CN117460513A - Combination therapy - Google Patents

Combination therapy Download PDF

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Publication number
CN117460513A
CN117460513A CN202280034525.XA CN202280034525A CN117460513A CN 117460513 A CN117460513 A CN 117460513A CN 202280034525 A CN202280034525 A CN 202280034525A CN 117460513 A CN117460513 A CN 117460513A
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China
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alkyl
group
formula
ethyl
triazol
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CN202280034525.XA
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Inventor
N·达斯卡拉基斯
C·D·古特克
权珉彻
L·A·费兰特
K·E·帕克曼
E·C·皮奇
U·费里帕尔
T·A·J·韦尔胡尔斯特
B·博加尔
孙宇
蔡伟
戴学东
O·A·G·凯罗勒
J·W·J·图灵
刘颖涛
刘连柱
徐彦平
付利强
厉铭
方李超
邓向君
A·T·F·吴
N·F·J·达尔维尔
V·潘德
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

The present invention discloses a combination comprising a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a BCL-2 inhibitor; and optionally, a therapeutically effective amount of at least one other antineoplastic agent. Also disclosed are methods for treating a subject who has been diagnosed with hematopoietic dysfunction using such combinations. The compound is represented by the following formula (I):wherein R is 1a 、R 1b 、R 2 、R 3 、R 4 、U、Y 1 、X 1 、X 2 N1, n2, n3 and n4 are as defined herein.

Description

Combination therapy
Technical Field
The present invention relates to a novel combination comprising a therapeutically effective amount of a multiple endocrine oncoprotein (mentin) mixed lineage leukemia 1 (multiple endocrine oncoprotein-MLL) inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of a B cell lymphoma 2 (BCL-2) inhibitor; and optionally, a therapeutically effective amount of at least one other antineoplastic agent; and also to a method for treating a subject who has been diagnosed with a hematopoietic disorder (hematopoietic disorder).
Background
Of the ten million cancer deaths recorded by GLOBOCAN in 2020, 7.1% were due to hematopoietic dysfunction. Thus, there is an urgent need for new therapeutic forms for hematopoietic disorders including Acute Myeloid Leukemia (AML), myelodysplastic syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), as described in further detail below.
AML is a common hematological malignancy with an incidence that rises from 3:100,000 in young people to greater than 20:100,000 in elderly people. Total survival (OS) is 40% to 50% for patients with an age <60 years, but only 5% for patients with an age >60 years. Most newly diagnosed AML patients are over 60 years of age. In this patient population, standard induction chemotherapy is generally not an option due to increased mortality associated with treatment due to age and co-morbidity. The standard of care for AML patients unsuitable for combination chemotherapy is treatment with hypomethylating agents (azacytidine or decitabine) or low doses of cytarabine. Despite these front treatments, median OS was only about 10 months. In all types of AML, disease recurrence is common despite the initial therapeutic response and is the most common cause of death. Standard chemotherapy and allogeneic stem cell transplantation (when used) are generally unable to eradicate all tumor proliferation cells and select chemotherapy-resistant leukemia proliferation subclones. Patients refractory to salvage therapy are palliatively treated because of the limited treatment options currently available. These patients had a median survival of 2 months. Furthermore, patients with newly diagnosed moderate or higher risk MDS and those who relapse after standard care have poor prognosis and a high risk of progressing to AML. Thus, there is an urgent need for new therapeutic modalities for relapsed/refractory (R/R) AML and MDS patients, AML patients based on age and co-morbidity that are not suitable for new diagnosis of induction chemotherapy, and new diagnosed medium/high/very high risk MDS patients.
ALL is a hematological malignancy that propagates through impaired differentiation, proliferation, and accumulation of lymphoid progenitor cells at the bone marrow and/or extramedullary sites. ALL represents 12% of ALL leukemia cases and is the most common pediatric acute leukemia with worldwide morbidity predicted to be 1 to 4.75 per 100,000. ALL represents about 20% of adult leukemias. Despite the high rate of Complete Remission (CR) of current therapies (80% to 90%), most adult patients with ALL relapse. The overall 5-year survival rate for adults and elderly patients is about 30% to 40%. Thus, there is an urgent need for new forms of treatment for relapsed/refractory ALL, particularly in adult and especially elderly patients.
Disclosure of Invention
Embodiments of the present invention relate to a novel combination of: a multiple endocrine oncoprotein-MLL inhibitor of formula (I) or a pharmaceutically acceptable salt or solvate thereof; and a BCL-2 inhibitor; and optionally at least one other antineoplastic agent.
Embodiments of the invention relate to the use of such a combination for treating a subject who has been diagnosed with a hematopoietic disorder (including but not limited to hematological cancer) using a combination of a multiple endocrine oncoprotein-MLL inhibitor as described herein with a BCL-2 inhibitor, and optionally at least one other antineoplastic agent.
Embodiments of the present invention relate to novel methods for treating subjects that have been diagnosed with hematopoietic dysfunction using such combinations. Embodiments of the novel methods comprise administering to a subject a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor as described herein; and a therapeutically effective amount of a BCL-2 inhibitor; and optionally a therapeutically effective amount of at least one other antineoplastic agent; wherein the multiple endocrine oncoprotein-MLL inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
Embodiments of the present invention relate to novel methods for treating subjects that have been diagnosed with hematopoietic dysfunction using such combinations. Embodiments of the novel methods comprise administering to a subject a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor as described herein; and a therapeutically effective amount of a BCL-2 inhibitor and a therapeutically effective amount of at least one other antineoplastic agent; wherein the multiple endocrine oncoprotein-MLL inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the invention relates to a method for treating a subject who has been diagnosed with hematopoietic dysfunction, the method comprising administering to the subject a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of valnemulin, or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, the invention relates to a method for treating a subject who has been diagnosed with hematopoietic dysfunction, the method comprising administering to the subject a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof; a therapeutically effective amount of valnemulin, or a pharmaceutically acceptable salt or solvate thereof; and a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt or solvate thereof; wherein the valnemulin-MLL inhibitor is administered to the subject prior to, concurrently with, or after administration of the multiple endocrine oncoprotein-MLL inhibitor; and wherein the azacitidine or pharmaceutically acceptable salt or solvate thereof is administered to the subject prior to, concurrently with, or after administration of the multiple endocrine oncoprotein-MLL inhibitor.
In embodiments, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is:
and tautomers and stereoisomers thereof, wherein
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o)-C 1-4 An alkyl group; wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, said one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 11 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide benzenesulfonate (besylate salt benzenesulfonate salt):
and solvates thereof.
The skilled artisan will appreciate that 'and solvates thereof' refer to the benzenesulfonate salt of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide benzenesulfonate or a hydrate thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bisbenzenesulfonate or a solvate thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bisbenzenesulfonate or a hydrate thereof.
