Use of a prodrug of a TPL2 inhibitor, such as teprenone, for the treatment of inflammatory bowel disease or ulcerative colitis

Abstract

This disclosure relates in general to methods for treating, stabilizing, or reducing the severity or slowing the progression of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), using an inhibitor of tumor progression site 2 (TPL2) kinase, and pharmaceutical compositions including TPL2 kinase inhibitors used in such methods.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 608,750, filed on December 11, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to inhibitors of tumor progression site 2 (TPL2) kinase, including methods of treating inflammatory bowel disease (IBD) with such inhibitors and pharmaceutical compositions comprising such inhibitors. Background Technology

[0004] Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, relapsing, and remission-prone disease thought to be caused by an inappropriate inflammatory response to the commensal flora in genetically susceptible individuals. Its incidence is increasing in newly industrialized countries, and prevalence is high in Western countries (up to 0.5% of the population).

[0005] Symptoms of UC (a disease limited to the colon) include rectal bleeding, abdominal pain, increased bowel movements, and urinary urgency. Treatment typically includes aminosalicylate (for mild cases) and immunomodulators, steroids, anti-tumor necrosis factor (TNF) agents, vedolizumab, and surgical resection or colectomy (for moderate to severe cases). Symptoms of CD that typically affect the entire gastrointestinal tract include chronic diarrhea, abdominal pain, weight loss, anorexia, and fever. Treatment for CD can vary depending on the location and severity of the disease and typically includes aminosalicylate (for mild cases), immunomodulators (for moderate cases), and steroids to induce remission. Steroid-resistant CD is usually treated with anti-TNF agents, immunomodulators, vedolizumab, or uterotumab.

[0006] Despite the availability of various medications for IBD, response and remission rates remain low, indicating a significant unmet need for safe and effective treatment of IBD (including CD and UC). Summary of the Invention

[0007] This article provides a method for treating inflammatory bowel disease (IBD) in patients in need, which includes administering a prodrug of compound A to the patient:

[0008] (Compound A)

[0009] Or a pharmaceutically acceptable salt of a prodrug, wherein the prodrug or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg / dose to about 1,500 mg / dose based on free base.

[0010] This article also provides a method for treating IBD in patients in need, the method comprising administering a prodrug of compound A to the patient, wherein the prodrug is administered at a dose of about 75 mg / dose to about 1,500 mg / dose.

[0011] A method for treating IBD in patients in need is also provided, the method comprising administering a prodrug to the patient, the prodrug being:

[0012] ,

[0013] The prodrug is administered at a dose of approximately 75 mg / dose to approximately 1,500 mg / dose.

[0014] This article also provides a method for treating IBD in patients of need, the method comprising administering a therapeutically effective amount of compound 1 to the patient:

[0015] Or a pharmaceutically acceptable salt thereof, wherein compound 1 is administered at a dose of about 75 mg / dose to about 1,500 mg / dose. This article also provides a method of treating IBD in a patient of need, comprising administering to the patient a prodrug of compound A or a pharmaceutically acceptable salt thereof, wherein the prodrug or a pharmaceutically acceptable salt thereof is administered with food.

[0016] This article also provides a method for treating IBD in patients in need, which includes administering a prodrug of compound A to the patient, wherein the prodrug is administered with a meal.

[0017] A method for treating IBD in patients in need is also provided, the method comprising administering a prodrug to the patient, the prodrug being:

[0018] ,

[0019] The prodrug is taken with meals.

[0020] This article also provides a method for treating IBD in patients in need, comprising administering to the patient a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug, wherein the prodrug or a pharmaceutically acceptable salt thereof is administered at a first dose of about 150 mg / dose to about 1,500 mg / dose based on free base for a first time period of up to about 24 weeks; and then at a second dose for a second time period.

[0021] This article also provides a method for treating IBD in patients in need, comprising administering a prodrug of compound A to the patient, wherein the prodrug is administered at a first dose of about 150 mg / dose to about 1,500 mg / dose for a first time period of up to about 24 weeks; and then at a second dose for a second time period.

[0022] A method for treating IBD in patients in need is also provided, the method comprising administering a prodrug to the patient, the prodrug being:

[0023] ,

[0024] The prodrug is administered at a first dose of about 150 mg / dose to about 1,500 mg / dose for a first period of up to about 24 weeks; then a second dose is administered for a second period.

[0025] This article also provides a method for treating IBD in patients in need, the method comprising administering to the patient a therapeutically effective amount of compound 1:

[0026] Or a pharmaceutically acceptable salt thereof, wherein compound 1 is administered at a first dose of about 150 mg / dose to about 1,500 mg / dose for a first period of up to about 24 weeks; and then at a second dose for a second period of time.

[0027] This article also provides a method for treating IBD in patients in need, the method comprising administering to the patient a therapeutically effective amount of compound 1:

[0028] Or a pharmaceutically acceptable salt thereof, wherein compound 1 is administered at a first dose of about 150 mg / dose, or about 300 mg / dose, or about 600 mg / dose for a first period of up to about 12 weeks; and then at a second dose of about 150 mg / dose, or about 300 mg / dose, or about 600 mg / dose for a second period of time.

[0029] This article also provides a method for treating IBD in patients in need, the method comprising administering to the patient a therapeutically effective amount of compound 1:

[0030] Or a pharmaceutically acceptable salt thereof, wherein compound 1 is administered at a first dose of about 150 mg / dose, or about 300 mg / dose, or about 600 mg / dose for a first time period of up to about 12 weeks; it is determined whether the patient achieves an adequate response to the first dose after the first time period; then a second dose of about 150 mg / dose, or about 300 mg / dose, or about 600 mg / dose is administered for a second time period.

[0031] A pharmaceutical composition comprising a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug is also provided, wherein the pharmaceutical composition further comprises a diluent, a disintegrant, or a lubricant, or any combination thereof.

[0032] A pharmaceutical composition comprising a prodrug of compound A is also provided, wherein the pharmaceutical composition further comprises a diluent, a disintegrant, or a lubricant, or any combination thereof.

[0033] A pharmaceutical composition comprising a prodrug is also provided, wherein the prodrug is:

[0034] ,

[0035] The pharmaceutical composition may also contain a diluent, a disintegrant, or a lubricant, or any combination thereof.

[0036] Also provided is an oral dosage form comprising a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug and a pharmaceutically acceptable excipient, wherein the oral dosage form is formulated to achieve one or more pharmacokinetic characteristics selected from the following after daily oral administration to a human patient in an empty stomach: an arithmetic mean steady-state AUC of compound A from about 10 h*µg / mL to about 80 h*µg / mL. tau Compound A at a concentration of approximately 0.9 µg / mL to approximately 9 µg / mL, with an arithmetic mean steady-state concentration of C. max The median steady-state T of compound A is approximately 1.5 hours to approximately 6 hours. max ; and the median steady-state t of compound A over approximately 18 to approximately 30 hours. 1 / 2 .

[0037] Also provided is an oral dosage form comprising a prodrug of compound A and a pharmaceutically acceptable excipient, wherein the oral dosage form is formulated to achieve one or more pharmacokinetic characteristics selected from the following when administered orally to a human patient daily on an empty stomach: an arithmetic mean steady-state AUC of compound A from about 10 h*µg / mL to about 80 h*µg / mL. tau Compound A at a concentration of approximately 0.9 µg / mL to approximately 9 µg / mL, with an arithmetic mean steady-state concentration of C. max The median steady-state T of compound A is approximately 1.5 hours to approximately 6 hours. max ; and the median steady-state t of compound A over approximately 18 to approximately 30 hours. 1 / 2 . Attached Figure Description

[0038] Figure 1 This is a plot of median (Q1, Q3) percentages of pERK signal inhibition normalized to baseline by dose cohort and after a single escalation dose of compound 1.

[0039] Figure 2 The plot shows the median (Q1, Q3) percentage of pERK signal inhibition reported by dose cohort after normalization to baseline following multiple escalations of compound 1 and one day after the first dose.

[0040] Figure 3The plot shows the median (Q1, Q3) percentage of pERK signal inhibition reported by dose cohort after normalization to baseline following multiple escalations of compound 1 and 10 days after the first dose.

[0041] Figure 4 These are simulated steady-state PK curves reflecting the plasma concentration (ng / mL) of compound A after taking 150 mg, 300 mg, and 600 mg of compound 1. Detailed Implementation

[0042] This disclosure relates to a method of treating inflammatory bowel disease (IBD) with a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug:

[0043]

[0044] Compound A

[0045] And it relates to pharmaceutical compositions and oral dosage forms that contain such prodrugs.

[0046] Compound A is a potent inhibitor of tumor progression site 2 (TPL2) kinase (a cytoplasmic serine / threonine kinase) and a major regulator of gene expression mediated by extracellular signal-regulated kinases (ERKs) downstream of various pro-inflammatory stimuli. Upon stimulation, the TPL2-ERK pathway is activated in a wide range of immune cells and drives the production of pro-inflammatory cytokines, including TNFα, IL-1β, IL-6, and IL-8, all of which are involved in the pathogenesis of ulcerative colitis (UC). TPL2 RNA is upregulated in colonic biopsies from patients with ulcerative colitis (UC), and its expression is associated with IBD-related genes. TPL2 gain-of-function polymorphisms have been identified as risk alleles in UC.

[0047] The synthesis and characterization of certain prodrugs or pharmaceutically acceptable salts of prodrugs of compound A, and methods of using thereof, are disclosed in U.S. Patent No. 10,947,259, the entire contents of which are incorporated herein by reference for all purposes.

[0048] Reference will now be made specifically to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it should be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0049] Definitions and general parameters

[0050] The following description illustrates exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0051] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0052] As used herein, the terms “treatment” or “treating” refer to a method used to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or attenuating the severity of the disease or condition); b) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying its spread (e.g., metastasis of the disease or condition); and / or c) alleviating the disease, i.e., leading to the resolution of clinical symptoms (e.g., improving the disease state, providing partial or overall relief from the disease or condition, enhancing the effects of another medication, delaying disease progression, increasing quality of life, and / or prolonging survival).

[0053] As used herein, the terms “prevention” or “preventing” refer to any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to patients (including humans) who are at risk or have a family history of the disease or condition.

[0054] As used herein, the term "patient" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some implementations, the patient is a human.

[0055] "Pharmaceutical composition" is intended to include a combination of an active agent and an inert or active carrier, such that the composition is suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.

[0056] The term "therapeutic effective amount" or "effective amount" refers to an amount sufficient to provide therapeutic benefit, such as improvement of symptoms or slowing of disease progression, when administered to a subject. This term is applicable to compounds, pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof. Therapeutic effective amounts can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the route of administration, which can be readily determined by those skilled in the art.

[0057] As used herein, the term "prodrug" refers to a biologically inactive derivative of a drug that, upon administration to a patient, can be converted into the parent drug via some chemical or enzymatic pathway. For example, when a prodrug of compound A or a pharmaceutically acceptable salt thereof is administered, the prodrug or a pharmaceutically acceptable salt thereof can be converted into compound A.

[0058] As used herein, the term "substantially converted" for prodrugs means that more than 50% of the prodrug (e.g., a prodrug of compound A) is converted to the parent compound (e.g., compound A). For example, the term "substantially converted" may refer to more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, or more than 99% of the prodrug of compound A, or a pharmaceutically acceptable salt thereof, being converted to compound A.

[0059] A steady state, as used in this article, is reached when the amount of drug eliminated in a given unit of time equals the amount of drug reaching systemic circulation in a unit of time. The term "steady-state" pharmacokinetic characteristics refer to the features that can be achieved when a steady state is reached.

[0060] A dash ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached by a carbon atom. A dash at the beginning or end of a chemical group is for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in the structure indicates the attachment point of a group. The order in which chemical groups are written or named does not indicate or imply directionality unless required by chemistry or structure.

