with a ketone in the presence of a suitable reducing agent can be used to prepare the compounds disclosed herein.

[0246] Further suitable amino protecting groups are well known in the art and include 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 some embodiments, the PG group is an alkyl or arylsulfonyl moiety. Examples of such groups include mesyl, tosyl, nosyl, brosyl, and 2,4,6-trimethylbenzenesulfonyl ("Mts"). Other such groups include Bn, PMB, Ms, Ts, SiR3, MOM, BOM, Tr, Ac, CO2R, CHOCH2CH2Si(CH3)3.

[0247] A suitable leaving group is a chemical group that is easily displaced by the desired chemical moiety to be incorporated. Thus, the selection of a particular suitable leaving group is premised on its ability to be easily displaced by the chemical moiety to be incorporated. Suitable leaving groups are well known in the art, see, for example, "Advanced Organic Chemistry," Jerry March, 5th Ed., pp. 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 diazonium moieties. Examples of suitable leaving groups include chloro, iodo, bromo, fluoro, methanesulfonyl (mesyl), tosyl, triflate, nitro-phenylsulfonyl (nosyl), and bromo-phenylsulfonyl (brosyl). Metabolites of ulixertinib

[0248] According to some embodiments, the compositions disclosed herein have an altered metabolite profile relative to non-isotopically enriched compounds. Some of the metabolites of ulixertinib have already been described by Bin Yu et al., "Pharmacokinetics and metabolism of ulixertinib in rat by liquid chromatography combined with electrospray ionization tandem mass spectrometry," Separation Science, vol. 43, issue 7, pages 1275-1283 (2020), the entire contents of which are incorporated herein by reference. Briefly, the metabolites of ulixertinib include: [ka] [ka]

[0249] In some embodiments, the metabolite of ulixertinib is [ka] Includes.

[0250] In some embodiments, the metabolite of ulixertinib is [ka] Includes.

[0251] In some embodiments, the metabolite of ulixertinib is [ka] Includes.

[0252] In some embodiments, the metabolite of ulixertinib is [ka] Includes.

[0253] Steady-state exposure levels of non-isotopically enriched parent ulixertinib and related metabolites in rats (day 5) and human subjects (day 15) are provided in Table 1 below. [Table 1]

[0254] In some embodiments, the deuterated compounds disclosed herein have reduced formation of one or more metabolites relative to non-isotopically enriched compounds. In some embodiments, the deuterated analogs of ulixertinib are effective in reducing the formation of the N-desalkyl metabolite of formula 34. In some embodiments, one or more of formula 21, formula 19, and formula 18 are effective in reducing the formation of the N-desalkyl metabolite of formula 34. See, for example, Tables 6 (HLM) and 8 (rat plasma). In some embodiments, the deuterated analogs of ulixertinib are effective in reducing the formation of the i-propyl hydroxyl metabolite of formula 35. In some embodiments, one or more of BVD-523-D1, BVD-523-D6, and BVD-523-D7 are effective in reducing the formation of the i-propyl hydroxyl metabolite of formula 35. See, for example, Tables 6 (HLM) and 8 (rat plasma). In some embodiments, one or more of Formula 21, Formula 19, and Formula 18 are effective to reduce the formation of the carboxylic acid metabolite of Formula 36. See, e.g., Table 6 (HLM).

[0255] In some embodiments, the deuterated compounds disclosed herein have increased, decreased, or similar formation of one or more metabolites relative to non-isotopically enriched compounds. In some embodiments, the deuterated analog of ulixertinib is effective to increase, decrease, or maintain similar formation of the N-oxide metabolite of formula 37. See, for example, Tables 6 (HLM) and 8 (rat plasma).

[0256] In some embodiments, the metabolism of the deuterated compounds disclosed herein is mediated by the polymorphically expressed cytochrome P 450The deuterated compounds disclosed herein are modified relative to non-isotopically enriched compounds through inhibition and / or induction of metabolic enzymes. In some embodiments, the deuterated compounds disclosed herein are modified relative to non-isotopically enriched compounds, such as CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4 F3, 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 some embodiments, the deuterated compounds disclosed herein are effective to induce and / or inhibit one or more of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6, and CYP2E1. In some embodiments, the deuterated compounds disclosed herein are effective in reducing the metabolism of the deuterated compounds through inhibition of one or more of the cytochrome P450 enzymes disclosed herein, hi some embodiments, the deuterated compounds disclosed herein are effective in inhibiting the metabolism of a co-administered drug. Use, Formulation and Administration

[0257] As discussed above, the present disclosure provides compounds that are inhibitors of protein kinases, and thus the compounds of the present invention are useful for treating diseases, disorders and conditions, including but not limited to cancer, autoimmune disorders, neurodegenerative 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, which comprise any of the compounds described herein, and optionally comprise pharmaceutically acceptable carriers, adjuvants or vehicles.In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0258] It will also be understood that some of the compounds of the present disclosure may be present in free form for treatment or, where appropriate, in their pharma- ceutically acceptable derivatives.According to the present disclosure, pharma-ceutically acceptable derivatives include, but are not limited to, pharma-ceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives that, when administered to a patient in need thereof, can directly or indirectly result in the compounds otherwise described herein, or metabolites or residues thereof.

[0259] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to any non-toxic salt or salt of an ester of a compound disclosed herein that, upon administration to a recipient, is capable of directly or indirectly yielding a compound disclosed herein or an inhibitory active metabolite or residue thereof. As used herein, the term "inhibitory active metabolite or residue thereof" refers to a metabolite or residue thereof that is also an inhibitor of ERK2 protein kinase.

[0260] Pharmaceutically acceptable salts are well known in the art.For example, S. M. Berge et al. describe pharma-ceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.Pharmaceutically acceptable salts of the compounds disclosed herein include suitable inorganic and organic acids and salts derived from inorganic bases and organics.The examples of pharma-ceutically acceptable non-toxic acid addition salts are the salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids, 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N-terminated salts, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109, 109, 109, 109, 109, 109, + (C 1~4The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water- or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate.

[0261] As described above, the pharma- ceutically acceptable compositions disclosed herein further comprise a pharma- ceutically acceptable carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, so long as they are compatible with the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses a variety of carriers used in formulating pharma- ceutical acceptable compositions, and known techniques for their preparation. Except where any conventional carrier medium is incompatible with the compounds disclosed herein, for example, by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharma- ceutical acceptable composition, its use is considered to be within the scope of the present disclosure.Some examples of materials which can serve as pharma- ceutically acceptable carriers include 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 silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and vinegar. Acid cellulose; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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 and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffers, and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, but not limited to, coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition according to the judgment of the pharmacist. Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0262] In yet another aspect, a method for treating or reducing the severity of cancer, autoimmune disorders, neurodegenerative or neurological disorders, liver disease, or cardiac disorders is provided, comprising administering an effective amount of a compound disclosed herein, or a pharma- tically acceptable composition comprising a compound disclosed herein, to a subject in need thereof. In certain embodiments of the present disclosure, an "effective amount" of the compound or pharma- tically acceptable composition is an amount effective to treat or reduce the severity of a disease, condition, or disorder selected from cancer, autoimmune disorders, neurodegenerative or neurological disorders, schizophrenia, bone-related disorders, liver disease, or cardiac disorders. According to the methods disclosed herein, the compounds and compositions may be administered in any amount and using any route of administration effective to treat or reduce the severity of cancer, autoimmune disorders, neurodegenerative or neurological disorders, schizophrenia, bone-related disorders, liver disease, or cardiac disorders. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its method of administration, and the like. The compounds disclosed herein are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically separate unit of drug suitable for treating a patient. However, it will be understood that the total daily use amount of the compounds and compositions disclosed herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of that disorder; the activity of the specific compound being used; the specific composition being used; the age, weight, general health, sex and diet of the patient; the administration time, route of administration and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination or simultaneously with the specific compound being used, and similar factors well known in the medical field. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

[0263] The pharma- ceutically acceptable compositions disclosed herein can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powder, ointment or drops), bucally, orally or as a nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds disclosed herein can be administered orally or parenterally, one or more times daily, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, of subject body weight per day, to obtain the desired therapeutic effect.