In particular, the present invention relates to (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate 0.5-2.0 equivalent of hydrate.
In particular, the present invention relates to (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate 2.0 equivalent of hydrate.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is crystalline form a of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bisbenzenesulfonate hydrate.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is crystalline form a of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate 0.5-2.0 equivalent of hydrate.
More particularly, the present invention relates to crystalline form a of 2.0 equivalents of hydrate of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate.
Additional embodiments, features and advantages of the invention will be apparent from the following detailed description and from the practice of the invention.
Drawings
Fig. 1 is an X-ray powder diffraction (XRPD) pattern of compound A4: crystalline form a of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate hydrate.
Figure 2 depicts a comparison of tumor volumes as a function of time for a control group and a treatment group treated with a regimen comprising varying amounts of compound A3.
Fig. 3 depicts a comparison of percent tumor survival as a function of time (e.g., kaplan-Meier survival curve) for control and treatment groups treated with regimens containing varying amounts of compound A3.
Figure 4A depicts a comparison of percent survival as a function of time for mice bearing established OCI-AML3 tumors following monotherapy with vehicle, with valnemulin, azacytidine, or compound A1, with a dual combination of valnemulin and azacytidine, or with a triple combination of compound A1, valnemulin, and azacytidine.
Figure 4B depicts a comparison of percent survival of mice bearing established MOLM-13 tumors as a function of time following monotherapy with vehicle, with valnemulin, azacytidine, or compound A1, with a dual combination of valnemulin and azacytidine, or compound A1 and valnemulin, or with a triple combination of compound A1, valnemulin, and azacytidine.
FIG. 5A is a contour plot of maxR showing the effect of compound A3 in combination with valnemulin on the in vitro proliferation of MOLM-13 cells.
FIG. 5B is a contour plot of maxR showing the effect of compound A3 in combination with azacytidine and valnemulin on the proliferation of MOLM-13 cells in vitro.
FIG. 6A is a contour plot of maxR showing the effect of compound A4 in combination with decitabine on in vitro proliferation of MOLM-13 cells.
FIG. 6B is a contour plot of maxR showing the effect of compound A4 in combination with decitabine and valnemulin on the proliferation of MOLM-13 cells in vitro.
Fig. 7A is a contour plot of maxR showing the effect of compound A4 in combination with decitabine on the proliferation of OCI-AML3 cells in vitro.
Fig. 7B is a contour plot of maxR showing the effect of compound A4 in combination with decitabine and valnemulin on the proliferation of OCI-AML3 cells in vitro.
Detailed Description
As used herein, the term 'halo' or 'halogen' means fluoro, chloro, bromo and iodo.
As used herein, the prefix' C x-y ' (wherein x and y are integers) refers to the number of carbon atoms in a given group. Thus C 1-6 The alkyl group contains 1 to 6 carbon atoms and so on.
The term 'C' as used herein as a group or part of a group 1-4 Alkyl' represents a straight or branched saturated hydrocarbon group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like.
Similarly, the term' C as used herein as a group or part of a group 1-6 Alkyl' represents a straight or branched chain fully saturated hydrocarbon group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.
The term 'C' as used herein as a group or part of a group 3-6 Cycloalkyl' is defined as a saturated cyclic hydrocarbon group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
It is clear to the skilled person that S (=o) 2 Or SO 2 Represents a sulfonyl moiety.
It is clear to the skilled person that CO or C (=o) represents a carbonyl moiety.
It will be clear to those skilled in the art that groups such as-CRR-represent
An example of such a group is-CR 5a R 5b -。
It will be clear to those skilled in the art that groups such as-NR-representExamples of such groups are-NR 5c -。
Non-limiting examples of a 'monocyclic 5-or 6-membered aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety' include, but are not limited to, pyrazolyl, imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or 1, 2-dihydro-2-oxo-4-pyridinyl.
Those skilled in the art will appreciate that 5-or 6-membered monocyclic aromatic rings containing one, two or three nitrogen atoms and carbonyl moieties include, but are not limited to
When any variable occurs more than one time in any component, each definition is independent.
When any variable occurs more than once in any formula (e.g., formula (I)), each definition is independent.
Generally, unless otherwise indicated or clear from the context, whenever the term 'substituted' is used in the present invention, it means that one or more hydrogens, especially 1 to 4 hydrogens, more especially 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or group indicated in the expression using 'substituted', are replaced with a selection from the indicated group, provided that the normal valence is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to withstand separation from the reaction mixture to a useful purity (after reaction, e.g. purification by silica gel chromatography). In certain embodiments, when the number of substituents is not explicitly specified, the number of substituents is 1.
Combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. By 'stable compound' is meant in this context a compound that is sufficiently robust to withstand separation from the reaction mixture to a useful purity (separation after reaction, e.g. purification by silica gel chromatography).
The skilled artisan will appreciate that the term 'optionally substituted' means that the atom or group indicated in the expression of using 'optionally substituted' may or may not be substituted (which means substituted or unsubstituted, respectively).
When two or more substituents are present on a moiety, they may replace hydrogen on the same atom, or they may replace hydrogen atoms on different atoms in the moiety, where possible and unless otherwise indicated or clear from the context.
In the context of the present invention, 'saturated' means 'fully saturated', if not otherwise indicated.
Unless otherwise indicated or clear from the context, an aromatic ring group may be attached to the remainder of the molecule of formula (I) through any available ring carbon atom (C-linked) or nitrogen atom (N-linked).
Unless otherwise indicated or clear from the context, according to embodiments, aromatic ring groups may optionally be substituted on carbon and/or nitrogen atoms where possible.
As used herein, the term "comprising" encompasses the terms "consisting of … …" and "consisting essentially of … …". All embodiments described herein that use the term "comprising" are also applicable to embodiments of the invention in which the term "comprising" is limited to "consisting of … …. Likewise, all embodiments described herein that use the term "comprising" are also applicable to embodiments of the invention in which the term "comprising" is limited to "consisting essentially of … ….
As used herein, the term "subject" refers to an animal, preferably a mammal (e.g., cat, dog, primate, or human), more preferably a human that was or was the subject of treatment, observation, or experiment.
The term "therapeutically effective amount" as used herein means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including alleviation or reversal of the symptoms of the disease or disorder being treated.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
As used herein, the terms "treatment" and "treating" are intended to refer to all processes in which there may be a slowing, interrupting, arresting or stopping of the progression of a disorder, or an improvement in one or more symptoms thereof, but not necessarily to the complete elimination of all symptoms.
As used herein, any chemical formula having a bond shown only as a solid line and not as a solid wedge or a hashed wedge bond or otherwise indicated as having a particular configuration (e.g., R, S) around one or more atoms contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.
In the foregoing and in the following, the term "compound of formula (I)" is intended to include tautomers thereof and stereoisomeric forms thereof.