[0061] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0062] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes an indicated amount ±10%. In other embodiments, the term "about" includes an indicated amount ±5%. In some other embodiments, the term "about" includes an indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Moreover, unless the context clearly specifies otherwise, the singular forms "a" and "the" include plural references. Thus, for example, reference to "compound" includes a variety of such compounds, and reference to "assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0063] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ...1-20 Alkyl groups, with 1 to 8 carbon atoms (i.e., C1646) 1-8 Alkyl groups, with 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl group or 1 to 4 carbon atoms (i.e., C4) 1-4 Alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by a chemical name or identified by a molecular formula, it can encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., (CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0064] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C10). 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C) 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C) 2-6 Alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0065] "Alkyne" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C12). 2-20 alkynyl group), 2 to 8 carbon atoms (i.e., C64) 2-8 alkynyl group), 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C4 group) 2-4 (Alkyne group). The term "alkynyl group" also includes those groups that have one triple bond and one double bond.

[0066] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0067] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0068] "alkyl sulfide" refers to the group "alkyl-S-".

[0069] "Acyl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of these can be optionally substituted, as defined herein. Examples of acyl groups include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0070] "Acylamine" refers to both "C-acylamine" and "N-acylamine" groups. The "C-acylamine" group refers to the -C(O)NR group. y R z The "N-amide" group refers to the -NR group. y C(O)R z , where R y and R z It is independently selected from: hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of them can be optionally substituted.

[0071] "Amino" refers to the -NR group. y R z , where R y and R z It is independently selected from: hydrogen, alkyl, haloalkyl, aryl or heteroaryl; each of them can be optionally substituted.

[0072] "Pyrimidine" refers to -C(NH)(NH2).

[0073] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C24 carbon atoms). 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group or 6 to 10 carbon ring atoms (i.e., C46) 6-10 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not encompass heteroaryl groups as defined below or overlap with them in any way. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is heterocyclic.

[0074] "Azide group" refers to -N3.

[0075] "Carbamoyl" refers to both the "O-carbamoyl" group and the "N-carbamoyl" group, while "C-carbamoyl" refers to the group -OC(O)NR. y R z The "N-carbamoyl" group refers to the -NR group. y C(O)OR z , where R y and Rz It is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of them can be optionally substituted.

[0076] "Carboxyl group" refers to -C(O)OH.

[0077] “Carboxy ester” refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of them may optionally be substituted as defined herein.

[0078] "Cyano" or "formonitrile" refers to the -CN group.

[0079] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or comprising multiple rings in fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C64 carbon atoms). 3-20 cycloalkyl groups, 3 to 12 cyclic carbon atoms (i.e., C12) 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C145-C ... 3-10 cycloalkyl groups, 3 to 8 cyclic carbon atoms (i.e., C1464) 3-8 cycloalkyl groups or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0080] "Guidinyl" refers to -NHC(NH)(NH2).

[0081] "Hydrazine" refers to -NHNH2.

[0082] "Imine" refers to the group -C(NR)R, where each R is an alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl group; each of these can be optionally substituted as defined herein.

[0083] "Halogen" or "halogenated group" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" refers to a non-branched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, in cases where residues are substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihalogenated and trihalogenated alkyl groups refer to alkyl groups substituted by two ("di") or three ("tri") halogenated groups, which may be, but are not necessarily, the same halogen. Examples of halogenated alkyl groups include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0084] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which can be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which can be optionally substituted. As used herein, heteroalkyl groups include 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0085] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl groups comprise 1 to 20 ring carbon atoms (i.e., C atoms). 1-20 heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl) or 3 to 8 carbon ring atoms (i.e., C) 3-8 (Heteroaryl); and one to five heteroatoms, one to four heteroatoms, one to three cyclic heteroatoms, one to two cyclic heteroatoms, or one cyclic heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group may be bonded via any ring of the fused system. Any aromatic ring having a single ring or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass aryl groups as defined above or overlap with them.

[0086] "Heterocyclic group" refers to a saturated or unsaturated cyclic alkyl group in which one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of its connection (i.e., bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom that may be fused to an aryl or heteroaryl ring, regardless of its connection to the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 cyclic carbon atoms (i.e., C64 carbon atoms). 2-20 Heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups; having 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 heteroatom independently selected from nitrogen, sulfur, or oxygen. Heterocyclic groups may contain one or more oxo and / or thio groups. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazine, oxetane, dioxopentane, azirone, and morpholinyl. As used herein, the term "bridged-heterocyclic group" refers to a four- to ten-membered ring moiety having one or more (e.g., 1 or 2) four- to ten-membered ring moiety having at least one heteroatom attached to two non-adjacent atoms of the heterocyclic group, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged-heterocyclic groups include bicyclic and tricyclic ring systems. As used herein, the term "spiro-heterocyclic" refers to a cyclic system in which a ternary to ten-membered heterocyclic group has one or more additional rings, wherein the one or more additional rings are ternary to ten-membered cycloalkyl or ternary to ten-membered heterocyclic groups, and wherein individual atoms of the one or more additional rings are also atoms of the ternary to ten-membered heterocyclic group. Examples of spiro-heterocyclic rings include bicyclic and tricyclic cyclic systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused-heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indoleyl, and isoyindoleyl, wherein the heterocyclic group may be linked via any ring of the fused system.

[0087] "Hydroxy" refers to the -OH group. "Hydroxyalkyl" refers to a non-branched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a hydroxyl group.

[0088] "Oxide group" refers to a group (=O) or (O).

[0089] "Nitro" refers to the group -NO2.

[0090] "Sulfoyl" refers to the group -S(O)2R, where R is an alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl group. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0091] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0092] "alkyl sulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0093] Thiocyanate - SCN.

[0094] "Thiol" refers to the group -SR, where R is an alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl group.

[0095] "Thio" or "thion" refers to the group (=S) or (S).

[0096] Certain commonly used alternative chemical names may be used. For example, divalent groups (such as divalent "alkyl" groups, divalent "aryl" groups) may also be referred to as "alkylene" groups, "arylene" groups, etc., respectively. Moreover, unless otherwise explicitly stated, the combination of groups herein is referred to as a part, such as arylalkyl, and the last mentioned group contains the atoms of that part that are connected to the rest of the molecule.

[0097] The terms “optional” or “optionally” mean that the event or situation described below may or may not occur, and the description includes instances where said event or situation occurs and instances where said event or situation does not occur. Furthermore, the term “optionally substituted” means that any one or more hydrogen atoms on a specified atom or group may or may not be substituted by portions other than hydrogen.

[0098] Some compounds exist as tautomers. These tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with their imine tautomers. Regardless of which tautomer is exhibited, and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound includes both amide and imine tautomers. Therefore, amide-containing compounds are understood to include their imine tautomers. Similarly, imine-containing compounds are understood to include their amide tautomers.

[0099] Any formula or structure given herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of chlorine. 2 H (deuterium, D), 3 H (tritium), 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotope-labeled compounds disclosed herein, such as those in which radioactive isotopes such as 3 H, 13 C and14 C is incorporated. These isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including the determination of tissue distribution of drugs or substrates, or for the treatment of patients with radiation.

[0100] This disclosure also includes “deuterated analogues” of compounds of formula I, wherein one to n hydrogen atoms bonded to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and can therefore be used to increase the half-life of any compound of formula I when administered to mammals such as humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0101] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve absorption, distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, or by following the procedures disclosed in the examples and formulations described below. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I.

[0102] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0103] In some cases, the compounds disclosed herein can form acid salts and / or base salts by means of amino groups and / or carboxyl groups or similar groups.

[0104] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0105] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts containing inorganic acids and salts containing organic acids. Additionally, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid according to conventional procedures for preparing acid addition salts from a base compound. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. For example, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), and trienylamines. Amines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), monocycloalkylamines, dicycloalkylamines, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoarylamines, diarylamines, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0106] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidine, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, haloyl, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of further substituents (e.g., substituted aryl groups having substituted alkyl groups themselves substituted by substituted aryl groups, which are further substituted by substituted heteroalkyl groups, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group having two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, groups are described as optionally substituted, and any substituted elements of these groups are themselves unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, haloyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with a haloyl, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogens, alkyl groups, haloalkyl groups, alkoxy groups, hydroxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, or heteroaryl groups, each of which is not substituted.

[0107] As used herein, "pharmaceutically acceptable carrier" or "pharmaceuticalally acceptable excipient" includes any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in a therapeutic composition should be considered. Additional active ingredients may also be incorporated into the composition.

[0108] "Solvates" are formed through the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0109] method

[0110] This article provides a method for treating inflammatory bowel disease (IBD) in a patient in need, the method comprising administering to the patient a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug, wherein the prodrug or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg / dose to about 1,500 mg / dose based on free base. In some embodiments, the method comprises administering to the patient a prodrug of compound A, wherein the prodrug is administered at a dose of about 75 mg / dose to about 1,500 mg / dose. In some embodiments, IBD is ulcerative colitis (UC) or Crohn's disease (CD). In some embodiments, the patient in need is a person.

[0111] In some implementations, the prodrug is a compound of formula I:

[0112] Formula I

[0113] Or its pharmaceutically acceptable salt, wherein

[0114] R 6 -C(O)OR 16 -OP(O)(OR 12 )2、-C(O)-R 16 -OP(O)(OR 12 )2、-R 16 -OP(O)(OR 12 )2、-C(O)OR 16 -OR 17 -C(O)OR 16 -OH, -C(O)OR 16 -OC(O)R 17 -C(O)-C(O)OR 12 or -C(O)OR 16 -OC(O)R 17 NH2;

[0115] Each R 12 Independently hydrogen or C1-9 alkyl;

[0116] R 16 Each can be arbitrarily assigned to one to four Cs. 1-3 Alkyl or cyclopropyl substituted -C 1-3 Alkyl or cyclopropyl; and

[0117] R 17Each can be arbitrarily assigned to one to three Rs. 16 Replacement C 1-9 Alkyl, cycloalkyl, or heterocyclic groups.

[0118] In some such implementations of Formula I, R 6 -C(O)OR 16 -OP(O)(OR 12 2. In some implementations, each R 12 It is hydrogen. In some implementations, R 16 C 1-3 Alkyl group. In some embodiments, R 6 for , , , or In some implementations, R 6 for In some implementations, R 6 for .

[0119] In some implementations, the prodrug is a compound from Table 1 or a pharmaceutically acceptable salt thereof.

[0120] Table 1

[0121]

[0122]

[0123] In some embodiments, the prodrug is compound 1. For example, in some such embodiments, the method includes administering the prodrug, which is compound 1, to a patient, wherein the prodrug is administered at a dose of about 75 mg / dose to about 1,500 mg / dose.

[0124] In some embodiments, the prodrug (e.g., a compound of formula I, or compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17) or a pharmaceutically acceptable salt thereof is administered at a dose of about 75 mg / dose to about 900 mg / dose, about 75 mg / dose to about 600 mg / dose, about 75 mg / dose to about 300 mg / dose, about 150 mg / dose to about 1,500 mg / dose, about 150 mg / dose to about 900 mg / dose, about 150 mg / dose to about 600 mg / dose, about 150 mg / dose to about 300 mg / dose, about 300 mg / dose to about 1,500 mg / dose, about 300 mg / dose to about 900 mg / dose, or about 300 mg / dose to about 600 mg / dose, based on the free base. In some implementations, the prodrug or its pharmaceutically acceptable salt is administered at doses of about 75 mg / dose, 150 mg / dose, about 300 mg / dose, about 600 mg / dose, or about 900 mg / dose based on the free base.

[0125] In some embodiments, the prodrug (e.g., a compound of formula I, or compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17) or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, the prodrug or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the prodrug or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 75 mg to about 1,500 mg, about 75 mg to about 1,200 mg, about 75 mg to about 900 mg, about 75 mg to about 600 mg, about 75 mg to about 300 mg, about 150 mg to about 1,500 mg, about 150 mg to about 1,200 mg, about 150 mg to about 900 mg, about 150 mg to about 600 mg, about 150 mg to about 300 mg, about 300 mg to about 1,500 mg, about 300 mg to about 1,200 mg, about 300 mg to about 900 mg, about 300 mg to about 600 mg, about 600 mg to about 1,500 mg, about 600 mg to about 1,200 mg, or about 600 mg to about 900 mg, based on the free base. In some implementations, the prodrug or a pharmaceutically acceptable salt thereof is administered at a total daily dose of about 75 mg, about 150 mg, about 300 mg, about 600 mg, about 900 mg, or about 1,200 mg based on the free base.