[0264] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially 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 inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0265] Injectable preparations, for example, injectable sterile aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be injectable sterile solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as 1,3-butanediol solutions. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, for example, oleic acid, can be used to prepare injectable preparations.

[0266] The injectable formulations can be sterilized, for example, by filtration through a bacterial-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 injectable sterile medium prior to use.

[0267] In order to prolong the effect of the compounds disclosed herein, it is often desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0268] 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 thus will melt in the rectal or vaginal cavity and release the active compound.

[0269] 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 pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, and the like. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[0270] Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can optionally contain opacifying agents, and can be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0271] The active compound may also be in microencapsulated form with one or more of the excipients described above. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, sustained release coatings and other coatings well known in the pharmaceutical formulation field. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants, and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is common practice. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0272] The dosage forms for topical or transdermal administration of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active components are mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives or buffers that may be required. 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 for the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made 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-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0273] As generally described above, the compounds disclosed herein are useful as inhibitors of ERK protein kinase. In one embodiment, the compounds and compositions disclosed herein are inhibitors of one or both of ERK1 and ERK2 protein kinases, and thus, 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, condition, or disorder in which activation of one or both of ERK1 and ERK2 protein kinases is involved in the disease, condition, or disorder. When activation of ERK1 and / or ERK2 protein kinases is involved in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as an "ERK1 or ERK2 mediated disease", condition, or disease symptom. Thus, in another aspect, the present disclosure provides a method for treating or reducing the severity of a disease, condition, or disorder in which activation of one or both of ERK1 and ERK2 protein kinases is involved in the disease, condition, or disorder.

[0274] The activity of inhibitors of ERK1 and / or ERK2 protein kinases can be assayed in vitro, in vivo or in cell lines. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated ERK1 or ERK2 protein kinase. An alternative in vitro assay quantifies the ability of an inhibitor to bind to ERK1 or ERK2 protein kinase. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / ERK1 or inhibitor / ERK2 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by performing a competition experiment in which new inhibitors are incubated with ERK1 or ERK2 protein kinase bound to a known radioligand.

[0275] The term "measurably inhibit," as used herein, refers to a measurable change in ERK1 or ERK2 protein kinase activity between a sample containing the composition and ERK1 or ERK2 protein kinase and an equivalent sample containing ERK1 or ERK2 protein kinase but not the composition. Such measurements of protein kinase activity are known to those of skill in the art and include methods described herein below.

[0276] According to another embodiment, the present disclosure provides a method of inhibiting ERK1 or ERK2 protein kinase activity in a patient, comprising administering to the patient a compound disclosed herein or a composition comprising said compound.

[0277] The term "ERK-mediated condition" or "ERK-mediated disease" as used herein means any disease or other deleterious condition in which ERK is known to play a role. The term "ERK-mediated condition" or "ERK-mediated disease" also means a disease or condition that is alleviated by treatment with an ERK inhibitor. Such conditions include, but are not limited to, cancer, stroke, diabetes, cardiovascular disease including hepatomegaly, cardiac hypertrophy, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders, and hormone-related diseases. The term "cancer" includes, but is not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary 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 adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic system disorders, Hodgkin's tumor, hairy cell carcinoma, buccal and pharyngeal (inside the mouth) cancer, lip cancer, tongue cancer, oral cavity cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, and leukemia.

[0278] Thus, in another embodiment, the present disclosure provides for treating or reducing the severity of one or more diseases in which ERK is known to play a role.In particular, the present disclosure provides a method for treating or reducing the severity of a disease or condition selected from cancer, stroke, diabetes, cardiovascular disease including hepatomegaly, cardiac hypertrophy, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune disease, atherosclerosis, restenosis, psoriasis, allergic disorder including asthma, inflammation, neurological disorder, and hormone-related disease, comprising administering to a patient in need thereof a composition according to the method disclosed herein.

[0279] According to another embodiment, the present disclosure provides a method of treating a cancer selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary 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 adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic system disorders, Hodgkin's tumor, hairy cell carcinoma, buccal and pharyngeal (inside the mouth) cancer, lip cancer, tongue cancer, oral cavity cancer, pharyngeal cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, brain cancer and central nervous system cancer, and leukemia.

[0280] Another embodiment relates to a method of treating melanoma, breast cancer, colon cancer, or pancreatic cancer in a patient in need thereof.

[0281] It will also be understood that the compounds and pharma- ceutically acceptable compositions disclosed herein can be used in combination therapy, i.e., the compounds and pharma- ceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired therapies or medical procedures. The particular combination of therapies (therapeutic agents or procedures) used in a combination regimen takes into account compatibility with the desired therapeutic agents and / or procedures, as well as the desired therapeutic effect to be achieved. It will also be understood that the therapies used can achieve a desired effect for the same disorder (e.g., the compounds disclosed herein can be administered simultaneously with another agent used to treat the same disorder), or can achieve a different effect (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0282] 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, for example, surgery, radiation therapy (gamma radiation, neutron radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes, to name just a few), endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name just a few), hyperthermia and cryotherapy, agents that attenuate the adverse effects of either (e.g., antiemetics), and alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine (Cytarabile), gemcitabine, cyclophosphamide ... Examples of other therapeutic or anti-cancer agents that may be used in combination with the anti-cancer agents disclosed herein include, but are not limited to, other approved chemotherapy drugs, including, but not limited to, 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™, adriamycin, dexamethasone, and cyclophosphamide. For a more comprehensive discussion of current cancer treatments, see http: / / www.nci.nih.gov / , the list of FDA-approved oncology drugs at http: / / www.fda.gov / cder / cancer / druglistframe.htm, and The Merck Manual, Seventeenth Ed. 1999, the contents of each of which are hereby incorporated by reference in their entirety.

[0283] Other examples of agents that can be combined with the inhibitors include treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®; agents for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian drugs; agents for treating cardiovascular disease such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders such as corticosteroids, anti-leukemia agents, and growth factors; and agents for treating immune deficiency disorders such as gamma globulins.

[0284] The amount of additional therapeutic agent present in the compositions disclosed herein is no more than the amount that would normally be administered in a composition containing that 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 that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0285] In alternative embodiments, the methods disclosed herein utilizing compositions that do not contain an additional therapeutic agent comprise the further step of separately administering to said patient an additional therapeutic agent, which, when administered separately, may be administered to the patient prior to, sequentially with, or after administration of the compositions disclosed herein.

[0286] The compounds disclosed herein or pharma- ceutically acceptable compositions thereof can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters.Accordingly, the present disclosure in another aspect provides a composition for coating an implantable device, comprising a compound generally described above and described in the classes and subclasses herein, and a carrier suitable for coating said implantable device.In yet another aspect, the present disclosure provides an implantable device coated with a composition comprising a compound generally described above and described in the classes and subclasses herein, and a carrier suitable for coating said implantable device.