In the above and below, the term "compound of formula (Z)" is intended to include tautomers thereof and stereoisomeric forms thereof.
The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably hereinabove or hereinbelow.
The present invention includes all stereoisomers of the compounds of the invention as pure stereoisomers or as mixtures of two or more stereoisomers.
Enantiomers are stereoisomers that are non-superimposable mirror images of each other. The 1:1 mixture of a pair of enantiomers is a racemate or a racemic mixture.
Atropisomers (or atropisomers) are stereoisomers with a specific spatial configuration that, due to large steric hindrance, create a limited rotation around a single bond. All atropisomeric forms of the compounds of formula (I) are intended to be included within the scope of the present invention.
Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., they are not related to mirror images. If the compound contains a double bond, the substituent may be in the E or Z configuration.
Substituents on divalent cyclic saturated or partially saturated groups may have cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, the substituents may be in cis or trans configuration.
Thus, whenever chemically possible, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof.
All those terms, i.e. enantiomer, atropisomer, diastereomer, racemate, E isomer, Z isomer, cis isomer, trans isomer and mixtures thereof, are known to the skilled person.
Absolute configuration was assigned according to Cahn-Ingold-Prelog system. The configuration at the asymmetric atom is designated by R or S. Resolved stereoisomers whose absolute configuration is unknown may be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For example, a resolved enantiomer whose absolute configuration is unknown may be designated by (+) or (-) depending on its direction of rotation of plane polarized light.
When a particular stereoisomer is identified, this means that said stereoisomer is substantially free of other stereoisomers, i.e. is associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other stereoisomers. Thus, when a compound of formula (I) is designated, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated E, for example, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is designated, for example, as cis, this means that the compound is substantially free of the trans isomer.
Some of the compounds according to formula (I) may also exist in their tautomeric forms. Although not explicitly indicated in formula (I) above, such forms (as long as they may exist) are intended to be included within the scope of the present invention. It follows that a single compound may exist in both stereoisomers and tautomeric forms.
Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional methods, for example by reacting the free acid or free base form with one or more equivalents of the appropriate base or acid, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., vacuum, by freeze drying, or by filtration). Salts may also be prepared by exchanging a counter ion of a compound of the invention in salt form with another counter ion, for example using a suitable ion exchange resin.
Pharmaceutically acceptable salts as mentioned above or below refer to the therapeutically active non-toxic acid and non-toxic base salt forms which comprise the compounds of formula (I) and solvates thereof which are capable of forming.
Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the salt form may be converted to the free base form by treatment with an appropriate base.
The compounds of formula (I) and solvates thereof containing acidic protons may also be converted into their non-toxic metal or amine salt forms by treatment with suitable organic and inorganic bases.
Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts (e.g., lithium, sodium, potassium, cesium, magnesium, calcium salts, etc.), salts with organic bases such as primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline; benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids (such as, for example, arginine, lysine, and the like). Conversely, the salt form can be converted to the free acid form by treatment with an acid.
The term "prodrug" includes any compound that is metabolized in vivo to a (more) active form in experimentally detectable amounts within a predetermined time (e.g., within a dosing interval between 0.5 and 24 hours, or, for example, within a dosing interval between 6 and 24 hours (i.e., once to four times per day)) following oral or parenteral administration (particularly oral administration). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration except oral administration, in particular Intravenous (IV), intramuscular (IM) and Subcutaneous (SC) injection.
Prodrugs can be prepared by modifying functional groups present on a compound such that when such a prodrug is administered to a mammalian subject, the modification is cleaved in vivo. These modifications are typically accomplished by synthesizing the parent compound with prodrug substituents. In general, prodrugs include compounds wherein a hydroxy, amino, sulfhydryl, carboxyl, or carbonyl group is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, sulfhydryl, carboxyl, or carbonyl group, respectively.
Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, ester groups of carboxy functional groups, N-acyl derivatives, and N-Mannich bases. General information about prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs", pages I-92, eleseveler, new York-Oxford (1985).
The term solvate includes solvent addition forms and salts thereof which the compounds of formula (I) are capable of forming. Examples of such solvent addition forms are, for example, hydrates, alcoholates and the like.
The compounds of the invention prepared in the following processes may be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which may be separated from one another according to resolution methods known in the art. The manner in which the enantiomeric forms of the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are separated involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously employ optically pure starting materials.
As used herein, the term "optically pure" means that the product contains at least 80% by weight of one enantiomer and 20% by weight or less of the other enantiomer. Preferably, the product contains at least 90% by weight of one enantiomer and 10% by weight or less of the other enantiomer. In a most preferred embodiment, the term "optically pure" means that the composition contains at least 99% by weight of one enantiomer and 1% or less of the other enantiomer.
Isotopically-labeled compounds are also encompassed by the present invention, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant atomic mass or mass number found in nature).
All isotopes and isotopic mixtures of any particular atom or element as specified herein, whether naturally occurring or synthetically produced, are contemplated within the scope of the present inventionWhether in natural abundance or in isotopically enriched form. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 O、 17 O、 18 O、 32 P、 33 P、 35 S、 18 F、 36 Cl、 122 I、 123 I、 125 I、 131 I、 75 Br、 76 Br、 77 Br and 82 br. Preferably, the isotope is selected from 2 H、 3 H、 11 C、 13 C and C 18 Group F. Preferably, the isotope is selected from 2 H、 3 H、 11 C and C 18 Group F. More preferably, the isotope is 2 H、 3 H or 13 C. More preferably, the isotope is 2 H or 13 C. More preferably, the isotope is 2 H. In particular, deuterated compounds and enriched 13 The compounds of C are intended to be included within the scope of the present invention. In particular, deuterated compounds are intended to be included within the scope of the present invention.
Certain isotopically-labeled compounds (e.g., with 3 H and 14 c-labeled) can be used, for example, in substrate tissue distribution assays. Tritiated% 3 H) And carbon-14% 14 C) Isotopes are useful for their ease of preparation and detectability. In addition, the use of heavier isotopes such as deuterium (i.e., 2 h) Performing a substitution may provide certain therapeutic advantages (e.g., an extended in vivo half-life or a reduced required dose) resulting from greater metabolic stability and thus may be preferred in some circumstances. Positron emitting isotopes such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies. PET imaging in cancer can be used to help locate and identify tumors, stage disease, and determine appropriate treatments. Human cancer cells overexpress many receptors or proteins, which are potential disease-specific molecular targets. Binding such receptors on tumor cells with high affinity and specificity Radiolabeled tracers of either body or protein have great potential for diagnostic imaging and targeted radionuclide therapy (Charron, carlie l. Et al, tetrahedron lett.2016,57 (37), 4119-4127). In addition, target-specific PET radiotracers can be used as biomarkers to examine and evaluate pathology by, for example, measuring target expression and therapeutic response (Austin R. Et al, cancer Letters (2016), doi: 10.1016/j.canlet.2016.05.008).