[0126] For example, in some embodiments, the method includes administering compound 1 to a patient once daily at a dose of about 150 mg / dose, about 300 mg / dose, or about 600 mg / dose. In some such embodiments, IBD is UC or CD.

[0127] In some embodiments, the prodrug or its pharmaceutically acceptable salt is administered to the patient on an empty stomach. In some embodiments, the prodrug or its pharmaceutically acceptable salt is administered to the patient after a meal. In some embodiments, the prodrug or its pharmaceutically acceptable salt is administered with a meal.

[0128] This article also provides a method for treating IBD in a patient in need, the method comprising administering to the patient a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug, wherein the prodrug or a pharmaceutically acceptable salt thereof is administered with food. In some embodiments, the method comprises administering to the patient a prodrug of compound A, wherein the prodrug is administered with food. In some embodiments, IBD is UC or CD.

[0129] In some implementations, the prodrug administered with food is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0130] R 6 -C(O)OR 16 -OP(O)(OR 12 )2、-C(O)-R 16 -OP(O)(OR 12 )2、-R 16 -OP(O)(OR 12 )2、-C(O)OR 16 -OR 17 -C(O)OR 16 -OH, -C(O)OR 16 -OC(O)R 17 -C(O)-C(O)OR 12 or -C(O)OR 16 -OC(O)R 17 NH2;

[0131] Each R 12 Independently hydrogen or C1-9 alkyl;

[0132] R 16 Each can be arbitrarily assigned to one to four Cs. 1-3 Alkyl or cyclopropyl substituted -C 1-3 Alkyl or cyclopropyl; and

[0133] R 17 Each can be arbitrarily assigned to one to three Rs. 16 Replacement C 1-9 Alkyl, cycloalkyl, or heterocyclic groups.

[0134] In some such implementations of Formula I, R 6 -C(O)OR 16 -OP(O)(OR12 2. In some implementations, each R 12 It is hydrogen. In some implementations, R 16 C 1-3 Alkyl group. In some embodiments, R 6 for , , , or In some implementations, R 6 for In some implementations, R 6 for .

[0135] In some embodiments, the prodrug is compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17, or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug is compound 1. For example, in some such embodiments, the method includes administering the prodrug, which is compound 1, to a patient, wherein the prodrug is administered with a meal.

[0136] In some embodiments, the prodrug (e.g., a compound of formula I, or compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17) or a pharmaceutically acceptable salt thereof is administered with food at doses of about 75 mg / dose to about 1,500 mg / dose, about 75 mg / dose to about 900 mg / dose, about 75 mg / dose to about 600 mg / dose, about 75 mg / dose to about 300 mg / dose, about 150 mg / dose to about 1,500 mg / dose, about 150 mg / dose to about 900 mg / dose, about 150 mg / dose to about 600 mg / dose, about 150 mg / dose to about 300 mg / dose, about 300 mg / dose to about 1,500 mg / dose, about 300 mg / dose to about 900 mg / dose, or about 300 mg / dose to about 600 mg / dose, based on the free base. In some implementations, the prodrug or its pharmaceutically acceptable salt is administered with food at a dose of about 75 mg / dose, 150 mg / dose, about 300 mg / dose, about 600 mg / dose, or about 900 mg / dose based on the free base.

[0137] In some embodiments, the prodrug (e.g., a compound of formula I, or compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17) or a pharmaceutically acceptable salt thereof is administered twice daily with food. In some embodiments, the prodrug or a pharmaceutically acceptable salt thereof is administered once daily with food. In some embodiments, the prodrug or a pharmaceutically acceptable salt thereof is administered with food at a total daily dose of about 75 mg to about 1,500 mg, about 75 mg to about 1,200 mg, about 75 mg to about 900 mg, about 75 mg to about 600 mg, about 75 mg to about 300 mg, about 150 mg to about 1,500 mg, about 150 mg to about 1,200 mg, about 150 mg to about 900 mg, about 150 mg to about 600 mg, about 150 mg to about 300 mg, about 300 mg to about 1,500 mg, about 300 mg to about 1,200 mg, about 300 mg to about 900 mg, about 300 mg to about 600 mg, about 600 mg to about 1,500 mg, about 600 mg to about 1,200 mg, or about 600 mg to about 900 mg, based on the free base. In some implementations, the prodrug or a pharmaceutically acceptable salt thereof is administered with food at a total daily dose of about 75 mg, about 150 mg, about 300 mg, about 600 mg, about 900 mg, or about 1,200 mg based on the free base.

[0138] This article also provides a method for treating IBD in patients of need, comprising administering to the patient a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug, wherein the prodrug or a pharmaceutically acceptable salt of the prodrug is administered at a first dose for a first time period, followed by a second dose for a second time period. The first dose is from about 150 mg / dose to about 1,500 mg / dose based on free base, and the first time period is up to about 24 weeks. In some embodiments, the method comprises administering a prodrug of compound A to the patient at a first dose of about 150 mg / dose to about 1,500 mg / dose during a first time period of up to about 24 weeks, followed by a second dose during a second time period. In some embodiments, the IBD is UC or CD.

[0139] In some embodiments, the prodrug administered at the first and second doses is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0140] R 6 -C(O)OR 16 -OP(O)(OR 12 )2、-C(O)-R 16 -OP(O)(OR 12 )2、-R 16 -OP(O)(OR 12 )2、-C(O)OR16 -OR 17 -C(O)OR 16 -OH, -C(O)OR 16 -OC(O)R 17 -C(O)-C(O)OR 12 or -C(O)OR 16 -OC(O)R 17 NH2;

[0141] Each R 12 Independently hydrogen or C1-9 alkyl;

[0142] R 16 Each can be arbitrarily assigned to one to four Cs. 1-3 Alkyl or cyclopropyl substituted -C 1-3 Alkyl or cyclopropyl; and

[0143] R 17 Each can be arbitrarily assigned to one to three Rs. 16 Replacement C 1-9 Alkyl, cycloalkyl, or heterocyclic groups.

[0144] In some such implementations of Formula I, R 6 -C(O)OR 16 -OP(O)(OR 12 2. In some implementations, each R 12 It is hydrogen. In some implementations, R 16 C 1-3 Alkyl group. In some embodiments, R 6 for , , , or In some implementations, R 6 for In some implementations, R 6 for .

[0145] In some embodiments, the prodrug administered at the first and second doses is compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17, or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug administered at the first and second doses is compound 1. For example, in some such embodiments, the method comprises administering a prodrug of compound 1 to a patient at a first dose of about 150 mg / dose to about 1,500 mg / dose over a first time period of up to about 24 weeks, followed by administration at a second dose over a second time period.

[0146] In some embodiments, the first dose is about 75 mg / dose to about 900 mg / dose, about 75 mg / dose to about 600 mg / dose, about 75 mg / dose to about 300 mg / dose, about 150 mg / dose to about 1,500 mg / dose, about 150 mg / dose to about 900 mg / dose, about 150 mg / dose to about 600 mg / dose, about 150 mg / dose to about 300 mg / dose, about 300 mg / dose to about 1,500 mg / dose, about 300 mg / dose to about 900 mg / dose, or about 300 mg / dose to about 600 mg / dose, based on free base. In some embodiments, the first dose is about 75 mg / dose, 150 mg / dose, about 300 mg / dose, about 600 mg / dose, or about 900 mg / dose, based on free base. In some embodiments, the first dose is administered twice daily. In some embodiments, the first dose is administered once daily.

[0147] In some implementations, the first time period is up to about 22 weeks, up to about 20 weeks, up to about 18 weeks, up to about 16 weeks, up to about 14 weeks, up to about 12 weeks, up to about 10 weeks, up to about 8 weeks, up to about 6 weeks, up to about 4 weeks, or up to about 2 weeks. In some implementations, the first time period is about 2 weeks to about 24 weeks, about 2 weeks to about 20 weeks, about 2 weeks to about 16 weeks, about 2 weeks to about 12 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 20 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 12 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 20 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 12 weeks, about 12 weeks to about 24 weeks, about 12 weeks to about 20 weeks, or about 12 weeks to about 16 weeks. In some implementations, the first time period is about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, or about 20 weeks.

[0148] In some embodiments, the second dose is less than or equal to the first dose. In some embodiments, the second dose is less than the first dose. In some embodiments, the second dose is greater than or equal to the first dose. In some embodiments, the second dose is equal to the first dose.

[0149] In some implementations, the second dose is selected based on the patient's response to the first dose after a first time period. For example, in some implementations, IBD is UC, and after the first time period, the patient's response to the first dose is determined based on the number of bowel movements, rectal bleeding, endoscopic findings, or any combination thereof. In some implementations, the second dose is selected, for example, based on the number of bowel movements, rectal bleeding, and endoscopic findings after the first time period, for patients who have a sufficient response to the first dose. In some implementations, for example, based on the number of bowel movements, rectal bleeding, and endoscopic findings after the first time period, the second dose is selected for patients who have an insufficient response to the first dose.

[0150] In some embodiments, the patient responds adequately to the first dose, and the second dose is less than or equal to the first dose. In some such embodiments, the second dose is about 75 mg / dose to about 600 mg / dose, about 75 mg / dose to about 300 mg / dose, about 150 mg / dose to about 600 mg / dose, about 150 mg / dose to about 300 mg / dose, or about 300 mg / dose to about 600 mg / dose, based on free base. In some such embodiments, the second dose is about 75 mg / dose, 150 mg / dose, or about 300 mg / dose, or about 600 mg / dose, based on free base. In some such embodiments, the second dose is administered twice daily. In some such embodiments, the second dose is administered once daily.

[0151] In some implementations, the patient does not respond adequately to the first dose, and the second dose is greater than or equal to the first dose. In some such implementations, the second dose is about 150 mg / dose to about 900 mg / dose, about 150 mg / dose to about 600 mg / dose, about 150 mg / dose to about 300 mg / dose, about 300 mg / dose to about 900 mg / dose, or about 300 mg / dose to about 600 mg / dose, based on free base. In some such implementations, the second dose is about 150 mg / dose, about 300 mg / dose, about 600 mg / dose, or about 900 mg / dose, based on free base. In some such implementations, the second dose is administered twice daily. In some such implementations, the second dose is administered once daily.

[0152] In some implementations, the second time period is at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 20 weeks, or at least about 24 weeks.

[0153] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 600 mg / dose during a first time period of up to about 24 weeks, determining that the patient achieves an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 300 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0154] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 600 mg / dose during a first time period of up to about 24 weeks, determining that the patient has not achieved an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 600 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0155] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 600 mg / dose during a first time period of up to about 24 weeks, determining that the patient has not achieved an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 300 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0156] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 300 mg / dose during a first time period of up to about 24 weeks, determining that the patient achieves an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 300 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0157] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 300 mg / dose during a first time period of up to about 24 weeks, determining that the patient achieves an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 150 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0158] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 300 mg / dose during a first time period of up to about 24 weeks, determining that the patient has not achieved an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 300 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0159] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 150 mg / dose during a first time period of up to about 24 weeks, determining that the patient achieves an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 150 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0160] In some embodiments, the method includes administering a prodrug of compound 1 to a patient at a first dose of about 150 mg / dose during a first time period of up to about 24 weeks, determining that the patient has not achieved an adequate response to the first dose after the first time period, and administering the prodrug at a second dose of about 300 mg / dose during a second time period. In some such embodiments, the prodrug is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC.

[0161] In some embodiments, the method includes administering compound 1 or a pharmaceutically acceptable salt thereof to a patient at a first dose of about 600 mg / dose, or about 300 mg / dose, or about 150 mg / dose during a first time period of up to about 24 weeks, followed by administering compound 1 or a pharmaceutically acceptable salt thereof at a second dose of about 600 mg / dose, or about 300 mg / dose, or about 150 mg / dose during a second time period. In some such embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In some such embodiments, the first time period is about 12 weeks. In some such embodiments, IBD is UC. In some such embodiments, the patient is a person. In some embodiments, the first dose is 600 mg / dose and the second dose is 300 mg / dose. In some embodiments, the first dose is 300 mg / dose and the second dose is 300 mg / dose. In some embodiments, the first dose is 600 mg / dose and the second dose is 150 mg / dose. In some embodiments, the first dose is 300 mg / dose and the second dose is 150 mg / dose. In some implementations, the first dose is 150 mg / dose, and the second dose is 150 mg / dose.