[0287] Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharma- ceutically acceptable composition that includes a kinase inhibitor. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material, such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating can be further coated, if desired, with a suitable topcoat of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof to impart controlled release characteristics to the composition.

[0288] 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 a patient a compound disclosed herein or a composition comprising said compound, or contacting said biological sample with a compound disclosed herein or a composition comprising said compound. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsies obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids, or extracts thereof.

[0289] Inhibition of ERK1 or ERK2 protein kinase activity in a biological sample is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0290] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0291] The following examples are provided to further illustrate the methods of the present disclosure. These examples are merely illustrative of the scope of the disclosure and are not intended to be limiting in any way. EXAMPLES

[0292] Example 1 D7-Ulixertinib was prepared as follows. [ka]

[0293] Preparation of intermediates of formula 7A [ka]

[0294] To a flask were added DMSO (128 mL, 6 V), 38 (21.37 g, 1.0 equiv), d7-isopropylamine hydrochloride (12.72 g, 1.5 equiv) and K2CO3 (25.84 g, 2.25 equiv) at ambient temperature. The temperature of the mixture was increased to 80-85 °C and stirred until the reaction was complete. The temperature of the mixture was decreased to 20-25 °C and water (770 mL, 36 V) was added to the mixture. The mixture was extracted with EtOAc (427 mL, 20 V x 3) and the organic phases were combined. The EtOAc solution was washed with water (427 mL, 20 V x 2) and brine (213 mL, 10 V x 1). The solution was then solvent switched to n-heptane (214 mL, 10 V x 2) to a final volume of 6. The temperature of the n-heptane mixture was decreased to 0-10 °C. The slurry was filtered and the isolated solid was dried to give 16 g of 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 (400 MHz, CDCl3): δ 8.01 (s, 1H), 6.88 (s, 1H).

[0295] Preparation of intermediates of formula 9A [ka]

[0296] To a solution of 7A (1.0 g, 3.29 mmol, 1 equiv) and 8A (1.28 g, 3.95 mmol, 1.2 equiv) in DME (15 mL, 15 V) and water (1 mL, 1 V) was added palladium acetate (0.01 g, 0.45 mmol, 0.14 equiv), tricyclochexylphosphonium tetrafluoroborate (0.01 g, 0.45 mmol, 0.14 equiv) and sodium carbonate (0.52 g, 4.9 mmol, 1.5 equiv) under nitrogen. The temperature of the mixture was raised to 75-85 °C and stirred for 12 h. The reaction was cooled to 20-25 °C and the mixture was filtered. The filtrate was collected and concentrated to give a residue that was reslurried 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 give 1.1 g of 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); 1 H-NMR (400 MHz, DMSO-d6): δ 8.35 (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).

[0297] Preparation of intermediates of formula 10A [ka]

[0298] An aqueous solution of LiOH (5.0 equiv, 7 wt%) and diethylamine (7.26 g, 2.0 equiv) was added to a solution of formula 9A (22 g, 1.0 equiv) in THF (4 V) at 15-30°C. The temperature of the mixture was increased to 60-70°C until the reaction was complete. The temperature of the reaction was reduced to 20-25°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 give 7.2 g of 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 (400 MHz, DMSO-d6): δ 12.17 (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).

[0299] Preparation of Compounds of Formula 18 [ka]

[0300] HOBt (1.2 equiv., 5.21 g) was added to a solution of 10A (1.0 equiv., 8 g) in DMF (1.5 V, 12 mL) at -10 to -20 °C, followed by EDCI (1.1 equiv., 5.94 g). The temperature of the mixture was lowered to -20 to -30 °C, and 19 (1.2 equiv., 5.84 g) and DIPEA (1.2 equiv., 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 × 3, 80 mL). The combined organic phase was washed sequentially with water (4V x 2, 32 mL each), 5% aqueous acetic acid (7V x 2), aqueous Na2CO3 (7V x 2, 17 wt%) and brine (10V x 2). Silica (1g / g, 8 g) was placed in the organic solution and the silica slurry was stirred for 2-4 h and filtered. The filter cake was rinsed with ethyl acetate (4.5g / g, 36 mL). The combined filtrate was concentrated under vacuum to 1-2 V, then MTBE (1.48g / g, 11.8 g) was added. The temperature of the mixture was reduced to 0°C and stirred for 2 h. The solid was collected by filtration and dried to give 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 (400 MHz, CD3OD): δ 7.99 (s, 1H), 7.48-7.52 (m, 3H), 7.39 (s, 1H), 7.27-7.31 (m, 2H), 7.23-7.26 (m, 2H), 6.55 (s, 1H), 5.15 (q, 1H), 3.85 (m, 2H).

[0301] The compound of formula 18 was further reacted with HCl to produce the HCl salt, formula 18A. At 15-25 °C, filtered absolute ethanol (0.26 V), filtered methanol (0.02 V), and filtered isopropanol (0.02 V) were placed in a glass flask and stirred for 20-30 min. Hydrogen chloride gas was then bubbled into the mixture under stirring at 10-25 °C. After 2 h, the mixture was sampled and analyzed every 2-4 h until the hydrogen chloride content reached 35 wt% or more. While maintaining the temperature at 15-25 °C, filtered absolute ethanol (9 V), filtered methanol (0.5 V), and filtered isopropanol (0.5 V) were placed in another reactor through an in-line fluid filter and stirred for 20-30 min. Formula 18 (1.0 equiv.) was then added. The temperature of the mixture was increased to 70-75°C at a rate of 15-25°C / hr and stirred until the solid was completely dissolved. At 70-75°C, seed crystals (0.1 wt%) were added to the mixture followed by anhydrous HCl solution. The mixture was maintained at 70-75°C for 1-2 hours with stirring. The temperature of the mixture was decreased to 15-25°C at a rate of 5-15°C / hr and then maintained at 15-25°C for 4-6 hours under stirring. The mixture was filtered and the filter cake was rinsed with filtered MTBE. The filter cake was dried under nitrogen at 40-50°C for 24 hours to give 8.29 g of the product (Formula 18A) as a white solid. Yield: 84.5%, HPLC purity: 99.4% (215nm); HPLC chiral purity (ee): 100.0% (254nm); HPLC assay 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 (400 MHz, CD3OD): δ 7.99 (s, 1H), 7.75 (s, 1H), 7.48 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.27-7.31 (m, 2H), 7.08 (s, 1H), 5.11 (q, 1H), 3.88 (m, 2H). Example 2

[0302] Formula 19 was prepared as follows. [ka]

[0303] Preparation of Formula 12A [ka]

[0304] Formula 38 (200 g, 777 mmol, 1 equiv), p-methoxybenzylamine (320 g, 2.33 mol, 3 equiv) and DMSO (2500 mL) were added to a flask. The temperature of the mixture was raised to 80 °C and stirred for 12 h. The temperature of the reaction mixture was lowered to 20-25 °C. The reaction was partitioned 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 3-4 with stirring. Stirring was stopped, 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, the aqueous layer was separated and discarded. The organic layer was dried and concentrated under reduced pressure to give 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 (400 MHz, DMSO-d6): δ 7.99 (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).

[0305] Preparation of Formula 13A [ka]

[0306] Formula 12A (143 g, 380 mmol, 1 equiv), Formula 8A (123 g, 380 mmol, 1.0 equiv), Pd(OAc)2 (2.56 g, 11.4 mmol, 0.03 equiv), PCy3.HBF4 (5.60 g, 15.2 mmol, 0.04 equiv), sodium carbonate (60.42 g, 570 mmol, 1.5 equiv), 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 portion of Formula 8A (32 g) was added to the flask and the reaction mixture was stirred overnight. The mixture was filtered through a pad of Celite, 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 give 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); 1 H-NMR (400 MHz, DMSO-d6): δ 8.22 (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).