Solid oral dosage forms (such as tablets or capsules) containing one or more compounds described herein may optionally be administered in at least one dosage form at a time. The compounds may also be administered in a sustained release formulation.
Additional oral dosage forms in which the compounds described herein can be administered include elixirs, solutions, syrups and suspensions; each dosage form optionally contains a flavoring agent and a coloring agent.
Alternatively, one or more of the compounds described herein may be administered by inhalation (intratracheal or intranasal) or in the form of suppositories or pessaries, or they may be topically applied in the form of lotions, solutions, creams, ointments or dusting powders. For example, they may be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycol or liquid paraffin. They may also be incorporated into a cream comprising, consisting of, and/or consisting essentially of a wax or soft paraffin base, as well as any stabilizers and preservatives (as may be desired), at a concentration of between about 1% to about 10% by weight of the cream. Alternative modes of administration include transdermal administration by use of skin patches or transdermal patches.
The pharmaceutical compositions (and the individual compounds) used in the methods of the invention may also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally or intrathecally. In this case, the composition will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
For parenteral administration, the pharmaceutical compositions of the invention are preferably used in the form of sterile aqueous solutions which may contain other substances, for example, sufficient salts and monosaccharides to prepare a solution isotonic with blood.
For buccal or sublingual administration, the pharmaceutical compositions of the invention may be administered in the form of tablets or lozenges which may be formulated in a conventional manner.
By way of further example, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a BCL-2 inhibitor and optionally at least one other anti-neoplastic agent as active ingredients may be prepared by mixing these compounds with a pharmaceutically acceptable carrier, pharmaceutically acceptable diluent and/or pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carriers, excipients, and diluents can take a variety of forms depending upon the route of administration desired (e.g., oral, parenteral, etc.). Thus for liquid oral formulations such as suspensions, syrups, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral formulations such as powders, capsules and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral formulations may also optionally be coated with a substance such as sugar, or enteric coated, in order to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient, and diluent typically include sterile water, and other ingredients may be added to increase the solubility and preservability of the composition. Injectable suspensions or solutions may also be prepared using aqueous carriers along with appropriate additives such as solubilizers and preservatives.
According to particular embodiments, in a regimen of about 1 to about 4 times daily of an average (70 kg) human, a method of using a therapeutically effective amount of a compound of (I) or a pharmaceutically acceptable salt or solvate thereof, and a BCL-2 inhibitor and optionally at least one other antineoplastic agent, may comprise about 0.1mg to about 3000mg or any specific amount or range thereof, especially about 1mg to about 1000mg or any specific amount or range thereof of the active ingredient; however, it will be apparent to those skilled in the art that the therapeutically effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and the BCL-2 inhibitor, and optionally at least one other antineoplastic agent, will vary with the disease, syndrome, condition, and disorder being treated.
One embodiment of the present invention relates to a method of using a pharmaceutical composition for oral administration comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 1mg to about 500 mg. Advantageously, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be administered in a single daily dose, or the total daily dose may be administered in divided doses of twice, three times and (4 x) daily.
The optimal dosage of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to be administered can be readily determined and will vary with the particular compound used, the mode of administration, the strength of the formulation and the progress of the hematopoietic dysfunction. In addition, factors related to the particular subject to be treated (including subject sex, age, weight, diet and time of administration) will result in the need to adjust the dosage to achieve the appropriate level of treatment and desired therapeutic effect. Thus, the above dosages are examples of general situations. Of course, there may be individual circumstances where higher or lower dosage ranges are beneficial, and such circumstances are within the scope of the invention.
Whenever the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, may be administered in any of the compositions and dosage regimens described above, or by means of those compositions and dosage regimens established in the art.
One embodiment of the present invention relates to a method of using a pharmaceutical composition for intravenous or subcutaneous administration comprising a BCL-2 inhibitor in an amount of about 1mg to about 500 mg. Advantageously, the BCL-2 inhibitor may be administered in a single daily dose, or the total daily dose may be administered twice, three times daily and (4 x) divided doses.
The optimal dosage of BCL-2 inhibitor to be administered can be readily determined and will vary with the particular compound used, the mode of administration, the strength of the formulation, and the progress of the disease, syndrome, condition or disorder. In addition, factors related to the particular subject to be treated (including subject sex, age, weight, diet and time of administration) will result in the need to adjust the dosage to achieve the appropriate level of treatment and desired therapeutic effect. Thus, the above dosages are examples of general situations. Of course, there may be individual circumstances where higher or lower dosage ranges are beneficial, and such circumstances are within the scope of the invention.
Whenever the use of a BCL-2 inhibitor is administered to a subject in need thereof, the BCL-2 inhibitor may be administered in any of the above-described compositions and dosage regimens, or by means of those compositions and dosage regimens established in the art.
As used herein, the term "multiple endocrine oncoprotein-MLL inhibitor" refers to an inhibitor of protein-protein interactions (UniProt accession # Q03164) between multiple endocrine oncoproteins and mixed lineage leukemia 1 (MLL 1) (also known as histone-lysine N-methyltransferase 2A (KMT 2A) proteins in the scientific field, which inhibits or reduces multiple endocrine oncoprotein-MLL 1 activity.
As used herein, the term "BCL-2 inhibitor" may refer to an agent that inhibits or reduces BCL-2 activity.
As used herein, the term "anti-neoplastic agent" refers to any agent that treats cancer.
As used herein, the term "hypomethylating agent" refers to an agent that inhibits or reduces DNA methylation.
As used herein, the term "kinase inhibitor" refers to an agent that inhibits or reduces the activity of at least one kinase (e.g., tyrosine and/or serine kinase, such as fms-like receptor tyrosine kinase-3 (FLT 3), bruton's Tyrosine Kinase (BTK), abalson (Abelson) tyrosine kinase 1 (ABL), aurora (Aurora) serine/tyrosine kinase).
As used herein, the term "FLT-3 inhibitor" refers to a Tyrosine Kinase Inhibitor (TKI) that is classified as a first and next generation inhibitor based on its potency and specificity for fms-like receptor tyrosine kinase 3 (FLT 3) and its associated downstream targets.
As used herein, the term "CD20 inhibitor" refers to any agent that reduces CD20 activity.
As used herein, the term "Isocitrate Dehydrogenase (IDH) inhibitor" refers to any agent that interferes with the conversion of isocitrate to alpha-ketoglutarate (α -KG) in the tricarboxylic acid (TCA) cycle.
As used herein, the term "immunomodulatory anti-tumor agent" refers to any agent that enhances the activity of anti-tumor immune cells.
As used herein, the term "inhibitor of apoptosis protein 1 (PD-1)" refers to any agent that inhibits or reduces PD-1 activity.
As used herein, the term "dihydroorotate dehydrogenase (DHODH) inhibitor" refers to any agent that inhibits or reduces the activity of dihydroorotate dehydrogenase.