[0162] This article also provides a method for treating IBD in patients of need, the method comprising administering the pharmaceutical composition or oral dosage form described herein to the patient. In some such embodiments, IBD is UC or CD.

[0163] Pharmaceutical compositions and oral dosage forms

[0164] This document also provides a pharmaceutical composition comprising a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug, and further comprising a diluent, a disintegrant, or a lubricant, or any combination thereof. In some embodiments, the pharmaceutical composition comprises a prodrug of compound A, and further comprises a diluent, a disintegrant, or a lubricant, or any combination thereof.

[0165] In some embodiments, the pharmaceutical composition comprises a prodrug, which is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0166] R 6 -C(O)OR 16 -OP(O)(OR 12 )2、-C(O)-R 16 -OP(O)(OR 12 )2、-R 16 -OP(O)(OR 12 )2、-C(O)OR 16 -OR 17 -C(O)OR 16 -OH, -C(O)OR 16 -OC(O)R 17 -C(O)-C(O)OR 12 or -C(O)OR 16 -OC(O)R 17 NH2;

[0167] Each R 12 Independently hydrogen or C1-9 alkyl;

[0168] R 16 Each can be arbitrarily assigned to one to four Cs. 1-3 Alkyl or cyclopropyl substituted -C 1-3 Alkyl or cyclopropyl; and

[0169] R 17 Each can be arbitrarily assigned to one to three Rs. 16 Replacement C 1-9 Alkyl, cycloalkyl, or heterocyclic groups.

[0170] In some such implementations of Formula I, R 6 -C(O)OR 16 -OP(O)(OR 12 2. In some implementations, each R 12 It is hydrogen. In some implementations, R 16 C 1-3 Alkyl group. In some embodiments, R 6 for , , , or In some implementations, R 6 for In some implementations, R 6 for .

[0171] In some embodiments, the pharmaceutical composition comprises a prodrug, which is compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a prodrug, which is compound 1.

[0172] In some embodiments, the pharmaceutical composition comprises a diluent, and the diluent comprises lactose, lactose monohydrate, mannitol, isomaltitol, sucrose, dextran, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, acidified cellulose, colloidal silica, calcium hydrogen phosphate dihydrate, calcium carbonate, or any combination thereof. In some embodiments, the pharmaceutical composition comprises lactose monohydrate, microcrystalline cellulose, or both.

[0173] In some embodiments, the pharmaceutical composition comprises a disintegrant, and the disintegrant comprises croscarmellose sodium, crospovidone, starch (e.g., partially pregelatinized corn starch), cellulose, low-substituted hydroxypropyl cellulose, alginate, sodium carboxymethyl starch, or any combination thereof. In some embodiments, the pharmaceutical composition comprises crospovidone.

[0174] In some embodiments, the pharmaceutical composition comprises a lubricant, and the lubricant comprises magnesium stearate, calcium stearate, stearic acid (stearin), talc, starch, fumed silica, hydrogenated oil, polyethylene glycol, sodium stearoyl fumarate, glyceryl behenate, or any combination thereof. In some embodiments, the pharmaceutical composition comprises magnesium stearate.

[0175] In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the dosage form comprises a prodrug or a pharmaceutically acceptable salt thereof, based on about 75 mg to about 600 mg, about 75 mg to about 300 mg, about 150 mg to about 600 mg, or about 15 mg to about 300 mg based on free base. In some embodiments, the dosage form comprises a prodrug or a pharmaceutically acceptable salt thereof, based on about 150 mg or about 300 mg based on free base.

[0176] In some embodiments, the dosage form is a tablet. In some such embodiments, the tablet comprises a film coating. In some embodiments, the film coating comprises a film-forming polymer, a pigment / opaque agent, a plasticizer, or a filler, or any combination thereof.

[0177] In some embodiments, the membrane coating comprises a film-forming polymer, and the film-forming polymer comprises hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), sodium carboxymethyl cellulose, polyvinyl alcohol, a copolymer of methacrylic acid, or any combination thereof. In some embodiments, the membrane coating comprises polyvinyl alcohol.

[0178] In some embodiments, the membrane coating comprises a pigment / opaque agent, and the pigment / opaque agent comprises aluminum flakes, iron oxides, titanium dioxide (titanium white), natural pigments, or any combination thereof. In some embodiments, the membrane coating comprises titanium dioxide.

[0179] In some embodiments, the film coating comprises a plasticizer, and the plasticizer comprises polyethylene glycol, glycerin, triethyl citrate, diethyl phthalate, or any combination thereof. In some embodiments, the film coating comprises polyethylene glycol.

[0180] In some embodiments, the membrane coating comprises a filler, and the filler comprises talc, fumed silica, bentonite, edible hydrogenated vegetable oil, or any combination thereof. In some embodiments, the membrane coating comprises talc.

[0181] This article also provides an oral dosage form comprising a prodrug of compound A or a pharmaceutically acceptable salt of the prodrug and a pharmaceutically acceptable excipient, the oral dosage form being formulated to achieve one or more pharmacokinetic characteristics selected from the following when administered orally to a human patient daily on an empty stomach:

[0182] Arithmetic mean steady-state AUC of compound A from approximately 10 h*µg / mL to approximately 80 h*µg / mL tau ;

[0183] Arithmetic mean steady state of compound A from approximately 0.9 µg / mL to approximately 9 µg / mL max ;

[0184] The median steady-state T of compound A from approximately 1.5 hours to approximately 6 hours max ;as well as

[0185] The median steady-state t of compound A is approximately 18 to approximately 30 hours. 1 / 2 .

[0186] In some implementations, the oral dosage form is formulated to achieve an arithmetic mean steady-state AUC of approximately 10 h*µg / mL to approximately 80 h*µg / mL after daily oral administration to human patients in an empty stomach. tau In some implementations, the oral dosage form is formulated to achieve an arithmetic mean steady-state concentration of compound A from approximately 0.9 µg / mL to approximately 9 µg / mL C after daily oral administration to human patients on an empty stomach. maxIn some implementations, the oral dosage form is formulated to achieve a median steady-state T of compound A for approximately 1.5 hours to approximately 6 hours after daily oral administration to human patients on an empty stomach. max In some implementations, the oral dosage form is formulated to achieve a median steady-state t of compound A for approximately 18 hours to approximately 30 hours after daily oral administration to human patients on an empty stomach. 1 / 2 .

[0187] In some implementations, the oral dosage form comprises a prodrug of compound A and a pharmaceutically acceptable excipient, and is formulated to achieve one or more pharmacokinetic characteristics after daily oral administration to human patients in an empty stomach.

[0188] In some embodiments, the oral dosage form comprises a prodrug, which is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0189] R 6 -C(O)OR 16 -OP(O)(OR 12 )2、-C(O)-R 16 -OP(O)(OR 12 )2、-R 16 -OP(O)(OR 12 )2、-C(O)OR 16 -OR 17 -C(O)OR 16 -OH, -C(O)OR 16 -OC(O)R 17 -C(O)-C(O)OR 12 or -C(O)OR 16 -OC(O)R 17 NH2;

[0190] Each R 12 Independently hydrogen or C1-9 alkyl;

[0191] R 16 Each can be arbitrarily assigned to one to four Cs. 1-3 Alkyl or cyclopropyl substituted -C 1-3 Alkyl or cyclopropyl; and

[0192] R 17 Each can be arbitrarily assigned to one to three Rs. 16 Replacement C 1-9 Alkyl, cycloalkyl, or heterocyclic groups.

[0193] In some such implementations of Formula I, R 6 -C(O)OR 16 -OP(O)(OR12 2. In some implementations, each R 12 It is hydrogen. In some implementations, R 16 C 1-3 Alkyl group. In some embodiments, R 6 for , , , or In some implementations, R 6 for In some implementations, R 6 for .

[0194] In some embodiments, the oral dosage form comprises a prodrug, which is compound 1, compound 2, compound 3, compound 4, compound 5, or compound 17, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral dosage form comprises a prodrug, which is compound 1.

[0195] In some embodiments, the oral dosage form is formulated to achieve, upon daily oral administration to human patients on an empty stomach, approximately 10 h*µg / mL to approximately 70 h*µg / mL, approximately 10 h*µg / mL to approximately 65 h*µg / mL, approximately 10 h*µg / mL to approximately 60 h*µg / mL, approximately 20 h*µg / mL to approximately 80 h*µg / mL, approximately 20 h*µg / mL to approximately 70 h*µg / mL, approximately 20 h*µg / mL to approximately 65 h*µg / mL, and approximately 20 h*µg / mL to approximately 60 h*µg / mL. The arithmetic mean steady-state AUC of compound A is calculated as follows: L, approximately 35 h*µg / mL to approximately 80 h*µg / mL, approximately 35 h*µg / mL to approximately 70 h*µg / mL, approximately 35 h*µg / mL to approximately 65 h*µg / mL, approximately 35 h*µg / mL to approximately 60 h*µg / mL, approximately 40 h*µg / mL to approximately 80 h*µg / mL, approximately 40 h*µg / mL to approximately 70 h*µg / mL, approximately 40 h*µg / mL to approximately 65 h*µg / mL, or approximately 40 h*µg / mL to approximately 60 h*µg / mL. tau In some implementations, the oral dosage form is formulated to achieve an arithmetic mean steady-state AUC of approximately 10.5 h*µg / mL, approximately 37.4 h*µg / mL, approximately 55.1 h*µg / mL, approximately 62.2 h*µg / mL, or approximately 77.5 h*µg / mL after daily oral administration to human patients on an empty stomach. tau .

[0196] In some implementations, the oral dosage form is formulated to achieve, upon daily oral administration to human patients in an empty stomach, a dosage of approximately 0.9 µg / mL to approximately 7 µg / mL, approximately 0.9 µg / mL to approximately 6 µg / mL, approximately 0.9 µg / mL to approximately 5 µg / mL, approximately 1.5 µg / mL to approximately 9 µg / mL, approximately 1.5 µg / mL to approximately 7 µg / mL, approximately 1.5 µg / mL to approximately 6 µg / mL, and approximately 1.5 µg / mL. The arithmetic mean steady state of compound A at concentrations of approximately 5 µg / mL, approximately 2.5 µg / mL to approximately 9 µg / mL, approximately 2.5 µg / mL to approximately 7 µg / mL, approximately 2.5 µg / mL to approximately 6 µg / mL, approximately 2.5 µg / mL to approximately 5 µg / mL, approximately 3 µg / mL to approximately 9 µg / mL, approximately 3 µg / mL to approximately 7 µg / mL, approximately 3 µg / mL to approximately 6 µg / mL, or approximately 3 µg / mL to approximately 5 µg / mL is as follows: max In some implementations, the oral dosage form is formulated to achieve an arithmetic mean steady-state concentration of compound A of about 0.1 µg / mL, about 3.2 µg / mL, about 3.8 µg / mL, about 5 µg / mL, or about 8.6 µg / mL after daily oral administration to human patients on an empty stomach. max .

[0197] In some embodiments, the oral dosage form is formulated to achieve a median steady-state T of compound A for approximately 1.5 hours to approximately 5 hours, approximately 1.5 hours to approximately 4 hours, approximately 2 hours to approximately 6 hours, approximately 2 hours to approximately 5 hours, approximately 2 hours to approximately 4 hours, approximately 2 hours to approximately 6 hours, approximately 2 hours to approximately 5 hours, or approximately 2 hours to approximately 4 hours after daily oral administration to human patients on an empty stomach. max In some implementations, the oral dosage form is formulated to achieve a median steady-state T of compound A for approximately 2 hours, approximately 3 hours, or approximately 4 hours after daily oral administration to human patients on an empty stomach. max .