[0307] Preparation of Formula 14A [ka]

[0308] Formula 13A (170 g, 323 mmol, 1 equiv), lithium hydroxide monohydrate (67.8 g, 1616 mmol, 5 equiv), 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 60-80 °C and stirred at that temperature for about 60 h. 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 under reduced pressure to about 0.33 V. The slurry was filtered and dried to give 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 (400 MHz, DMSO-d6): δ 12.44 (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).

[0309] Preparation of Formula 15A [ka]

[0310] EDCI HCl (132 g, 690 mmol, 1.3 equiv), HOBt (107 g, 795 mmol, 1.5 equiv) and DIEA (103 g, 795 mmol, 1.5 equiv) were added to a solution of formula 14A (190 g, 530 mmol, 1 equiv) in dry DMF (1330 mL) at -10 to -20 °C. The mixture was stirred for 20 min, and then compound of formula 8B (109 g, 640 mmol, 1.2 equiv) was added to the mixture. The temperature of the reaction mixture was raised to 20-25 °C and stirred for 16 h. The mixture was partitioned between EtOAc (1 L) and water (1 L). The aqueous phase was extracted twice with EtOAc (3 L). The combined organic layers were washed with water (2 L), brine (2 L) 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 give 173 g of product (Formula 15A) as a yellow solid. Yield (two steps): 100%: HPLC purity: 97% (254 nm); LC-MS: m / z 511.1 (M+1); 1 H-NMR (400 MHz, DMSO-d6): δ 11.86 (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);

[0311] Preparation of Formula 16A [ka]

[0312] Anisole (25.4 g, 235 mmol) was placed in a solution of formula 15A (80 g, 156 mmol) in TFA (480 mL) at 20-25 °C. The mixture was stirred at 50 °C for 14 h, then the temperature was reduced to 20-25 °C. The solution was concentrated under reduced pressure. The residue was dissolved in water, the solution was adjusted to pH 8 with saturated aqueous NaHCO3, EtOAc (800 ml, 10 vol) was added to the aqueous solution, and the mixture was stirred. The solid was filtered and recrystallized with EtOAc (50 vol) to give 38 g of 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); 1 H-NMR (400 MHz, DMSO-d6): δ 11.86 (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).

[0313] Preparation of compound 118217 (BVD-523-D6) [ka]

[0314] A mixture of 16A (20 g, 52.1 mmol) and acetone-d6 (80 mL) in buffer (2000 mL, NaOAc: 48 g, AcOH: 68 mL, MeOH: 2000 mL) was stirred at 20-25 °C for 1 h. Then, NaBH3(CN) (48.3 g, 768 mmol) was added to the solution. The mixture was stirred at 55 °C for 18 h and then cooled to 20-25 °C. Buffer (400 mL) and acetone-d6 (30 mL) were added. The mixture was stirred at 20-25 °C for 1 h and then additional NaBH3(CN) (16 g) was added. The temperature of the mixture was increased to 55 °C and stirred for an additional 14 h. The temperature of the mixture was reduced to 20-25 °C and washed with saturated aqueous NaHCO3. The mixture was concentrated under reduced pressure and diluted with 2-MeTHF (1500 mL, 75 volumes). The solution was washed with saturated aqueous NaHCO3 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 recrystallized with the crude solid (MeOH:H2O=2.4:1, 96ml:40ml) to give 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: (400 MHz, DMSO-d6): δ 11.87 (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).

[0315] The compound of formula 19 was further reacted with HCl to produce the HCl salt form, formula 19A. At 15-25°C, filtered absolute ethanol (145 g, 0.26 V), filtered methanol (8.1 g, 0.02 V), and filtered isopropanol (8.1 g, 0.02 V) were placed in a 20 L glass flask and stirred for 20-30 min. Hydrogen chloride gas was then bubbled into the mixture under stirring at 10-25°C. After 2 h, the mixture was sampled and analyzed every 2-4 h until the hydrogen chloride content reached 35 wt% or more. While maintaining the temperature at 15-25°C, filtered absolute ethanol (4292 g, 9 V), filtered methanol (232 g, 0.5 V), and filtered isopropanol (232 g, 0.5 V) were placed in a separate 20 L reactor through an in-line fluid filter and stirred for 20-30 min. Formula 19 (580 g, 1.0 equiv.) was then added. The temperature of the mixture was increased to 70-75 °C at a rate of 15-25 °C / hr and stirred until the solid was completely dissolved. At 70-75 °C, seed crystals (0.58 g, 0.1 wt%) were added to the mixture, followed by anhydrous HCl solution (141 g). The mixture was maintained at 70-75 °C for 1-2 h with stirring. The temperature of the mixture was decreased to 15-25 °C at a rate of 5-15 °C / hr and then maintained at 15-25 °C for 4-6 h under stirring. The mixture was filtered and the filter cake was rinsed with filtered MTBE for 20-30 min. The filter cake was dried under nitrogen at 40-50 °C for 24 h to give 12.9 g of product (Formula 19A) as a white solid. Yield: 84.5%, HPLC purity: 99.4% (215nm); HPLC chiral purity (ee): 100.0% (254nm): HPLC assay purity: 98.3% (215nm): Chloride content: 7.2%: Isotopic purity: 97.9%; LC-MS: m / z 439.2 (M+1); 1 H-NMR (400 MHz, DMSO-d6): δ 8.10 (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). Example 3

[0316] Formula 21 was prepared as follows. [ka]

[0317] Preparation of Formula 39 [ka]

[0318] A solution of propan-2-one oxime (1.0 equiv.) in THF was placed into a suspension of LiAlD4 (1.5 equiv.) in THF (16.7 V) at 50-55 °C. The mixture was stirred at 60-65 °C for 12 h. The temperature was lowered to 0-10 °C and quenched by adding sodium sulfate (0.5 equiv.). The mixture was stirred for 1 h 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 15-30 °C. The mixture was stirred at 20-25 °C for 2 h and stirred at a temperature of 0-10 °C for an additional 2 h. The slurry was filtered and the filter cake was washed with THF (1 V). The solid was dried under nitrogen to give 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 (400 MHz, D2O): δ 6.22 (s, 2H), 1.18 (s, 6H).

[0319] Preparation of Formula 7B [ka]

[0320] 39 (3.0 equiv.) and K2CO3 (4.5 equiv.) were placed in a suspension of 38 (1.0 equiv.) in DMSO (20 V) at 15-30 °C. The temperature of the mixture was increased to 75-85 °C and stirred for 24 h. The temperature of the mixture was decreased to 15-25 °C and water (36 V) was added. The product was extracted with EtOAc (6 V x 3) and the organic phases were combined. The combined organic phases were washed with water (10 V x 2) and aqueous NaCl (10 V x 1). The solution was concentrated under reduced pressure to 2 V and n-heptane (5 V) was added to the mixture. The heptane mixture was concentrated under reduced pressure to 2 V and this process was repeated twice. (N-heptane (1V) was added to the concentrated residue and stirred at 15-25 °C for 4 h. The mixture was filtered and the filter cake was dried under nitrogen at 20-30 °C for 12 h to give 640 g of 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 (400 MHz, CDCl3): δ 8.01 (s, 1H), 6.88 (s, 1H), 1.22 (s, 6H).