As used herein, unless otherwise indicated, the term "affected" or "affected" (affected by inhibition or alteration of multiple endocrine oncoprotein-MLL activity when referring to a disease, disorder, or medical condition) includes a reduction in the frequency and/or severity of one or more symptoms or clinical manifestations of the hematopoietic disorder; and/or comprises preventing the development of said hematopoietic dysfunction or the development of one or more symptoms or clinical manifestations of said hematopoietic dysfunction.
As used herein, the term "hematopoietic dysfunction" refers to any disorder associated with the production of cellular components in blood and plasma, including, but not limited to, hematological cancers.
According to one embodiment, the present invention provides a combination as described herein.
According to one embodiment, the invention provides a combination as described herein for use as a medicament.
According to one embodiment, the present invention provides a combination as described herein for use in the preparation of a medicament.
According to one embodiment, the present invention provides a combination as described herein for the preparation of a medicament for the treatment or prophylaxis of any of the disease conditions mentioned herein.
According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment (particularly the treatment) of a disease as described herein.
According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment (in particular treatment) of hematopoietic disorders including, but not limited to, hematological cancers, including, but not limited to, lymphomas, myelomas and leukemias.
According to one embodiment, the present invention provides a combination as described herein for use in the prevention or treatment (in particular treatment) of hematopoietic dysfunction.
According to one embodiment, the hematopoietic dysfunction is selected from, but is not limited to, lymphoma, myeloma, myelodysplasia and leukemia.
According to one embodiment, the hematopoietic disorder is a lymphoma selected from hodgkin's lymphoma and non-hodgkin's lymphoma.
According to one embodiment, the lymphoma is non-hodgkin's disease, which is burkitt's lymphoma, anaplastic large cell lymphoma, splenic marginal zone lymphoma, hepatosplenic T cell lymphoma, or angioimmunoblastic T cell lymphoma (AILT).
According to one embodiment, the hematopoietic disorder is myeloma. According to one embodiment, the hematopoietic disorder is multiple myeloma, fahrenheit macroglobulinemia, or plasmacytoma.
According to one embodiment, the hematopoietic disorder is spinal cord dysplasia, including, but not limited to myelodysplastic syndrome (MDS).
According to one embodiment, the hematopoietic disorder is leukemia.
According to one embodiment, the hematopoietic disorder is leukemia selected from acute leukemia and chronic leukemia. According to one embodiment, the leukemia is acute leukemia. According to one embodiment, the leukemia is chronic leukemia.
According to one embodiment, the hematopoietic disorder is myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia. According to one embodiment, the hematopoietic disorder is leukemia selected from, but not limited to, acute Lymphoblastic Leukemia (ALL), chronic Lymphoblastic Leukemia (CLL), small Lymphoblastic Leukemia (SLL), acute Myeloid Leukemia (AML), chronic idiopathic Myelofibrosis (MF), chronic Myelogenous Leukemia (CML), T-cell prolymphocytic leukemia (T-PLL), B-cell prolymphocytic leukemia (B-PLL), chronic Neutrophilic Leukemia (CNL), hairy Cell Leukemia (HCL), T-cell large granular lymphoblastic leukemia (T-LGL), and invasive NK cell leukemia. According to one embodiment, AML is acute megakaryoblastic leukemia (AMKL).
According to one embodiment, the leukemia is MDS, CLL, SLL, ALL or AML. According to one embodiment, the leukemia is CLL, SLL or AML. According to one embodiment, the leukemia is CLL or SLL. In some embodiments, CLL or SLL is a CD20 expressing cancer. According to one embodiment, the leukemia is ALL or AML. According to one embodiment, the leukemia is ALL. According to one embodiment, the leukemia is AML. According to one embodiment, the hematopoietic disorder is macroglobulinemia Fahrenheit.
According to one embodiment, the hematopoietic disorder is MLL rearranged leukemia, MLL partial tandem repeat (PTD) leukemia, MLL amplified leukemia, MLL positive leukemia, or leukemia that exhibits an elevated HOX/MEIS1 gene expression signature.
According to one embodiment, the leukemia is a MLL rearranged leukemia and/or a nucleophosmin 1 (NPM 1) mutated leukemia. According to one embodiment, the hematopoietic disorder is MLL rearranged leukemia.
According to one embodiment, the hematopoietic disorder is a nucleophosmin 1 (NPM 1) mutant leukemia (e.g., NPM1 c).
According to one embodiment, the present invention provides a method of treating hematopoietic disorders, which are myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute Lymphoblastic Leukemia (ALL), acute Myeloid Leukemia (AML), small Lymphoblastic Lymphoma (SLL) or Chronic Lymphocytic Leukemia (CLL), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a BCL-2 inhibitor, and optionally at least one other antineoplastic agent.
According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN).
According to one embodiment, the hematopoietic disorder is Acute Lymphoblastic Leukemia (ALL).
According to one embodiment, the hematopoietic disorder is acute bone-like leukemia (AML).
According to one embodiment, the hematopoietic disorder is Small Lymphocytic Lymphoma (SLL) or Chronic Lymphocytic Leukemia (CLL).
According to one embodiment, the hematopoietic disorder is SLL or CLL, wherein SLL or CLL is a CD20 expressing cancer.
According to one embodiment, the hematopoietic disorder is myelodysplastic syndrome (MDS).
According to one embodiment, the hematopoietic disorder is a myeloproliferative neoplasm (MPN).
According to one embodiment, the hematopoietic disorder is NPM1 mutant leukemia with FLT3 mutation.
According to one embodiment, the hematopoietic disorder is FLT3 dependent leukemia.
According to one embodiment, the hematopoietic disorder is MEF 2G-dependent leukemia.
According to one embodiment, the hematopoietic dysfunction has one or more MLL1 (KMT 2A) rearrangements or alterations (e.g., repeats or amplifications) and/or NPM1 mutations.
According to one embodiment, the hematopoietic dysfunction has (i) one or more MLL1 (KMT 2A) rearrangements or changes (e.g., repeats or amplifications) and/or NPM1 mutations plus (ii) FLT3 mutations.
According to one embodiment, the hematopoietic disorder is MLL rearranged leukemia.
According to one embodiment, the hematopoietic disorder is acute bone-like leukemia (AML).
According to one embodiment, the hematopoietic disorder is Small Lymphocytic Lymphoma (SLL).
According to one embodiment, the hematopoietic disorder is Chronic Lymphocytic Leukemia (CLL).
According to one embodiment, the hematopoietic disorder is acute leukemia, chronic leukemia, myeloid leukemia, myelogenous leukemia, lymphoblastic leukemia, acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), acute Lymphoblastic Leukemia (ALL), chronic Lymphocytic Leukemia (CLL), T-cell prolymphocytic leukemia (T-PLL), large granule lymphoblastic leukemia, hairy Cell Leukemia (HCL), MLL rearranged leukemia, MLL-PTD leukemia, MLL amplified leukemia, MLL positive leukemia, or leukemia that exhibits an elevated HOX/MEIS1 gene expression signature.