[0198] In some embodiments, the oral dosage form is formulated to achieve a median steady-state t of compound A for approximately 18 to 29 hours, approximately 18 to 28 hours, approximately 19 to 30 hours, approximately 19 to 29 hours, approximately 19 to 28 hours, approximately 21 to 30 hours, approximately 21 to 29 hours, or approximately 21 to 28 hours after daily oral administration of the dosage form to a human patient on an empty stomach. 1 / 2 In some implementations, the oral dosage form is formulated to achieve a median steady-state t of compound A for approximately 19 hours, approximately 22 hours, approximately 28 hours, or approximately 29 hours after daily oral administration to human patients on an empty stomach. 1 / 2 .

[0199] In some embodiments, pharmaceutically acceptable excipients include diluents, disintegrants, binders, lubricants, or any combination thereof. In some embodiments, pharmaceutically acceptable excipients include the diluents, disintegrants, lubricants, or any combination thereof described herein. In some such embodiments, pharmaceutically acceptable excipients comprise lactose monohydrate, crospovidone, or magnesium stearate, or any combination thereof.

[0200] In some embodiments, the oral dosage form is a tablet. In some such embodiments, the tablet comprises a film coating. In some embodiments, the film coating comprises the film-forming polymer described herein, the pigment / opaque agent described herein, the plasticizer described herein, the filler described herein, or any combination thereof. In some such embodiments, the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, or any combination thereof. In some such embodiments, the film coating comprises polyvinyl alcohol, polyethylene glycol, talc, or any combination thereof.

[0201] In some embodiments, the oral dosage form comprises a prodrug or a pharmaceutically acceptable salt thereof, based on about 75 mg to about 600 mg, about 75 mg to about 300 mg, about 150 mg to about 600 mg, or about 15 mg to about 300 mg, calculated as a free base. In some embodiments, the dosage form comprises a prodrug or a pharmaceutically acceptable salt thereof, based on about 150 mg or about 300 mg, calculated as a free base.

[0202] Example

[0203] Example 1. Dose escalation study in healthy participants

[0204] A two-part, single-escalation and multiple-escalation sponsor-initiated phase 1 study was conducted in cohorts 1–9 to evaluate the safety, tolerability, pharmacokinetic (PK), and PD of compound 1 in healthy participants. Up to 72 participants aged 18–55 years (inclusive) with a body mass index (BMI) ≥19.0 and ≤30.0 kg / m² were recruited. 2 For cohort 9, participants were allele homozygous for UGT1A1*28 (UGT1A1 *28 / *28:TA7 / TA7).

[0205] Part A: Cohorts 1-4; Single escalation dose

[0206] Part A was conducted in four staggered dose-escalation cohorts. Within each cohort of cohorts 1–4, eight unique participants were randomized 3:1 to receive either blinded compound 1 (N=6) or matched placebo (PTM) (N=2). The dose of compound 1 for all adaptive cohorts (cohorts 2, 3, and 4) was determined based on minimum cumulative safety data up to day 3 from previous cohorts and available PK data, not exceeding the specified upper dose limits (Table 2). Dosing in Part A was completed before Part B.

[0207] Table 2

[0208]

[0209] Part B: Cohorts 5-9; Multiple escalation doses

[0210] Part B was conducted in up to five staggered dose-escalation cohorts. Within each cohort of cohorts 5–9, eight unique participants were randomized in a 3:1 ratio to receive either blinded compound 1 (N=6) or PTM (N=2). The initiation of multiple dosing in adaptive cohort 5 was determined by reviewing cumulative safety and PK data from the last cohort in Part A up to at least day 3. The initiation of subsequent multiple-dose cohorts at higher doses (cohorts 6, 7, 8, and 9) was determined based on cumulative safety data from all participants enrolled in the previous multiple-dose cohorts up to at least day 10 (Table 3).

[0211] Table 3

[0212]

[0213] a Cohort 9 included only participants who were homozygous for the UGT1A1*28 allele (UGT1A1*28 / *28:TA7 / TA7).

[0214] Compound 1 is administered in tablet form at strengths of 25 mg or 150 mg. In addition to the active ingredient, Compound 1 tablets also contain lactose monohydrate, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0215] PTM is administered in tablet form that is identical in size, shape, color, and appearance to the corresponding active compound 1 tablet. PTM tablets contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0216] For cohorts 1-4, plasma pharmacokinetic (PK) samples were taken at the following time points relative to the dose of compound 1:

[0217] • Day 1: 0 hours (before administration, ≤5 minutes before administration), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours after administration

[0218] If applicable, collect a single plasma PK sample upon early termination (ET).

[0219] For cohorts 1-4, whole blood PD samples were taken at the following time points relative to the dose of compound 1:

[0220] • Day 1: 0 hours before administration (≤5 minutes before administration), and 1, 2, 3, 4, 8, 12, 24, and 36 hours after administration.

[0221] For cohorts 5-9, plasma pharmacokinetic samples were taken at the following time points relative to the dose of compound 1:

[0222] • Day 1 (Cohorts 8 and 9): Before administration (≤5 minutes before administration), and 0.5, 1, 2, 3, 4, 6, 8, 12, 13, 14, 15, 16, 18, and 20 hours after administration (relative to AM administration)

[0223] • Day 10 (Cohorts 5-9): Before administration (≤5 minutes before administration), and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours after administration.

[0224] • Collect samples before administration on days 2, 4, 7 and 8.

[0225] If applicable, collect a single plasma PK sample upon early termination (ET).

[0226] For cohorts 5-9, whole blood PD samples were taken at the following time points relative to the dose of compound 1:

[0227] • Day 1: 0 hours before administration (≤5 minutes before administration), and 1, 2, 3, 4, 8, 12, and 24 hours after administration.

[0228] • Day 10: 0 hours before administration (≤5 minutes before administration), and 1, 2, 3, 4, 8, 12, 24, 36, 48, 72, 96, and 120 hours after administration.

[0229] The concentrations of compound 1 and its corresponding metabolites compound A and compound B in plasma PK samples were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) bioanalytical method.

[0230] Whole blood PD samples were stimulated in vitro with lipopolysaccharide (LPS) or phosphate-buffered saline (PBS), and the phosphorylation of extracellular signal-related kinase (pERK) in monocytes was detected by flow cytometry.

[0231] Safety assessment includes monitoring for adverse events (AEs) and concomitant medications, clinical laboratory analysis, vital sign measurement, electrocardiogram (ECG), and physical examination.

[0232] Pharmacokinetic results

[0233] The pharmacokinetic parameters of compound 1 and its metabolites were determined from plasma concentration-time curves of all evaluable participants. The parameters are listed in Table 4 below.

[0234] Table 4

[0235]

[0236] Compound 1 is administered on an empty stomach for at least 10 hours after fasting (no food or beverage other than water); food may be consumed 4 hours after administration of Compound 1.

[0237] Following a single oral dose of compound 1 (300 mg to 1500 mg) under such fasting conditions, the plasma exposure of compound A (C... max AUC inf and AUC last The exposure of compound A increased in a dose-dependent manner within the dose range of 300 mg to 900 mg, with no further increase in exposure beyond 1500 mg. The median time to reach maximum plasma concentration (Tmax) for compound A was between 3 and 4 hours post-dose. At the evaluated dose levels, the median terminal elimination t1 / 2 was between 22 and 29 hours. Inter-individual variability in single-dose compound A was [not specified]. max AUC inf and AUC last Typically low to medium, ranging from 23% CV to 63% CV.

[0238] After administration of multiple once-daily doses of compound 1 (75 mg to 900 mg) or twice-daily 600 mg of compound 1 under fasting conditions, steady-state plasma exposure to compound A (C) was determined. max The PK parameters (and AUC) were increased from 75 mg to 900 mg in a dose-dependent manner. The PK parameters after administration of compound 1 once daily (75 mg, 300 mg, 600 mg or 900 mg) or twice daily (600 mg) on ​​day 1 under fasting conditions and after 10 days of administration are shown in Tables 5 and 6 below.

[0239] Table 5

[0240]

[0241] BID = twice daily; %CV = percentage of coefficient of variation; MAD = multiple dose escalation; PK = pharmacokinetics; QD = once daily; UGTIA1 = uridine diphosphate glucuronide transferase 1A1

[0242] The average value presented by a is the unadjusted arithmetic mean.

[0243] The b value is for the morning dose (AM) of cohort 8.

[0244] The value of c represents the median (minimum, maximum).

[0245] Table 6

[0246]

[0247] BID = twice daily; %CV = percentage of coefficient of variation; MAD = multiple dose escalation; PK = pharmacokinetics; QD = once daily; UGTIA1 = uridine diphosphate glucuronide transferase 1A1

[0248] The average value presented by a is the unadjusted arithmetic mean.

[0249] The b value is for the morning dose (AM) of cohort 8.

[0250] The value of c represents the median (minimum, maximum).

[0251] The median Tmax value of compound A was in the range of 2 to 4 hours after administration of compound 1, and the median t value of compound A was... 1 / 2 Values ​​ranged from 19 to 28 hours. The differences in AUC and Cmax parameters for compound A ranged from 14% CV to 39% CV, consistent with the single-dose cohort. Maximum plasma concentrations of compound A were reached between 2.0 and 4.0 hours after administration of compound 1 (median T). max ).

[0252] At the evaluated dose levels of compound 1, compound A showed a median t-value of 20 to 30 hours after a single or multiple dose. 1 / 2 Inter-individual variability (%CV) was typically low to moderate in the cohort, ranging from 13% CV to 46% CV. (This is in contrast to compound A eliminating t...) 1 / 2Consistently, after multiple daily doses of 600 mg, the cumulative exposure (AUC) of compound A was approximately 2-fold. Steady-state exposure to compound A was achieved on day 7 of daily administration of compound 1.

[0253] Pharmacodynamic results

[0254] The pharmacodynamic changes of compound 1 after single and multiple doses were also investigated by monitoring whole blood samples stimulated at 37°C with lipopolysaccharide (LPS) or PBS for 15 minutes. Changes in phosphorylation of extracellular signal-regulated kinase (pERK), defined as CD15-CD14+, were measured in monocytes by flow cytometry.

[0255] The pharmacodynamic parameters of compound 1 were calculated as the percentage change in pERK signal in all evaluable participants relative to day 1 before administration (baseline).

[0256] Single-dose escalation: Following a single oral dose of compound 1 (300 mg to 1500 mg) under fasting conditions, dose-dependent and reversible inhibition of LPS-stimulated pERK was observed, with peak inhibition at 3 hours post-dose for all administered doses of compound 1. At 3 hours post-dose, the median changes in pERK relative to baseline for placebo, 75 mg compound 1, 300 mg compound 1, 900 mg compound 1, and 1500 mg compound 1 were 0.2%, -86.8%, -95.6%, -99.9%, and -99%, respectively. At 12 hours post-dose, the median changes in pERK relative to baseline for placebo, 75 mg compound 1, 300 mg compound 1, 900 mg compound 1, and 1500 mg compound 1 were 9%, -51.3%, -76.6%, -92.1%, and -96.3%, respectively. The percentage of pERK signal inhibition, normalized to baseline and categorized by dose cohort, following a single dose of compound 1 (75 mg, 300 mg, 900 mg, or 1500 mg) is shown in Table 7 below.

[0257] Table 7. Summary statistics of pERK signal, by inhibition percentage in the dose cohort, normalized to baseline (SAD cohort).

[0258]

[0259]

[0260] P-value (Wilcoxon): Wilcoxon rank-sum test comparing the treatment group with the placebo group.

[0261] P-value (JT): Jonckheere's trend test, indicating the probability of a dose-dependent response.

[0262] Multiple escalation doses: The pharmacodynamic parameters of compound 1 were also calculated as the percentage change in pERK signal in all evaluable participants relative to day 1 before administration (baseline).

[0263] On day 10, a dose-dependent and reversible trend toward LPS-stimulated pERK inhibition was observed in multiple once-daily doses of compound 1 (75 mg to 900 mg) administered under fasting conditions or twice-daily doses of 600 mg of compound 1. The maximum PD effect was observed on day 10, between 2 and 4 hours after the last dose.