[0321] Preparation of Formula 9B [ka]

[0322] Purified water (1V) and anhydrous sodium carbonate (1.5 eq.) were added to a solution of 7B (1.0 eq.) and 8A (1.1 eq.) in glycol dimethyl ether (8V) at 20-30°C. The mixture was degassed with nitrogen for 30 min. Pd(OAc)2 (0.02 eq.) and P(cy)3HBF4 (0.05 eq.) were added to the mixture under nitrogen protection. After the addition, the mixture was degassed and filled with nitrogen. This process was repeated 10 times. The temperature of the mixture was increased to 75-85°C and stirred for 4 h. The temperature of the reaction mixture was reduced to 25-35°C and filtered. The filter cake was rinsed with THF (1.3V x 2). The filtrates were combined and concentrated under reduced pressure to 1V. MeOH (1.3 vol.) was added to the mixture at 15-25°C and stirred at 15-25°C for 2 h. The slurry was filtered and the filter cake was rinsed with methanol (1V x 2). The solid was reslurried in a mixture of EtOAc:hexanes (1:6.5, 5.6V) at 15-25°C for 2 hours. The slurry was filtered and the filter cake was rinsed with hexanes (1V) and dried under nitrogen for 8 hours to give 351 g of product (Formula 9B) as a light yellow solid. Yield: 85.0%, HPLC purity: 96.5% (215 nm): HPLC assay purity: 95.1% (215 nm): Isotopic purity: 98%; 1 H-NMR (400 MHz, CDCl3): δ 8.15 (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).

[0323] Preparation of Formula 10B [ka]

[0324] Aqueous LiOH (5.0 equiv, 7 wt%) was added to a solution of 9B (1.0 equiv) in THF (5 V) at 15-30 °C. Et2NH (2.0 equiv) was then added to the mixture and the mixture was stirred at 60-70 °C for 30 h. The temperature of the mixture was reduced to 20-25 °C. MTBE (5 V) was added to the mixture at 15-25 °C and stirred for 30 min. The phases were separated and the organic phase was discarded. The pH of the aqueous phase was adjusted to between 1-2 with 6 N HCl. An aqueous solution of sodium carbonate was added to the mixture at 15-25 °C to adjust the pH to between 9-10 to dissolve the solids. The pH of the solution was adjusted to 6.2 with 6 N HCl. The mixture was filtered and the filter cake was reslurried in water (10 V) and stirred for 2 h. The slurry was filtered and dried at 55-65° C. for 40 hours. The solid was slurried in MTBE (6V) at 20-25° C. for 2 hours and filtered. The filter cake was dried to give 138 g of 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 (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.49 (s, 1H), 7.13 (s, 1H), 6.62 (s, 1H), 1.13 (s, 6H).

[0325] Preparation of Formula 21 [ka]

[0326] HOBt (1.2 equiv.) and EDCI (1.1 equiv.) were added to a solution of 10B (1.0 equiv.) in DMF (10V) at -10 to -20°C. The temperature of the mixture was lowered to -20 to -30°C. Then, 8B (1.05 equiv.) and DIPEA (1.2 equiv.) were added. The mixture was stirred at 0 to 10°C for 8 h. The reaction mixture was diluted with ethyl acetate (9V) and water (4V). The phases were separated and the aqueous phase was extracted with ethyl acetate (9V x 3). The organic phases were combined and washed successively with water (4V x 2), 5% HOAc (7V x 2), aqueous Na2CO3 solution (7V x 2, 17 wt%) and brine (10V x 2). Silica gel (1g / g) was added to the organic phase and stirred at 15 to 30°C for 4 h, then filtered. The filter cake was rinsed with ethyl acetate (4.5 V). The combined filtrates were concentrated under reduced pressure to 2 V. MTBE (2 V) was added to the mixture. The mixture was cooled to 0° C.-10° C. and stirred for 1 h. The mixture was filtered and the solid was dried to give 181 g of the product (Formula 21) as a yellow solid. Yield: 69.0%, HPLC purity: 99.6% (215 nm); HPLC chiral purity (ee): 100.0% (254 nm): HPLC assay purity: 99.0% (215 nm): Isotopic purity: 99%; 1 H-NMR (400 MHz, DMSO-d6): δ 7.98 (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).

[0327] Preparation of Formula 21A [ka] At 15-25 °C, filtered absolute ethanol (145 g, 0.26 V), filtered methanol (8.1 g, 0.02 V), and filtered isopropanol (8.1 g, 0.02 V) were placed in a flask and stirred for 20-30 min. Hydrogen chloride gas was then bubbled into the mixture under stirring at 10-25 °C. After 2 h, the mixture was sampled and analyzed every 2-4 h until the hydrogen chloride content reached 35 wt% or more. While maintaining the temperature at 15-25 °C, filtered absolute ethanol (4292 g, 9 V), filtered methanol (232 g, 0.5 V), and filtered isopropanol (232 g, 0.5 V) were placed in a separate 20 L reactor through an in-line fluid filter and stirred for 20-30 min. Formula 21 (580 g, 1.0 equiv.) was then added. The temperature of the mixture was increased to 70-75 °C at a rate of 15-25 °C / hr and stirred until the solid was completely dissolved. At 70-75 °C, seed crystals (0.58 g, 0.1 wt%) were added to the mixture followed by anhydrous HCl solution (141 g). The mixture was maintained at 70-75 °C for 1-2 h with stirring. The temperature of the mixture was decreased to 15-25 °C at a rate of 5-15 °C / hr and then maintained at 15-25 °C for 4-6 h under stirring. The mixture was filtered and the filter cake was rinsed with filtered MTBE for 20-30 min. The filter cake was dried under nitrogen at 40-50 °C for 24 h to give 580 g of the product (Formula 21A) as a white solid. Yield: 92.0%, HPLC purity: 99.9% (215 nm); HPLC chiral purity (ee): 100.0% (254 nm); HPLC assay purity: 99% (215 nm); Chloride content: 7.6%; Isotopic purity: 99%; 1 H-NMR (400 MHz, DMSO-d6): δ 12.32 (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). Example 4 Characterization data for deturated analogues of ulixertinib

[0328] Mechanism of Action (MOA) Cellular Assays - A375 Cell Proliferation, pERK / ERK and pRSK / RSK Analysis

[0329] A375 proliferation assay results [Table 2]

[0330] Briefly, A375 cells were plated at 10,000 cells / well in three 96-well plates. Plates were incubated overnight at 37° C. to allow recovery. Cells were washed with 150 μL DPBS and 90 μL fresh medium was added to each well. Cells were then treated with selected compounds in a dose response. Compounds were diluted from stock concentrations (10 mM in DMSO). Serial dilutions were performed in DMSO to give a total of eight different concentrations per compound. Upon compound addition, control plates were analyzed using Cell TiterGlo to establish a baseline for proliferation. Compound-treated cells were grown at 37° C. / 5% CO2 for 72 hours and then analyzed using Cell TiterGlo according to the kit protocol.