According to one embodiment, the hematopoietic dysfunction is AML, in particular nuclear phosphoprotein (NPM 1) mutated AML (i.e., NPM 1) mut AML), more particularly abstract NPM1 mutated AML.
According to one embodiment, the hematopoietic disorder is MLL rearranged leukemia, in particular MLL rearranged AML or ALL.
According to one embodiment, the hematopoietic dysfunction comprises an MLL gene alteration, in particular the hematopoietic dysfunction is AML or ALL with an MLL gene alteration. In certain embodiments, the MLL gene alterations are duplicates. In certain embodiments, the MLL gene alteration is amplification.
According to one embodiment, the hematopoietic dysfunction includes NPM1 gene mutations and/or MLL1 (also known as KMT 2A) gene mutations.
According to one embodiment, the MLL1 gene mutation includes, but is not limited to, MLL1 gene rearrangement, duplication or amplification.
According to one embodiment, the hematopoietic disorder is Mixed Lineage Leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-induced leukemia, MLL-related leukemia, acute leukemia, chronic leukemia, myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN).
All embodiments of the methods described herein for treating hematopoietic dysfunction are also suitable for use in treating the hematopoietic dysfunction.
All embodiments described herein for use in treating hematopoietic disorders are also applicable to methods of treating the hematopoietic disorders.
All embodiments of the methods for treating hematopoietic dysfunction described herein are also suitable for use in the methods for treating the hematopoietic dysfunction.
All embodiments described herein for use in a method of treating a hematopoietic disorder are also applicable to a method of treating the hematopoietic disorder.
In one embodiment, the present invention relates to a novel combination comprising:
a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a tautomer or stereoisomer form thereof, or a pharmaceutically acceptable salt or solvate thereof;
a therapeutically effective amount of a BCL-2 inhibitor; and
optionally a therapeutically effective amount of at least one other anti-neoplastic agent.
According to one embodiment, the compound of formula (I) is a multiple endocrine oncoprotein-MLL inhibitor having the structure:
and tautomers and stereoisomers thereof, wherein
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
Wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group; wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 11 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting ofThe group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group;
wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo or-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 9a 、R 9b 、R 10a 、R 10b 、R 11 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
Wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with oneAnd each of the one, two or three substituents is independently selected from the group consisting of: cyano, halo, OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b 、R 10c Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 10a And R is 10b Each independently selected from hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb Or Het;
het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is substituted with one C 3-6 Cycloalkyl substitution;
R xa and R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group;
wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 11 、R 12a And R is 12b Each independently selected from the group consisting of:hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb Or Het;
het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6-membered monocyclic aromatic ring is substituted with one C 3-6 Cycloalkyl substitution;
R xa and R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b And R is 10c Each independently selected fromThe group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b And R is 10c Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb Or Het;
het is represented by C 3-6 Cycloalkyl-substituted pyrimidinyl;
R xa and R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one-OH;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted by one or two substituents 1-6 Alkyl, the one or two substituents each being independently selected from the group consisting of: halo, -O-C 1-4 Alkyl and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b And R is 10c Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb Or Het;
het represents quiltC (C) 3-6 Cycloalkyl-substituted pyrimidinyl;
R xa and R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n2 is 2;
n1, n3 and n4 are 1;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one-OH;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted by one or two substituents 1-6 Alkyl, the one or two substituents each being independently selected from the group consisting of: halo, -O-C 1-4 Alkyl and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b And R is 10c Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n2 is 2;
n1, n3 and n4 are 1;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted by one or two substituents 1-6 Alkyl, the one or two substituents each being independently selected from the group consisting of: halo, -O-C 1-4 Alkyl and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b And R is 10c Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n2 is 2;
n1, n3 and n4 are 1;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting ofAnd (3) a group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted by one or two substituents 1-6 Alkyl, the one or two substituents each being independently selected from the group consisting of: halo, -O-C 1-4 Alkyl and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 10a 、R 10b And R is 10c Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 10a And R is 10b Each independently selected from hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 10a And R is 10b Each independently selected from hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represents hydrogen or C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 10a And R is 10b Each independently selected from hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represents hydrogen or C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 representing different kindsA propyl group;
R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the And
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH and-O-C 1-4 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 8a And R is 8b Each independently selected from the group consisting of: c (C) 1-6 An alkyl group; and is covered with an-O-C 1-4 Alkyl substituted C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 represents hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 8a And R is 8b Each independently selected from the group consisting of: c (C) 1-6 An alkyl group; and is covered with an-O-C 1-4 Alkyl substituted C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Or Het;
het represents a 6-membered monocyclic aromatic ring containing two nitrogen atoms; wherein the 6 membered monocyclic aromatic ring is optionally substituted with one C 3-6 Cycloalkyl substitution;
R xa and R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 Is hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation of-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl and-O-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
According to one embodiment, the compounds of formula (I) are as defined herein, and tautomers and stereoisomeric forms thereof, wherein
R 1a represents-C (=O) -NR xa R xb ；
R xa And R is xb Represent C 1-4 An alkyl group;
R 1b represents F;
Y 1 represents-O-;
R 2 is hydrogen;
u represents N;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b or-C 1-6 alkyl-OH；
R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl and-O-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group;
and pharmaceutically acceptable salts and solvates thereof.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 1b And represents F.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 2 Represents hydrogen.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein n1 is 1, n2 is 2, n3 is 1 and n4 is 1.
In one embodiment, the invention includes those compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents-O-.
In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents-O-; and U represents N.
In one embodiment, the present invention relates to compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Y 1 represents-O-; u represents N; r is R 1b Represents F; and R is 2 Represents hydrogen.
In one embodiment, the invention includes compounds of formula (I), as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents
In one embodiment, the invention includes those compounds of formula (I) as mentioned in any other embodiment, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 5-or 6-membered aromatic ring containing one or two nitrogen atoms;
Wherein the monocyclic 5-or 6-membered aromatic ring is substituted with one C 3-6 Cycloalkyl substitution.
In one embodiment, the invention includes those compounds of formula (I) as mentioned in any other embodiment, as well as pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 5-or 6-membered aromatic ring containing one or two nitrogen atoms; wherein the monocyclic 5-or 6-membered aromatic ring is substituted with one C 3-6 Cycloalkyl substitution; and R is 1b And represents F.
In one embodiment, the invention includes those compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing one or two nitrogen atoms; wherein the monocyclic 6-membered aromatic ring is substituted with one C 3-6 Cycloalkyl substitution.