[0264] On day 10, 12 hours after the last dose, the median percentage change in pERK relative to baseline for placebo, 75 mg compound 1 QD, 300 mg compound 1 QD, 900 mg compound 1 QD, and 600 mg compound 1 BID were 14.2%, -48.3%, -95.7%, -96.7%, and -100.2%, respectively. On day 10, 24 hours after the last dose, the median percentage change in pERK relative to baseline for placebo, 75 mg compound 1 QD, 300 mg compound 1 QD, 900 mg compound 1 QD, and 600 mg compound 1 BID were -3.9%, -39.8%, -91.6%, -98.5%, and -101.5%, respectively. The percentage inhibition of pERK signaling, normalized to baseline by dose cohort, after multiple doses of compound 1 (75 mg, 300 mg, and 900 mg QD and 600 mg BID) is shown in Table 8 below.

[0265] Table 8. Summary statistics of pERK signal, by inhibition percentage in the dose cohort, normalized to baseline (MAD cohort).

[0266]

[0267]

[0268]

[0269] P-value (Wilcoxon): Wilcoxon rank-sum test comparing the treatment group with the placebo group.

[0270] P-value (JT): Jonckheere's trend test, indicating the probability of a dose-dependent response.

[0271] Results from the SAD and MAD cohorts demonstrated that administration of compound 1 achieved dose-dependent and reversible inhibition of LPS-stimulated pERK in ex vivo whole blood samples, indicating TPL2 pathway inhibition. Surprisingly, each dose tested was effective in inhibiting the TPL-2 pathway.

[0272] The results further demonstrated that administration of 300 mg compound 1 QD, 900 mg compound 1 QD and 600 mg compound 1 BID each achieved the mean steady-state exposure to compound A, which resulted in >90% inhibition of LPS-stimulated pERK 24 hours after the last dose, also indicating inhibition of TPL-2.

[0273] Example 2. Single-dose and multiple-dose studies were conducted in healthy participants to evaluate drug-drug interactions and Food effect

[0274] A phase 1, open-label, single-center, multi-cohort study was conducted to evaluate the pharmacokinetic (PK) effects of a combination of OATP / P-gp inhibitors (cyclosporine A; CsA) or food on compound 1 in healthy participants, the PK effects of compound 1 on midazolam (MDZ), the PK effects of compound 1 on OATP / CYP3A / BCRP substrates used with atorvastatin (ATV), pravastatin (PRA), and rosuvastatin (ROS), and the PK effects of compound 1 on representative combination oral contraceptives (drospirenone / ethinylestradiol; DRSP / EE). Seventy participants aged 18 to 55 years (inclusive) with a BMI ≥ 18.0 kg / m² were recruited. 2 And ≤30.0kg / m 2 The participants were included. For cohorts 1-3, there was a roughly even distribution of healthy participants who were designated as male at birth and non-pregnant, non-lactating participants who were designated as female at birth. Cohort 4 included only healthy, non-pregnant, non-lactating participants who were designated as female at birth.

[0275] Cohort 1 - Mixed OATP / P-gp inhibitors: CsA 600mg

[0276] Participants in queue 1 will be randomly assigned to one of the two treatment sequences (ABC or BAC) at a 1:1 ratio.

[0277] Treatment A Under fasting conditions, a single dose of the compound, 1600 mg, was administered via AM.

[0278] Treatment B : Administer a single dose of compound 1600 mg via AM within 5 minutes of completing a high-fat / high-calorie meal.

[0279] Treatment C Under fasting conditions, a single dose of compound 1600 mg and a single dose of CsA 600 mg were administered with AM.

[0280] Table 9

[0281]

[0282] CsA = Cyclosporin A; WO = Elution

[0283] Cohort 2 - CYP3A substrate: MDZ 2mg

[0284] Participants in cohort 2 received the treatment sequence DEFG.

[0285] Treatment D On day 1 of cycle 1, administer a single dose of MDZ 2mg on an empty stomach.

[0286] Treatment E During cycle 2, from day 1 to day 11, administer 1600 mg of the compound once daily on an empty stomach for 11 consecutive days.

[0287] Treatment F On day 12 of cycle 2, a single dose of MDZ 2 mg was administered on an empty stomach, along with a 1600 mg dose of compound.

[0288] Treatment of G On day 13 of cycle 2, a single dose of compound 1600 mg was administered on an empty stomach.

[0289] Table 10

[0290]

[0291] MDZ = Midazolam; QD = Once daily; WO = Washout

[0292] Cohort 3 - OATP / CYP3A substrate: ATV 40 mg; or OATP / BCRP substrate mixture: PRA 40 mg + ROS 10 mg

[0293] Participants in cohort 3 received the treatment sequence HIJKLMN.

[0294] Treatment of H On day 1 of cycle 1, administer a single dose of ATV 40mg on an empty stomach.

[0295] Treatment I On day 1 of cycle 2, administer a single dose of PRA+ROS 40mg / 10mg on an empty stomach.

[0296] Treatment J : Administer 1600 mg of the compound once daily on an empty stomach during days 1 to 5 of cycle 3.

[0297] Treatment K On day 6 of cycle 3, administer a single dose of ATV 40 mg on an empty stomach, along with a 1600 mg dose of compound.

[0298] Treatment L : On days 7 to 9 of cycle 3, administer 1600 mg of the compound once daily on an empty stomach.

[0299] Treatment of M On day 10 of cycle 3, administer a single dose of compound 1600 mg on an empty stomach, along with a single dose of PRA+ROS 40 mg / 10 mg.

[0300] Treatment N : On days 11 to 13 of cycle 3, administer 1600 mg of the compound once daily on an empty stomach.

[0301] Table 11

[0302]

[0303] ATV = Atorvastatin; PRA = Pravastatin; QD = Once daily; ROS = Rosuvastatin; WO = Washout

[0304] Cohort 4 - Representative combination of oral contraceptives: DRSP 3mg and EE 0.02mg

[0305] Participants in cohort 4 received the treatment sequence OPQR.

[0306] Treatment O On day 1 of cycle 1, administer a single dose of DRSP 3 mg and EE 0.02 mg on an empty stomach.

[0307] Treatment of P During days 1 to 11 of cycle 2, administer 1600 mg of the compound once daily on an empty stomach.

[0308] Treatment Q On day 12 of cycle 2, a single dose of DRSP 3 mg and EE 0.02 mg were administered on an empty stomach, along with a single dose of compound 1600 mg.

[0309] Treatment R : On days 13 to 15 of cycle 2, administer 1600 mg of the compound once daily on an empty stomach.

[0310] Table 12

[0311]

[0312] DRSP = drospirenone; EE = ethinylestradiol; QD = once daily; WO = washout

[0313] Plasma PK sampling was performed at the following time points relative to the dose of compound 1, as specified below.

[0314] Queue 1 :

[0315] • Cycles 1, 2, and 3: Day 1, 0 hours (before administration, ≤5 minutes before administration), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, and 96 hours after administration; and at the time of early termination (ET) visit (if applicable).

[0316] Queue 2 :

[0317] • Cycle 1: Day 1, 0 hours (before administration, ≤5 minutes before administration), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 and 24 hours after administration; and at ET visits (if applicable).

[0318] • Cycle 2: Day 1, 0 hours (before administration, ≤5 minutes before administration), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours after administration; Day 12, 0 hours (before administration, ≤5 minutes before administration), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours after administration; Day 13, 0 hours (before administration, ≤5 minutes before administration), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48, 72, and 96 hours after administration; and at ET visits (if applicable).

[0319] Queue 3 :

[0320] • Cycles 1 and 2: Day 1, 0 hours (before administration, ≤5 minutes before administration), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48, 72, and 96 hours after administration, and at the ET visit (if applicable) (PK samples were collected 96 hours after administration on Day 1 of Cycles 1 and 2, respectively, before administration on Day 1 of Cycles 2 and 3).

[0321] • Cycle 3: Day 6, 0 hours (before administration, ≤5 minutes before administration), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48, 72, and 96* hours after administration; Day 10, 0 hours (before administration, ≤5 minutes before administration), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48, 72, and 96* hours after administration; and at ET visits (if applicable) (samples were collected on Day 6 before administration on Day 10 of Cycle 3, and 96 hours after administration. Samples were collected on Day 10 on Day 3, and 96 hours after administration.)

[0322] Queue 4 :

[0323] • Cycle 1: Day 1, 0 hours (before administration, ≤5 minutes before administration), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, and 96* hours after administration; and at ET visits (if applicable) (PK samples were collected 96 hours after administration on Day 1 of Cycle 2 before administration on Day 1 of Cycle 2).

[0324] • Cycle 2: Day 12, 0 hours (before administration, ≤5 minutes before administration), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72 and 96 hours after administration; and at ET visits (if applicable).

[0325] For PK samples collected at 5 hours post-dose, a time window of ±10% is allowed. All other PK samples collected more than 5 hours post-dose have a time window of ±30 minutes.

[0326] The concentrations of compound 1 and its active metabolites compound A and compound B, MDZ and its metabolite 1-OH-MDZ, ATV and its metabolite 2-OH-ATV, PRA, ROS, DRSP and EE in plasma PK samples were determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) bioanalytical method.

[0327] Safety assessment includes monitoring for adverse events (AEs) and concomitant medications, clinical laboratory analysis, estimated glomerular filtration rate (eGFR) based on cysteine ​​protease inhibitor C, vital sign measurements, electrocardiogram (ECG), and physical examination.

[0328] Pharmacokinetic results

[0329] Pharmacokinetic parameters were determined for compound 1 and its metabolites in all cohorts, MDZ and 1-OH-MDZ in cohort 2; ATV, 2-OH-ATV, PRA and ROS in cohort 3; and DRSP and EE in group 4. The parameters are listed in Table 13 below.

[0330] Table 13

[0331]

[0332] Table 14 shows the plasma PK parameters and statistical comparisons of compound A after a single oral administration of compound 1,600 mg under fasting and non-fasting (high-fat / high-calorie diet) conditions.

[0333] Table 14

[0334]

[0335] %CV = percentage of coefficient of variation; CI = confidence interval; GLSM = geometric least squares mean; n = number of participants in the PK analysis set; PK = pharmacokinetics; Q1 = first quartile; Q3 = third quartile

[0336] The value of 'a' is represented as the median (Q1, Q3).

[0337] Treatment A: Compound 1 600mg, on an empty stomach; Treatment B: Compound 1 600mg, on a high-fat / high-calorie diet.

[0338] The average value presented is the unadjusted arithmetic mean.

[0339] Compared with a single dose of compound A (1600 mg) administered on an empty stomach, a high-fat / high-calorie diet increased the AUC of compound A. inf Increased by 92%, while C max No change. Food intake also slightly delayed the absorption of compound A: median T max Increase the fasting time from 4 hours to 5 hours for high-fat / high-calorie meals.

[0340] Co-administration of compound 1 with the mixed OATP / P-gp inhibitor CsA resulted in the reduction of compound AC... max and AUC inf Increased by 27% and 122%.

[0341] Compared to MDZ alone, co-administration of compound 1 (600 mg) with the CYP3A substrate MDZ resulted in a decrease in the C of MDZ. max and AUC inf They increased by 54% and 99% respectively.

[0342] Compared to ATV alone, co-administration of compound 1 (600 mg) with probe OATP / BCRP substrate and CYP3A substrate ATV resulted in a C of ATV. max and AUC inf They increased by 61% and 206% respectively.

[0343] Compared to the administration of PRA+ROS alone, co-administration of compound 1 (600 mg) with the probe OATP / BCRP substrate PRA (along with ROS) resulted in a C of PRA. max and AUC inf They increased by 204% and 173% respectively.

[0344] Compared to the administration of PRA+ROS alone, the co-administration of compound 1 (600 mg) with the probe OATP / BCRP substrate ROS (along with PRA) resulted in a decrease in the C of ROS. max and AUCinf They increased by 780% and 367% respectively.

[0345] Compared to DRSP / EE alone, co-administration of compound 1 (600 mg) with the representative combination oral contraceptive DRSP / EE resulted in a C-level of DRSP. max AUC of DRSP decreased by 49% inf No change, and EE's AUC inf Increase by 75% and C max No change.

[0346] Example 3. Dosage range study in participants with moderate to severe active ulcerative colitis

[0347] A phase 2, double-blind, randomized, placebo-controlled, dose-range study was conducted in participants with moderate to severe active ulcerative colitis (UC) to evaluate the efficacy and safety of compound 1. Approximately 176 participants aged 18 to 75 years who were designated male at birth or female at birth and were not pregnant or lactating were recruited.