[0331] A375 pERK / ERK dose response study [Table 3]

[0332] Briefly, A375 cells were plated at 30,000 cells / well in 2x96-well plates, allowed to recover overnight, washed and fed with fresh medium the next day, and then treated with selected compounds in a dose response. After the indicated pretreatment times with compounds at 37°C / 5%CO2, medium was aspirated and cells were lysed with chilled complete MESO Scale Discovery (MSD) lysis buffer. pERK and total ERK1 / 2 levels were measured using the MESO Scale Discover phospho(Thr202 / Tyr204:Thr185 / Tyr187) / total ERK1 / 2 kit. Protocol and all reagents were provided in the kit. All wells were blocked with 150μl blocking solution for 1 hour. 25ml of cell lysate plus 25ml of lysis buffer was added per well and incubated overnight at 4°C. After overnight incubation, wells were washed 3 times with Tris wash buffer, then 25ml of 1x detection antibody was added per well and incubated for 1 hour at room temperature with vigorous shaking. All wells were then washed 3 times with Tris wash buffer before adding 150 μl of 1× read buffer per well and reading the plates using an MSD Sector imager. Data were calculated as a ratio of phospho-ERK1 / 2 to total ERK1 / 2 to allow for sample normalization.

[0333] A375 pRSK / RSK dose response study [Table 4]

[0334] Briefly, A375 cells were plated at 30,000 cells / well in 2x96-well plates, allowed to recover overnight, washed the next day, fed with fresh medium, and then treated with selected compounds in a dose response. After the indicated pretreatment with compounds at 37°C / 5%CO2, medium was aspirated and cells were lysed with chilled 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 with 90% of the remaining samples analyzed with pRSK and 10% of the remaining samples analyzed with total RSK ELISA, which were performed according to the kit protocols.

[0335] Half-life determination of ulixertinib, formula 18, formula 19, and formula 21 in human liver microsomes (HLM) [Table 5]

[0336] Human microsomes from a pool of 10 donors were obtained from a commercial source. Microsomes prepared in potassium phosphate buffer were spiked with ulixertinib, formula 18, formula 19, and formula 21 individually in sextuplicate at a final concentration of 1 μM. NADPH was used to initiate the experiment. A control without NADPH (no cofactor) was also run in parallel with human liver microsome stability. After spiking with the test article, microsomal replicates were placed in a 37° C. incubator for the following time courses: 0, 5, 10, 15, 20, 30, 45, and 60 minutes. Samples were extracted with a protein precipitation quench solution consisting of ice-cold acetonitrile containing an internal standard (tolbutamide). Samples were analyzed for ulixertinib, formula 18, formula 19, and formula 21. The half-life of ulixertinib, Formula 18, Formula 19, and Formula 21 was characterized by the natural logarithm of the slope of the line from % remaining versus time to determine the excretion rate (ke) using the formula below.

number

[0337] The formation of N-desalkyl, i-propyl hydroxyl, aldehyde, pyridine N-oxide and carboxylic acid metabolites was monitored simultaneously with each parent test article. The percentage of metabolite formation for the N-desalkyl (M2), i-propyl hydroxyl (M3), N-oxide (M6) and carboxylic acid (M7) metabolites was calculated based on the peak areas of the metabolites formed and the peak areas of the test article for the same time points. formation%=[(PA 代謝産物 ) / (PA p0 )] x 100 PA 代謝産物 : Peak area ratio of metabolites at a given time point PA p0 : Peak area ratio of the test substance at time 0

[0338] Table 5 shows that Formula 21 has a half-life in the assay that is 30% longer than ulixertinib, Formula 18 has a half-life that is 21% longer than ulixertinib, while Formula 19 has a half-life that is 7% shorter than ulixertinib.

[0339] Observed mean percentage of metabolites formed after incubation with human liver microsomes [Table 6]

[0340] Table 6 shows that Formula 21 (D1) reduces the formation of M2 by 53%, reduces the formation of M3 by 25%, reduces the formation of M6 by 8%, and increases the formation of M7 by 26% relative to ulixertinib in the assay. Formula 19 (D6) reduces the formation of M2 by 15%, reduces the formation of M3 by 100%, reduces the formation of M6 by 7%, and reduces the formation of M7 by 100% relative to ulixertinib in the assay. Formula 18 reduces the formation of M2 by 69%, reduces the formation of M3 by 100%, increases the formation of M6 by 59%, and reduces the formation of M7 by 100% relative to ulixertinib in the assay.

[0341] Pharmacokinetic and metabolite formation evaluation in rats for example compounds of formulas 18, 19, and 21

[0342] Urixertinib, Formulas 18A, 19A, and 21A, were administered to rats by oral gavage (PO) twice daily (12 hours apart, ±30 min) for 5 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 1% (w / v) carboxymethylcellulose (CMC) in water at a concentration of 1.25 mg / mL. After the second (afternoon) dose on day 5, blood samples were collected from each rat at approximately 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Blood samples were centrifuged to obtain plasma. Plasma samples were analyzed for concentrations of administered compound and selected metabolites using established LC-MS / MS methods. The lower limit of quantification for each compound was 1.00 ng / mL. The rat half-life values ​​for each compound (determined by non-compartmental analysis using WinNonlin software) are shown in Table 7, along with the area under the curve (AUC) from 0 to 12 hours calculated using the linear trapezoidal method for each administered compound and selected metabolite. 0-12 ) are presented in Table 8. [Table 7]

[0343] Table 7 shows that Formula 21A (D1) has a mean half-life that is 4% longer than ulixertinib, Formula 19A (D6) has a mean half-life that is 9% longer than ulixertinib, and Formula 18A (D7) has a mean half-life that is 14% longer than ulixertinib. [Table 8]

[0344] Evaluation of inhibition and induction of cytochrome P450 metabolic enzymes

[0345] In vitro CYP inhibition studies

[0346] This study was designed to evaluate the ability of four test articles to directly and time-dependently inhibit the major CYP enzymes (i.e., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5) in human liver microsomes. Incubations were performed with a cocktail of seven prototypic CYP substrates to confirm the potential ability of each test article to inhibit the metabolism of co-administered drugs. A gender-mixed pool of 200 human liver microsome samples was used for this study. Incubations were carried out at approximately 37°C in 200 μL of incubation mixture (pH 7.4) containing water, potassium phosphate buffer (50 mM), MgCl2 (3 mM), EDTA (1 mM), NADPH regenerating system (NADP [1 mM], glucose-6-phosphate [5 mM], glucose-6-phosphate dehydrogenase [1 unit / mL]), and probe substrates (i.e., a cocktail of seven substrates) at the final concentrations specified in Table 9. Reactions were initiated by the addition of the NADPH regenerating system and automatically terminated after approximately 5 minutes by the addition of the internal standard mixed in acetonitrile, a stop reagent. Samples were centrifuged at 920×g for 10 minutes at 10°C. The supernatant fraction was analyzed by LC-MS / MS. Each test article (at the same concentrations used to assess direct inhibition (i.e., 0, 0.02, 0.06, 0.2, 0.6, 2, 6, 20 μM) was preincubated with NADPH-enriched human liver microsomes for approximately 30 min at 37 ± 2 °C to examine its ability to act as a time-dependent inhibitor of CYP enzymes. Preincubation was initiated by adding an NADPH regenerating system. After 30 min, the probe substrate incubation was initiated by adding the probe substrate cocktail. The incubation was terminated and samples were analyzed by LC-MS / MS. If inhibition was observed, the IC 50 Process the data using LIMS by utilizing the Levenberg-Marquardt algorithm for the determination of the following four-parameter sigmoid-logistic IC 50 A nonlinear regression fitting of the data to the equation was performed.

number

[0347] Since we are using a percent of control value, set the Min to 0 and the Max to 100 (or other value as appropriate). The LIMS will use the IC 50 The IC value is only considered if it is within the concentration range of the inhibitor studied. 50 Therefore, IC 50 If the IC value is outside the concentration range studied, 50 Values ​​are reported as being greater than the highest concentration of the test substance evaluated. [Table 9]