In one embodiment, the invention includes those compounds of formula (I) as mentioned in any other embodiment, and the pharmaceutically acceptable salts thereofSalts and solvates acceptable above, or any subgroup thereof, wherein Het represents a monocyclic 6-membered aromatic ring containing one or two nitrogen atoms; and wherein the monocyclic 6-membered aromatic ring is substituted with one C 3-6 Cycloalkyl substitution; and R is 1b And represents F.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting ofThe group consisting of: cyano, halo and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group;R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; is one and two C substituted by one or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 1-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 Alkyl-)NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting ofThe group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting of: c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl and-C (=o) -NR 10a R 10b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 2-6 alkyl-NR 8a R 8b The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 3 C in the definition 2-6 The alkyl moiety may be substituted with one, two or three substituents each independently selected from the group consisting of: cyano, halo and-O-C 1-4 An alkyl group; r is R 8a And R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b ；
R 8a And R is 8b Each independently selected from the group consisting of: c (C) 1-6 An alkyl group; and C substituted with one, two or three substituents 1-6 Alkyl, the one, two or three substituents each being independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b ；R 8a Represent C 1-6 An alkyl group; and R is 8b Is represented by an-O-C 1-4 Alkyl substituted C 1-6 An alkyl group.
In one embodiment, the invention relates to the use of a compound of formula (I) as mentioned in any other embodiment and pharmaceutically acceptable salts thereofMethods of acceptable salts and solvates, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group; wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo or-O-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group. Wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group.
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 represents-CH 2 -CH 2 -CH 2 -NR 8a R 8b ；R 8a Represents methyl; and R is 8b represents-CH 2 -CH 2 -OCH 3 。
In one embodiment, the invention includes compounds of formula (I) as mentioned in any other embodiment, and pharmaceutically acceptable salts and solvates thereof, or any subgroup thereof, wherein R 3 C in the definition 1-6 alkyl-C 1-6 alkyl-NR 8a R 8b Limited to-CH 2 -CH 2 -CH 2 -。
In one embodiment, the invention includes a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof, as set forth in any other embodiment wherein the compound of formula (I) is limited to a compound of formula (Ia) or formula (Ib):
wherein R is 1a 、R 1b 、R 3 、R 4 、R 5a 、R 5b 、X 1 、X 2 N1, n2, n3, n4 and halo are as defined for the compounds of formula (I) or any subgroup thereof mentioned in any other embodiment.
In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof, mentioned in any other embodiment is limited to a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof, mentioned in any other embodiment is limited to a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof.
In one embodiment, the invention includes a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or any subgroup thereof, as set forth in any other embodiment wherein the compound of formula (I) is limited to a compound of formula (I-y):
Wherein R is 3 As defined for the compounds of formula (I) as mentioned in any other embodiment or any subgroup thereof.
In formula (I-y), n1 is 1, n2 is 2, n3 is 1, and n4 is 1.
In a particular embodiment, the compound of formula (I) is compound a:
/>
or a pharmaceutically acceptable salt or solvate thereof.
In a particular embodiment, the compound of formula (I) is compound A1:
in a particular embodiment, the compound of formula (I) is compound A2:
in a particular embodiment, the compound of formula (I) is compound A3:
in a particular embodiment, the compound of formula (I) is compound A4-a:
or a solvate thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide benzenesulfonate or a hydrate thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bisbenzenesulfonate or a solvate thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bisbenzenesulfonate (compound A4-b) or a hydrate thereof.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is compound A4: crystalline form a of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate hydrate.
In a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is crystalline form a of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate 0.5-2.0 equivalent of hydrate.
In one embodiment, the invention relates to a subgroup of formula (I) as defined in the general reaction scheme.
In one embodiment, the compound of formula (I) is selected from the group consisting of: exemplary compounds, tautomers and stereoisomers thereof, and any of its free base, any pharmaceutically acceptable salt, and solvate.
In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a combination as described in any other embodiment.
In some embodiments, combination therapies comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and optionally at least one other anti-neoplastic agent are provided.
According to an embodiment, the multiple endocrine oncoprotein-MLL inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
According to a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound a or a pharmaceutically acceptable salt or solvate thereof.
According to a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound A1.
According to a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound A2.
According to a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound A3.
According to a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound A4-a or a solvate thereof.
According to a specific embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound A4-b or a hydrate thereof.
According to a particular embodiment, the multiple endocrine oncoprotein-MLL inhibitor is compound A4.
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitors may have improved metabolic stability characteristics.
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitor may have an extended in vivo half-life (T1/2).
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitor may have improved oral bioavailability.
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitors can reduce tumor growth, e.g., tumors harboring MLL (KMT 2A) gene rearrangements/alterations and/or NPM1 mutations.
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitors may have improved PD characteristics in vivo over an extended period of time, e.g., inhibition of target gene expression such as MEIS1 and upregulation of differentiation markers over a period of at least 16 hours.
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitor may have improved safety profiles (e.g., reduced hERG inhibition; improved cardiovascular safety).
In particular embodiments, the multiple endocrine oncoprotein-MLL inhibitor may be suitable for q.d. administration (once daily).
According to an embodiment, the BCL-2 inhibitor is selected from obatuk (obatux), HA14-1, nanotuk, ABT-737, TW-37, AT101, sha Butuo grams (sabutoclax), gambogic acid and valnemtuk, or pharmaceutically acceptable salts or solvates thereof.
According to a particular embodiment, the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt or solvate thereof.
According to embodiments, the at least one other anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an IDH inhibitor, an immunomodulatory anti-neoplastic agent, or a DHODH inhibitor.
According to an embodiment, the at least one other anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an Isocitrate Dehydrogenase (IDH) inhibitor.
According to an embodiment, the hypomethylating agent includes, but is not limited to, azacytidine, decitabine, or a pharmaceutically acceptable salt or solvate thereof.
According to embodiments, DNA intercalators include, but are not limited to, anthracyclines (e.g., daunorubicin, doxorubicin, idarubicin).
According to an embodiment, the DNA intercalator is daunorubicin.
According to an embodiment, the DNA intercalator is doxorubicin.
According to an embodiment, the DNA intercalator is idarubicin.
According to an embodiment, pyrimidine analogs include, but are not limited to, cytarabine (ARA-C).
According to an embodiment, the purine analog is fludarabine.
According to embodiments, the kinase inhibitor is a FLT-3 inhibitor, a BTK inhibitor, an ABL inhibitor, an aurora inhibitor or a multi-kinase inhibitor of two or more thereof.
According to embodiments, the kinase inhibitor is a multi-kinase inhibitor of FLT-3 inhibitors, ABL inhibitors, and aurora inhibitors. According to embodiments, such multi-kinase inhibitors include, but are not limited to KW-2449.
According to an embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.
According to embodiments, the tyrosine kinase inhibitor is a FLT-3 inhibitor or a BTK inhibitor.