[0348] The study includes:

[0349] Screening period: Day -30 to Day -1

[0350] Blind treatment phase: Day 1 to Week 12

[0351] At baseline / randomization (day 1), participants were randomly assigned to one of the following four treatment groups in a 1:1:1:1 ratio:

[0352] Treatment group 1 (n=44): Compound 1 600 mg, once daily

[0353] Treatment group 2 (n=44): Compound 1 300 mg, once daily

[0354] Treatment group 3 (n=44): Compound 1 150 mg, once daily

[0355] Treatment group 4 (n=44): placebo, once daily

[0356] At the week 12 follow-up, participants underwent efficacy assessments to determine if they had achieved a clinical response. Week 12 medication allocation was based on the blinded treatment phase allocation from week 1 and the clinical response status at week 12. Participants achieving a clinical response at week 12 continued into the blinded treatment phase. Participants who did not achieve a clinical response at week 12 were eligible to proceed to the non-responder treatment phase.

[0357] Participants whose data were insufficient to assess clinical response at week 12 discontinued the study drug, were not eligible for the non-responder treatment phase, and were assessed in a blinded treatment phase at week 12, followed by a post-treatment (PTx) assessment 30 days after the last dose of the study drug.

[0358] Blinded treatment phase: Week 12 to Week 52

[0359] Treatment allocation for participants in week 12 of the blinded treatment phase was based on allocation on day 1 of the blinded treatment phase:

[0360] Treatment group 1: Compound 1 300mg, once daily

[0361] Treatment group 2: Compound 1 300mg, once daily

[0362] Treatment group 3: Compound 1 150 mg, once daily

[0363] Treatment group 4: Compound 1 150 mg, once daily

[0364] Treatment phase for non-responders: Day 1 to Week 12

[0365] The first day visit of the treatment phase for non-responders and the 12th week visit of the blinded treatment phase occurred on the same day.

[0366] During the non-responder phase, participants received either 600 mg or 300 mg of compound 1 once daily in a double-blind manner until week 12 of the non-responder phase. Treatment allocation for participants who did not achieve a clinical response by week 12 of the blinded phase was based on allocation on day 1 of the blinded phase:

[0367] Treatment group 1: Compound 1 600mg, once daily

[0368] Treatment group 2: Compound 1 300mg, once daily

[0369] Treatment group 3: Compound 1 300mg, once daily

[0370] Treatment group 4: Compound 1 600mg, once daily

[0371] Treatment phase for non-responders: (Week 12 to Week 52)

[0372] At the week 12 follow-up of the non-responder phase, participants underwent efficacy assessments using endoscopic findings with local scoring to determine whether they had achieved a clinical response. Participants who achieved a clinical response received 1,300 mg of the compound once daily until week 52 of the non-responder phase.

[0373] Participants who did not achieve a clinical response or whose data were insufficient to assess a clinical response during week 12 of the non-responder treatment phase discontinued the study drug and underwent a week 12 non-responder treatment phase assessment, followed by a PTx assessment 30 days after the last dose of the study drug.

[0374] Preliminary analysis of week 12

[0375] When all randomized participants completed the blinded treatment phase 12 visit or discontinued the study, a preliminary analysis of week 12 was conducted, and relevant safety and efficacy assessments were completed.

[0376] Participants who remain in the blinded treatment phase (between weeks 12 and 52) after the initial analysis at week 12 may maintain the same dose as their assigned study drug regimen during week 12. These participants may continue the blinded treatment phase study visit schedule until week 52. Participants in the non-responder treatment phase continue the non-responder treatment phase study visit schedule until week 52. Participants who choose not to continue the study after the initial analysis at week 12 will be seen at their next scheduled study visit or earlier and will undergo an ET assessment, followed by a PTx assessment 30 days after the last dose of study drug.

[0377] Post-treatment (PTx) assessment

[0378] Participants who discontinued the study medication returned for a PTx assessment 30 days after their last dose. Participants who discontinued the study medication ≥30 days prior to their ET visit will not need to complete a separate post-treatment assessment.

[0379] Compound 1 is administered in tablet form at strengths of 150 mg or 300 mg. In addition to the active ingredient, Compound 1 tablets also contain lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0380] PTM is administered in the form of PTM-1 and PTM-2 tablets, which are identical in size, shape, color, and appearance to the corresponding active compound 1 tablets. PTM-1 and PTM-2 tablets contain lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc.

[0381] Compound 1 is administered on an empty stomach; food may be consumed 4 hours before and 2 hours after administration of compound 1.

[0382] Efficacy evaluation

[0383] The Mayo Clinical Score (MCS) is a scoring system used to assess ulcerative colitis (UC) activity and utilizes four sub-scores: defecation frequency, rectal bleeding, endoscopic findings, and physician overall assessment (PGA). Each sub-score is graded from 0 to 3, and the sum of the sub-scores (ranging from 0 to 12) determines the overall MCS. Modified MCS scoring systems utilize the defecation frequency, rectal bleeding, and endoscopic findings sub-scores but exclude the PGA. Some MCS scoring systems utilize defecation frequency, rectal bleeding, and PGA but exclude the endoscopic findings sub-score.

[0384] Bowel movement frequency and rectal bleeding sub-scores were recorded in the participants' electronic diaries and collected daily. During screening, week 12, and week 52, endoscopic examination result sub-scores were reported by the central reader and the endoscopist who performed the procedure (local reader).

[0385] Clinical response was defined as a reduction of ≥2 points and at least 30% in all three components of the modified Mayo Clinical Score (MCS) at week 12, except for a reduction of ≥1 point from baseline in the rectal bleeding sub-score or a reduction of ≤1 point in the rectal bleeding sub-score from baseline.

[0386] Clinical remission was defined as a bowel movement frequency subscore ≤1 and not greater than baseline at week 12, a rectal bleeding subscore of 0, and an endoscopic findings subscore ≤1.

[0387] Endoscopic response was defined as an endoscopy outcome sub-score ≤1 at week 12.

[0388] Histological endoscopic mucosal improvement was defined as an endoscopic outcome score ≤1 and a Geboes score ≤3.1 at week 12 (indicating neutrophil infiltration in <5% of crypts, without crypt destruction, and without erosion, ulceration, or granulation tissue).

[0389] Security assessment

[0390] Safety assessment includes monitoring for adverse events (AEs) and concomitant medications, clinical laboratory analysis, vital sign measurement, electrocardiogram (ECG), and physical examination.

[0391] Pharmacokinetic assessment

[0392] For all participants, blood samples were collected for pharmacokinetic analysis at weeks 2, 4, 8, 12, 24, and 52 after administration of the study drug (at least 30 minutes and at most 3 hours after administration). Blood samples were collected at weeks 4 and 12 prior to administration of the study drug for pharmacokinetic analysis.

[0393] Analyze the plasma concentration of compound 1. Perform additional analyses (e.g., metabolites of compound 1) where applicable.

[0394] Basic principles and expected results of dose selection

[0395] A population pharmacokinetic model for compound 1 was developed and incorporated early clinical data, including data from 63 healthy volunteers from the Phase 1 clinical studies described in Examples 1 and 2, encompassing single-dose ranges from 300 mg to 1500 mg and multiple-dose ranges from 75 mg to 900 mg. Analysis was performed using nonlinear mixed-effects modeling software (NONMEM). The pharmacokinetics of compound A was fully described using a two-compartment model characterized by three transport and absorption compartments and first-order elimination.

[0396] Compound 1 was selected at the highest dose (600 mg) to ensure maximum target coverage across the dosing intervals for most participants. Based on in vitro LPS-stimulated phosphorylated ERK (pERK) assays in whole blood, it is projected that approximately 90% of study participants will achieve an IC50 greater than 600 mg once daily after administration of Compound 1. 90 The steady-state trough concentration. Furthermore, it is estimated that approximately 60% and 20% of participants achieved IC50 greater than 1 after administration of 300 mg once daily and 150 mg once daily, respectively. 90 Target coverage. Table 15 below reflects the expected percentage of target (TPL2 kinase) coverage at the various doses tested.

[0397] Table 15

[0398]

[0399] Within the dose range of compound 1, based on data from the 75 mg to 900 mg dose range of compound 1 observed in the dose escalation study as described in Example 1, limited overlap in compound A exposure is expected for the selected doses of 600 mg, 300 mg, and 150 mg. Therefore, the 150 mg, 300 mg, and 600 mg doses selected in the dose range study as described in Example 3 are expected to achieve therapeutic exposure in patients with UC at all time points of the study (i.e., during the induction and maintenance phases) and establish a plateau in the therapeutic response.

[0400] All references, including publications, patents, and patent documents, are incorporated herein by reference as if separately cited. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many changes and modifications can be made while maintaining the spirit and scope of this disclosure. In making this description, it should be understood that it is intended to be illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments described.

Claims

1. A method for treating inflammatory bowel disease (IBD) in a patient in need, the method comprising administering a prodrug of compound A to the patient: (Compound A) Or a pharmaceutically acceptable salt of the prodrug, The prodrug or its pharmaceutically acceptable salt is administered at a dose of about 75 mg / dose to about 1,500 mg / dose based on free base.

2. A method of treating IBD in a patient in need, the method comprising administering a prodrug of compound A to the patient: (Compound A), or a pharmaceutically acceptable salt of the prodrug, The prodrug is administered at a dose of about 75 mg / dose to about 1,500 mg / dose.

3. The method according to claim 1 or claim 2, wherein the prodrug is a compound of formula I: (Equation I) Or its pharmaceutically acceptable salt, wherein R 6 is -C(O)O-R 16 -OP(O)(OR 12 )2, -C(O)-R 16 -OP(O)(OR 12 )2, -R 16 -OP(O)(OR 12 )2, -C(O)O-R 16 -OR 17 , -C(O)O-R 16 -OH, -C(O)O-R 16 -OC(O)R 17 , -C(O)-C(O)OR 12 or -C(O)O-R 16 -OC(O)R 17 NH2; Each R 12 Independently hydrogen or C1-9 alkyl; R 16 Each can be arbitrarily assigned to one to four Cs. 1-3 Alkyl or cyclopropyl substituted -C 1-3 Alkyl or cyclopropyl; and R 17 Each can be arbitrarily assigned to one to three Rs. 16 Replacement C 1-9 Alkyl, cycloalkyl, or heterocyclic groups.

4. The method according to claim 3, wherein R 6 -C(O)OR 16 -OP(O)(OR 12 )2.

5. The method according to claim 3 or claim 4, wherein each R 12 For hydrogen 。 6. The method according to any one of claims 3 to 5, wherein R 16 C 1-3 alkyl.

7. The method of claim 3, wherein R 6 for , , , or .

8. The method of claim 3, wherein R 6 for 。 9. The method of claim 3, wherein R 6 for 。 10. The method of claim 2, wherein the prodrug is 、 、 、 、 , , or their pharmaceutically acceptable salts.

11. A method of treating IBD in a patient in need, the method comprising administering a prodrug to the patient, the prodrug being: Or its pharmaceutically acceptable salt, The prodrug is administered at a dose of about 75 mg / dose to about 1,500 mg / dose.

12. The method according to any one of claims 2 to 11, wherein the prodrug is administered at a dose of about 75 mg / dose to about 900 mg / dose.

13. The method according to any one of claims 2 to 11, wherein the prodrug is administered at a dose of about 150 mg / dose to about 600 mg / dose.

14. The method according to any one of claims 2 to 11, wherein the prodrug is administered at a dose of about 150 mg / dose, about 300 mg / dose, or about 600 mg / dose.

15. The method according to any one of claims 2 to 11, wherein the prodrug is administered at a dose of about 150 mg / dose.

16. The method according to any one of claims 2 to 11, wherein the prodrug is administered at a dose of about 300 mg / dose.

17. The method according to any one of claims 2 to 11, wherein the prodrug is administered at a dose of about 600 mg / dose.