[0348] In vitro CYP induction studies

[0349] This study was designed to evaluate the ability of four test articles (BVD-523 ulixertinib, 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. Triplicate wells for each of the cultures were treated (37±2° C.) in 48-well plates with supplemented MCM containing 0.1 v / v % DMSO (solvent control), one of three concentrations of each test article (1, 10, and 20 μM), or the positive control CYP enzyme inducers omeprazole (50 μM), phenobarbital (1000 μM), or rifampin (20 μM). Cultures were incubated in a humidified incubation chamber (37±2°C with 95% relative humidity and 95 / 5% air / CO2). Approximately 24 hours after treatment, hepatocytes were lysed in Buffer RLT reagent containing β-mercaptoethanol (100:1). The medium was aspirated and Buffer RLT was added to each well. Cell lysates were prepared by repeated pipetting and shaking. Total RNA was isolated using the RNeasy Mini kit. RNA quality and concentration were determined by measuring absorbance at 260 and 280 nm in a plate reader. Single-stranded cDNA was prepared from RNA using RT Master Mix. RT Master Mix contains 10x RT buffer, 25x deoxy NTPs, 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 reaction components. A no template 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 analyzed by qRT-PCR and then stored at -20 ± 5°C. Each PCR was performed in quadruplicate. Primer mixes were prepared for each gene expression assay.A typical primer mix contained TaqMan Fast Advanced Master mix (1x), Gene Expression Assay (1x, 900 nM forward and reverse primers) and RNase-free water. Reaction mixes were prepared by adding the primer mix to the cDNA. A percentage of samples (10% or more) contained 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 PCR fluorescent signal. Reactions were analyzed with a PCR sequence detection system. The relative amount of target cDNA compared to the relative amount of control cDNA (GAPDH) is expressed as ΔΔC. t Relative quantification is performed by the method described above. Relative quantification measures the change in mRNA expression in a test sample relative to the change in 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 approximately equal.

[0350] Treatment with ulixertinib, formula 18, formula 21A, and formula 19 up to 20 μM resulted in 6.63-fold, 7.56-fold, 8.51-fold, and 12.1-fold increases in CYP1A2 mRNA expression, respectively. Of note, the greatest fold changes were observed at 10 μM for ulixertinib, formula 21A, and formula 19, followed by a decline to 6.42-fold, 4.00-fold, and 9.52-fold changes, respectively. Treatment with ulixertinib, formula 18, formula 21A, and formula 19 up to 20 μM resulted in 2.43-fold, 2.54-fold, 2.22-fold, and 2.44-fold changes in concentration-dependent increases in CYP2B6 mRNA expression, respectively. Treatment with up to 20 μM ulixertinib, Formula 18, Formula 21A, and Formula 19 resulted in a concentration-dependent increase in CYP3A4 mRNA expression of up to 8.26-fold, 7.06-fold, 6.86-fold, and 11.7-fold, respectively. The results are summarized in Table 10 below. [Table 10] References [Table 11-1] [Table 11-2]

[0351] All documents cited in this application are hereby incorporated by reference as if fully set forth herein.

[0352] Although illustrative embodiments of the present invention have been described herein, it should be understood that the invention is not limited to what has been described, and that various other changes or modifications may be made by those skilled in the art without departing from the scope or spirit of the invention.

Claims

1. Compound of formula 1: 【Chemistry 135】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein X] １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ Each of them independently consists of hydrogen, deuterium, and C １～４ Selected from a group consisting of aliphatic organisms, R １ is hydrogen, C １～３ is aliphatic, fluoro, or chloro, and A is a optionally substituted group selected from a 5-6 member monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or a 5-6 member saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is aliphatic, m is 0, 1, or 2.

2. Compound of formula 2A: 【Transformation 136】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein each X] １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ These are, independently, hydrogen and deuterium or C １～４ Selected from aliphatic species, R ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is aliphatic, m is 0, 1, or 2, and A, B, C, D, E, and F are independently selected from carbon or nitrogen.

3. Compound of formula 2B: 【Chemistry 137】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein each X] １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ These are, independently, hydrogen and deuterium or C １～４ Selected from aliphatic species, R ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is an aliphatic molecule, and m is 0, 1, or 2.

4. Compound of formula 3A: 【Chemistry 138】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein R] ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is an aliphatic molecule, and m is 0, 1, or 2.

5. Compound of formula 3B: 【Chemistry 139】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein R] ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is an aliphatic molecule, and m is 0, 1, or 2.

6. Compound of formula 3C: [Chemical 140] or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein R] ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is an aliphatic molecule, and m is 0, 1, or 2.

7. Compound of formula 4 【Chemistry 141】 or a pharmaceutically acceptable salt, solvate, or prodrug thereof [wherein each X] １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ These are, independently, hydrogen and deuterium or C １～４ [Selected from aliphatic species].

8. 4-(5-chloro-2-((propan-2-yl-d7)amino)pyridine-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)pyridine-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)pyridine-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)pyridine-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,1,2-d3)amino)pyridine-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-1,2-d2)amino)pyridine-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, 4-(5-chloro-2-((propan-2-yl-2-d1)amino)pyridine-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-2-carboxamide, The compound according to claim 1, as well as selected from pharmaceutically acceptable salts, solvates, and prodrugs thereof.

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is an enantiomerically pure 1S- or 1R-urixerutinib analog.

10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein any atom not designated as deuterium is present in its natural isotopic abundance.

11. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of the deuterium-containing positions has a deuterium concentration of at least 1%.

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

13. A composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating a disease, disorder, or condition, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, characterized in that the composition or pharmaceutical composition is administered in a therapeutically effective amount to a subject requiring treatment, wherein the disease, disorder, or condition comprises one or more of cancer, autoimmune disorders, neurodegenerative disorders and neuropathy, schizophrenia, bone-related disorders, liver disease, and cardiac disorders.

14. After administering the therapeutically effective amount of the composition or pharmaceutical composition, per dose unit of the compound, at least one polymorphically expressed cytochrome P is present compared to the corresponding non-isotope enriched compound. ４５０ The composition or pharmaceutical composition according to claim 13, wherein there is a reduced metabolism of the compound due to the isoform.

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

16. Compared to non-isotope-enriched compounds, the compound contains at least one cytochrome P per dose unit. ４５０ The composition or pharmaceutical composition according to claim 12, having reduced inhibition.

17. The aforementioned cytochrome P ４５０ is, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, C YP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4 A composition or pharmaceutical composition according to claim 16, selected from the group consisting of F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

18. A composition for use as a pharmaceutical, comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the compound described in any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

19. A composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the prevention or treatment of a disorder induced into remission by inhibition of ERK protein kinase, or a pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

20. A compound according to claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each deuterium-containing position has a deuterium incorporation rate of at least 1%, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

21. X １ 、X ２ 、X ３ 、X ４ 、X ５ 、X ６ 、and X ７ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein at least one of X １ 、X ２ 、X ３ 、X ４ 、X ５ 、X ６ 、およびX ７ is deuterium, or a pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

22. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein at least two of the elements are deuterium, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

23. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein at least three of the elements are deuterium, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

24. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein at least four of the elements are deuterium, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

25. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein at least five of the elements are deuterium, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

26. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein at least six of the elements are deuterium, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

27. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each of the elements is deuterium, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

28. X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ Each of them is deuterium, X １ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is hydrogen, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle, comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

29. X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ Each of them is hydrogen, X １ A compound according to claims 1 to 3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is deuterium, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

30. A composition comprising one of the compounds described in claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in a method for inhibiting ERK1 / 2 in cells, or a pharmaceutical composition comprising one of the compounds described in any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle, wherein the method comprises the step of contacting the cells with the compound or the pharmaceutical composition.

31. The compound or pharmaceutical composition exhibits at least one polymorphically expressed cytochrome P compared to the corresponding non-isotope-enriched compound. ４５０ A compound according to claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, which is effective in reducing the metabolism of the compound or pharmaceutical composition by isoform, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

32. The aforementioned cytochrome P ４５０ The isoforms are CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2 J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3ASP1, CYPa5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, C A compound according to claim 31, selected from the group consisting of YP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51, or a pharmaceutically acceptable salt thereof, solvate, prodrug, or pharmaceutical composition.

33. The aforementioned cytochrome P ４５０ The compound according to claim 32, or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutical composition thereof, wherein the isoform is selected from the group consisting of CYP3A4, CYP3A5, CYP2C8, CYP2C9, CYP2D6, CYP2C19, CYP1A2, CYP2B6, and CYP2E1.

34. A compound according to claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutically acceptable carrier, excipient, or vehicle, which, when administered to a subject requiring it, results in a reduction of the metabolism of the compound or pharmaceutically acceptable compound or pharmaceutically acceptable salt, solvate, or prodrug thereof, compared to the corresponding non-deuterated form of the compound or pharmaceutically acceptable compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

35. Formula 1: 【Chemistry 142】 A method for synthesizing deuterated compounds according to the following, (i) Compound of formula 5: 【Chemistry 143】 The compound of formula 6: 【Chemistry 144】 When reacted with the compound in formula 7: 【Chemistry 145】 The steps to generate, (ii) The compound of formula 7 above, the compound of formula 8: 【Chemistry 146】 When reacted with the compound in formula 9: 【Chemistry 147】 The steps to generate, (iii) The compound of formula 9 is reacted with LiOH to form the compound of formula 10: 【Chemistry 148】 The steps to generate, (iv) The compound of formula 10 is the compound of formula 11: 【Chemistry 149】 When reacted with the compound of formula 1: [Chemical 150] A method including the step of generating [In the formula, X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ Each of them independently consists of hydrogen, deuterium, and C １～４ Selected from a group consisting of aliphatic organisms, R １ is hydrogen, C １～３ It is aliphatic, fluoro, or chloro. A is a optionally substituted group selected from a 5-6 member monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or a 5-6 member saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ And each R is independently either hydrogen or C １～４ It is aliphatic, m is 0, 1, or 2. PG is a protecting group, L １ and L ２ [These are independently selected leaving groups.]

36. Formula 1: 【Chemistry 151】 A method for synthesizing deuterated compounds according to the following, (i) Compound of formula 12: 【Chemistry 152】 The compound of formula 8: 【Chemistry 153】 When reacted with the compound of formula 13: 【Chemistry 154】 The steps to generate, (ii) The compound of formula 13 is reacted with LiOH to form the compound of formula 14: 【Chemistry 155】 The steps to generate, (iii) The compound of formula 14 above, 【Chemistry 156】 When reacted with the compound of formula 15: 【Chemistry 157】 The steps to generate, (iv) Deprotect the compound of formula 15 to obtain the compound of formula 16: 【Chemistry 158】 The steps to generate, (v) The compound of formula 16 is the compound of formula 17: 【Chemistry 159】 When reacted with the compound of formula 1: [Chemical 160] A method including the step of generating [In the formula, X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ Each of them independently consists of hydrogen, deuterium, and C １～４ Selected from a group consisting of aliphatic organisms, R １ is hydrogen, C １～３ It is aliphatic, fluoro, or chloro. A is a optionally substituted group selected from a 5-6 member monocyclic heteroaryl ring having 1-5 heteroatoms independently selected from phenyl, nitrogen, oxygen, or sulfur, or a 5-6 member saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R ２ These are independently -R, halogen, -haloalkyl, -OR, -SR, -CN, and -NO ２ , -SO ２ R, -SOR, -C(O)R, -CO ２ R, -C(O)N(R) ２ , -NRC(O)R, -NRC(O)N(R) ２ , -NRSO ２ R, or N(R) ２ Each R is independently selected from hydrogen or C1'4 aliphatic, m is 0, 1, or 2. PG is a protecting group, L ２ [ is a leaving group].

37. Formula 18: 【Chemistry 161】 A method for synthesizing deuterated urixerutinib or a pharmaceutically acceptable salt thereof, wherein (i) a compound of formula 7A: 【Chemistry 162】 The compound of formula 8A: 【Chemical 163】 When reacted with the compound of formula 9A: 【Chemistry 164】 The steps to generate, (ii) The compound of formula 9A is reacted with LiOH to form the compound of formula 10A: 【Chemistry 165】 The steps to generate, (iii) The compound of formula 10A is the compound of formula 8B: 【Chemistry 166】 When reacted with the compound of formula 18: 【Chemistry 167】 A method including the step of generating a

38. Reacting formula 18 or a pharmaceutically acceptable salt thereof with HCl yields the compound of formula 18A: 【Chemical 168】 The method according to claim 37, further comprising the step of generating a.

39. Deuterated urixerutinib of formula 19, or its pharmaceutically acceptable salt. 【Chemistry 169】 A method for synthesizing, (i) Compound of formula 12A: 【Chemistry 170】 The compound of formula 8A: 【Chemistry 171】 When reacted with the compound of formula 13A: 【Chemistry 172】 The steps to generate, (ii) The compound of formula 13A is reacted with LiOH to form the compound of formula 14A: 【Chemistry 173】 The steps to generate, (iii) The compound of formula 14A, the compound of formula 8B: 【Chemistry 174】 When reacted with the compound of formula 15A: 【Chemistry 175】 The steps to generate, (iv) The compound of formula 15A is reacted with TFA to form the compound of formula 16A: 【Chemistry 176】 The steps to generate, (v) The compound of formula 16A, 【Chemistry 177】 When reacted with the compound of formula 19: 【Chemistry 178】 A method including the step of generating a

40. Reacting formula 19 or a pharmaceutically acceptable salt thereof with HCl yields the compound of formula 19A: 【Chemistry 179】 The method according to claim 39, further comprising the step of generating a.

41. Deuterated urixerutinib of formula 21, or a pharmaceutically acceptable salt thereof: 【Chemistry 180】 A method for synthesizing, (i) Compound of formula 7B: 【Chemistry 181】 The compound of formula 8A: 【Chemistry 182】 Reacting with it, the compound of formula 9B 【Chemistry 183】 The steps to generate, (ii) The compound of formula 9B is reacted with LiOH to form the compound of formula 10B: 【Chemistry 184】 The steps to generate, (iii) The compound of formula 10B is the compound of formula 8B: 【Chemistry 185】 When reacted with the compound of formula 21: 【Chemical 186】 A method including the step of generating a

42. A method for synthesizing deuterated urixerutinib of formula 21A, wherein the compound of formula 21: 【Chemistry 187】 Alternatively, a pharmaceutically acceptable salt thereof may be reacted with HCl to form the compound of formula 21A: 【Chemical 188】 A method including the step of generating. 【Request Item 43】 【Chemistry 189】 【Chemistry 190】 【Chemistry 191】 【Chemistry 192】 【Chemistry 193】 【Chemistry 194】 Compounds selected from pharmaceutically acceptable salts, solvates, and prodrugs thereof.

44. A kit for treating or alleviating the effects of a disease in a subject, packaged together with instructions for use thereof, comprising a compound according to claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, or vehicle.

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

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