18. The method according to any one of claims 2 to 17, wherein the prodrug is administered once daily.

19. The method according to any one of claims 2 to 17, wherein the prodrug is administered twice daily.

20. The method according to any one of claims 2 to 19, wherein the prodrug is administered with a meal.

21. A method of treating IBD in a patient in need, the method comprising administering a prodrug of compound A to the patient: (Compound A) Or a pharmaceutically acceptable salt of the prodrug, The prodrug or its pharmaceutically acceptable salt is administered with meals.

22. A method of treating IBD in a patient in need, the method comprising administering a prodrug of compound A to the patient: (Compound A) The prodrug is administered with meals.

23. The method of claim 22, wherein the prodrug is 、 、 、 、 , , or their pharmaceutically acceptable salts.

24. A method of treating IBD in a patient in need, the method comprising administering a prodrug to the patient, said prodrug being: Or its pharmaceutically acceptable salt, The prodrug is administered with meals.

25. The method according to any one of claims 22 to 24, wherein the prodrug is administered at a dose of about 150 mg / dose.

26. The method according to any one of claims 22 to 24, wherein the prodrug is administered at a dose of about 300 mg / dose.

27. The method according to any one of claims 22 to 24, wherein the prodrug is administered at a dose of about 600 mg / dose.

28. The method according to any one of claims 22 to 27, wherein the prodrug is administered once daily.

29. The method according to any one of claims 22 to 27, wherein the prodrug is administered twice daily.

30. A method of treating IBD in a patient in need, the method comprising administering a prodrug of compound A to the patient: (Compound A) Or a pharmaceutically acceptable salt of the prodrug, The prodrug or its pharmaceutically acceptable salt is administered as follows: A first dose, based on free base, of approximately 150 mg / dose to approximately 1,500 mg / dose, was administered for a first period of up to approximately 24 weeks; then... Continue with the second dose for the second time period.

31. A method of treating IBD in a patient in need, the method comprising administering a prodrug of compound A to the patient: (Compound A) The prodrug is administered as follows: A first dose of approximately 150 mg / dose to approximately 1,500 mg / dose was administered for a first period of up to approximately 24 weeks; then... Continue with the second dose for the second time period.

32. The method of claim 31, wherein the prodrug is 、 、 、 、 , , or their pharmaceutically acceptable salts.

33. A method of treating IBD in a patient in need, the method comprising administering a prodrug to the patient, said prodrug being: Or its pharmaceutically acceptable salt, The prodrug is administered as follows: A first dose of approximately 150 mg / dose to approximately 1,500 mg / dose was administered for a first period of up to approximately 24 weeks; then... A second dose less than or equal to the first dose is administered for a second time period.

34. The method according to any one of claims 31 to 33, wherein the first dose is about 75 mg / dose to about 900 mg / dose.

35. The method according to any one of claims 31 to 33, wherein the first dose is about 600 mg / dose.

36. The method according to any one of claims 31 to 33, wherein the first dose is about 300 mg / dose.

37. The method according to any one of claims 31 to 33, wherein the first dose is about 150 mg / dose.

38. The method according to any one of claims 31 to 36, wherein the second dose is less than or equal to the first dose.

39. The method of claim 38, wherein the patient responds adequately to the first dose.

40. The method of claim 39, wherein the second dose is about 75 mg / dose to about 600 mg / dose.

41. The method of claim 39, wherein the second dose is about 300 mg / dose.

42. The method of claim 39, wherein the second dose is about 150 mg / dose.

43. The method according to any one of claims 31 to 38, wherein the patient does not respond adequately to the first dose.

44. The method of claim 43, wherein the second dose is about 150 mg / dose to about 900 mg / dose.

45. The method of claim 43, wherein the second dose is about 600 mg / dose.

46. ​​The method of claim 43, wherein the second dose is about 300 mg / dose.

47. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 600 mg for a first period of up to approximately 24 weeks; Determine that the patient achieves a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 300 mg / dose for a second duration.

48. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 600 mg for a first period of up to approximately 24 weeks; Determining that the patient did not achieve a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 600 mg / dose for a second duration.

49. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 600 mg for a first period of up to approximately 24 weeks; Determining that the patient did not achieve a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 300 mg / dose for a second duration.

50. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 300 mg for a first period of up to approximately 24 weeks; Determine that the patient achieves a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 300 mg / dose for a second duration.

51. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 300 mg for a first period of up to approximately 24 weeks; Determine that the patient achieves a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 150 mg / dose for a second duration.

52. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: Or its pharmaceutically acceptable salt, Administer a first dose of approximately 300 mg for a first period of up to approximately 24 weeks; Determining that the patient did not achieve a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 300 mg / dose for a second duration.

53. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 150 mg / dose for a first period of up to approximately 24 weeks. Determine that the patient achieves a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 150 mg / dose for a second duration.

54. A method for treating IBD in a patient in need, the method comprising: The patient is given a prodrug, wherein the prodrug is: ， Administer a first dose of approximately 150 mg / dose for a first period of up to approximately 24 weeks. Determining that the patient did not achieve a sufficient response to the first dose after the first time period; and The prodrug was administered to the patient at a second dose of approximately 300 mg / dose for a second duration.

55. The method according to any one of claims 31 to 54, wherein the first time period is about 12 weeks.

56. The method according to any one of claims 31 to 55, wherein the second time period is at least about 12 weeks.

57. The method according to any one of claims 31 to 56, wherein the prodrug is administered once daily.

58. The method according to any one of claims 31 to 56, wherein the prodrug is administered twice daily.

59. The method according to any one of claims 1 to 59, wherein the IBD is ulcerative colitis (UC).

60. A method of treating UC in a patient in need, the method comprising administering compound 1 to the patient: Or its pharmaceutically acceptable salt, Compound 1 was administered as follows: The first dose was administered continuously for a first time period at approximately 600 mg / dose, approximately 300 mg / dose, or approximately 150 mg / dose; then... The second time period was continued with a second dose of approximately 300 mg / dose or approximately 150 mg / dose.

61. The method of claim 60, wherein compound 1 is administered once daily.

62. The method of claim 60, wherein compound 1 is administered twice daily.

63. The method of claim 60, wherein the first time period is approximately 12 weeks.

64. The method according to any one of claims 60 to 63, wherein the first dose is about 600 mg / dose and the second dose is about 300 mg / dose.

65. The method according to any one of claims 60 to 63, wherein the first dose is about 300 mg / dose, and the second dose is about 300 mg / dose.

66. The method according to any one of claims 60 to 63, wherein the first dose is about 150 mg / dose, and the second dose is about 150 mg / dose.

67. The method according to any one of claims 60 to 63, wherein the first dose is about 600 mg / dose and the second dose is about 150 mg / dose.

68. The method according to any one of claims 60 to 63, wherein the first dose is about 300 mg / dose and the second dose is about 150 mg / dose.

69. The method according to any one of claims 60 to 63, wherein the first dose is about 150 mg / dose and the second dose is about 300 mg / dose.

70. A pharmaceutical composition comprising a prodrug of compound A: (Compound A) Or a pharmaceutically acceptable salt of the prodrug, The pharmaceutical composition further comprises a diluent, a disintegrant, or a lubricant, or any combination thereof.

71. A pharmaceutical composition comprising a prodrug of compound A: (Compound A) The pharmaceutical composition further comprises a diluent, a disintegrant, or a lubricant, or any combination thereof.

72. The pharmaceutical composition according to claim 71, wherein the prodrug is 、 、 、 、 or .

73. A pharmaceutical composition comprising a prodrug, said prodrug being: ， The pharmaceutical composition further comprises a diluent, a disintegrant, or a lubricant, or any combination thereof.

74. The pharmaceutical composition according to any one of claims 71 to 73, wherein the pharmaceutical composition comprises lactose monohydrate, microcrystalline cellulose, crospovidone, or magnesium stearate, or any combination thereof.

75. The pharmaceutical composition according to any one of claims 71 to 74, wherein the pharmaceutical composition is an oral dosage form.

76. The pharmaceutical composition of claim 75, wherein the dosage form comprises about 75 mg to about 600 mg of the prodrug.

77. The pharmaceutical composition of claim 75, wherein the dosage form comprises about 150 mg of the prodrug.

78. The pharmaceutical composition of claim 75, wherein the dosage form comprises about 300 mg or about 600 mg of the prodrug.

79. The pharmaceutical composition according to any one of claims 75 to 78, wherein the dosage form is a tablet.

80. The pharmaceutical composition of claim 79, wherein the tablet comprises a film coating.

81. The pharmaceutical composition of claim 80, wherein the film coating comprises a film-forming polymer, a pigment / opaque agent, a plasticizer, or a filler, or any combination thereof.

82. The pharmaceutical composition of claim 80, wherein the film coating comprises polyvinyl alcohol, titanium dioxide, polyethylene glycol, or talc, or any combination thereof.

83. The pharmaceutical composition of claim 80, wherein the film coating comprises polyvinyl alcohol, polyethylene glycol, or talc, or any combination thereof.

84. An oral dosage form comprising a prodrug of compound A: (Compound A) Or a pharmaceutically acceptable salt of the prodrug, and a pharmaceutically acceptable excipient. The oral dosage form is formulated to achieve one or more pharmacokinetic characteristics selected from the following when administered orally to a human patient daily on an empty stomach: Arithmetic mean steady-state AUC of compound A from approximately 10 h*µg / mL to approximately 80 h*µg / mL tau ; The arithmetic mean steady state of compound A from approximately 0.9 µg / mL to approximately 9 µg / mL max ; The median steady-state T of compound A from approximately 1.5 hours to approximately 6 hours max ;as well as The median steady-state t of compound A is approximately 18 to approximately 30 hours. 1 / 2 .

85. An oral dosage form comprising a prodrug of compound A: (Compound A) And pharmaceutically acceptable excipients, The oral dosage form is formulated to achieve one or more pharmacokinetic characteristics selected from the following when administered orally to a human patient daily on an empty stomach: Arithmetic mean steady-state AUC of compound A from approximately 10 h*µg / mL to approximately 80 h*µg / mL tau ; The arithmetic mean steady state of compound A from approximately 0.9 µg / mL to approximately 9 µg / mL max ; The median steady-state T of compound A from approximately 1.5 hours to approximately 6 hours max ;as well as The median steady-state t of compound A is approximately 18 to approximately 30 hours. 1 / 2 .

86. The oral dosage form according to claim 85, wherein the prodrug is 、 、 、 、 or .

87. The oral dosage form according to claim 85, wherein the prodrug is 。 88. The oral dosage form according to any one of claims 85 to 87, wherein the oral dosage form is formulated to achieve an arithmetic mean AUC of compound A of about 10 h*µg / mL to about 65 h*µg / mL. tau .

89. The oral dosage form according to any one of claims 85 to 87, wherein the oral dosage form is formulated to achieve an arithmetic mean AUC of compound A of about 35 h*µg / mL to about 65 h*µg / mL. tau .

90. The oral dosage form according to any one of claims 85 to 89, wherein the oral dosage form is formulated to achieve an arithmetic mean C of compound A of about 0.9 µg / mL to about 5 µg / mL. max .

91. The oral dosage form according to any one of claims 85 to 89, wherein the oral dosage form is formulated to achieve an arithmetic mean C of compound A of about 3 µg / mL to about 5 µg / mL. max .

92. The oral dosage form according to any one of claims 85 to 91, wherein the oral dosage form comprises about 75 mg to about 600 mg of the prodrug.

93. The oral dosage form according to any one of claims 85 to 91, wherein the oral dosage form comprises about 150 mg of the prodrug.

94. The oral dosage form according to any one of claims 85 to 91, wherein the oral dosage form comprises about 300 mg or about 600 mg of the prodrug.

95. The oral dosage form according to any one of claims 85 to 91, wherein the oral dosage form comprises the pharmaceutical composition according to any one of claims 75 to 83.

96. A method of treating IBD in a patient in need, the method comprising administering to the patient a pharmaceutical composition according to any one of claims 70 to 83 or an oral dosage form according to any one of claims 84 to 95.

97. The method of claim 96, wherein the IBD is UC.

98. The method of claim 96, wherein the IBD is Crohn's disease.

99. The method according to any one of claims 1 to 69, wherein the patient is a person.

100. The method of claim 96, wherein the patient is a person.

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