According to embodiments, FLT3 inhibitors include, but are not limited to, sorafenib, sunitinib, midostaurin (PKC 412), letatinib (CEP-701), tandutinib (MLN 518), quinidine (AC 220), giritinib (ASP 2215), and KW-2449.
According to embodiments, BTK inhibitors include, but are not limited to ibrutinib.
According to embodiments, CD20 inhibitors include, but are not limited to, anti-CD 20 antibodies (e.g., obbine You Tuozhu mab (GA 101)).
According to embodiments, IDH inhibitors include, but are not limited to Ai Funi cloth and enasinib (enasinib).
According to an embodiment, the isocitrate dehydrogenase 1 inhibitor includes, but is not limited to, ai Funi cloth.
According to an embodiment, the isocitrate dehydrogenase 2 inhibitor includes, but is not limited to, iranib.
According to embodiments, immunomodulatory anti-neoplastic agents include, but are not limited to, PD-1 inhibitors (e.g., nivolumab, alemtuzumab, and pamidzumab), thalidomide, lenalidomide, pomalidomide, BCG, and levamisole.
According to embodiments, PD-1 inhibitors include, but are not limited to, nivolumab, alemtuzumab, and pamphlet Li Zhushan.
According to an embodiment, DHODH inhibitors include, but are not limited to, compounds having the structure of formula (Z):
wherein the method comprises the steps of
X is CH or N;
y is CH or N;
R 1 selected from the group consisting of: c (C) 1-6 An alkyl group; by OH or OCH 3 Substituted C 1-6 An alkyl group; c (C) 2-6 Alkenyl groups; c (C) 1-6 A haloalkyl group; by OH or OCH 3 Substituted C 1-6 A haloalkyl group; c (C) 2-6 A haloalkenyl group; n (CH) 3 ) 2 ；C 3-6 Cycloalkyl; quilt C 1-6 Alkyl substituted C 3-6 Cycloalkyl; a phenyl group;
R 2 Is thatWherein the method comprises the steps of
R a Selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;
R b is C 1-6 Alkyl or C substituted by a member selected from the group consisting of 1-6 Alkyl: OH, halo, CN, OC 1-6 Alkyl, OC 1-6 Haloalkyl and OC 3-6 Cycloalkyl;
R 3 selected from the group consisting of: H. halo, CH 3 And OCH 3 ；
R 4 Selected from the group consisting of:
·C 1-6 an alkyl group; is covered by one or two OCH 3 Substituted C 1-6 An alkyl group; c (C) 3-6 Cycloalkyl; quilt CH 3 Or OCH (optical wavelength) 3 Substituted C 3-6 Cycloalkyl; CH (CH) 2 -C 3-6 Cycloalkyl; and
·
· and
·
Wherein the method comprises the steps of
Each R c Independently selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 ；NO 2 ；OH；O-CH 2 CH 2 OH; OC and OC 1-6 An alkyl group;
R d selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the A CN; OC and OC 1-6 An alkyl group;
R g selected from the group consisting of: h is formed; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; quiltC substituted by a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
n is 1 or 2;
or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof;
or a compound selected from
/>
Or a pharmaceutically acceptable salt, N-oxide, solvate or stereoisomer thereof.
According to an embodiment, DHODH inhibitors include, but are not limited to, compounds having the structure of formula (Z):
wherein the method comprises the steps of
X is CH or N;
y is CH or N;
R 1 selected from the group consisting of: c (C) 1-6 An alkyl group; by OH or OCH 3 Substituted C 1-6 An alkyl group; c (C) 2-6 Alkenyl groups; c (C) 1-6 A haloalkyl group; by OH or OCH 3 Substituted C 1-6 A haloalkyl group; c (C) 2-6 A haloalkenyl group; n (CH) 3 ) 2 ；C 3-6 Cycloalkyl; quilt C 1-6 Alkyl substituted C 3-6 Cycloalkyl; a phenyl group;
R 2 is thatWherein the method comprises the steps of
R a Selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;
R b is C 1-6 Alkyl or C substituted by a member selected from the group consisting of 1-6 Alkyl: OH, halo, CN, OC 1-6 Alkyl, OC 1-6 Haloalkyl and OC 3-6 Cycloalkyl;
R 3 selected from the group consisting of: H. halo, CH 3 And OCH 3 ；
R 4 Selected from the group consisting of:
·C 1-6 an alkyl group; is covered by one or two OCH 3 Substituted C 1-6 An alkyl group; c (C) 3-6 Cycloalkyl; quilt CH 3 Or OCH (optical wavelength) 3 Substituted C 3-6 Cycloalkyl; CH (CH) 2 -C 3-6 Cycloalkyl; and
·
· and
·
Wherein the method comprises the steps of
Each R c Independently selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 ；NO 2 ；OH；O-CH 2 CH 2 OH; OC and OC 1-6 An alkyl group;
R d selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the A CN; OC and OC 1-6 An alkyl group;
R g selected from the group consisting of: h is formed; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; and C substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
n is 1 or 2;
or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.
In the context of formula (Z), the following definitions apply:
the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like). The term alkenyl also includes alkenyl groups that include oxygen, nitrogen, sulfur, or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, the linear or branched alkenyl groups have 6 or fewer carbon atoms in their backbone (e.g., C for linear chain 2-6 For branched chains C 3-6 )。
The term "haloalkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms in the chain, optionally substituted with halogen. As used herein, the term "C 1-6 Haloalkyl "refers to a straight or branched alkyl group having 1 to 6 carbon atoms in the chain, optionally substituted with halogen. Such as the bookAs used herein, the term "C 1-4 Haloalkyl "refers to a straight or branched alkyl group having 1 to 4 carbon atoms in the chain, optionally substituted with halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF 3 ) Difluoromethyl (CF) 2 H) Monofluoromethyl (CH) 2 F) Pentafluoroethyl (CF) 2 CF 3 ) Tetrafluoroethyl (CHFCF) 3 ) Monofluoroethyl (CH) 2 CH 2 F) Trifluoroethyl (CH) 2 CF 3 ) Tetrafluorotrifluoromethyl ethyl (CF) 3 ) 2 ) And will be recognized by those of ordinary skill in the art and in light of the teachings provided herein as equivalent to any of the foregoing examples.
The term "haloalkenyl" includes unsaturated aliphatic groups of similar length to the alkyl groups described above and which may be substituted, but which contain at least one double bond and have from 1 to 6 carbon atoms in the chain, optionally with halogen substituted hydrogen.
The term "aryl" refers to a monocyclic aromatic carbocyclic ring having 6 atoms per ring (ring structure having all carbon ring atoms). (the carbon atom in the aryl group is sp <1id = Superscript >2</1> hybridized.)
The term "heteroaryl" refers to a monocyclic or fused bicyclic heterocycle having 3 to 9 ring atoms per heterocycle (having a ring structure selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur). Illustrative examples of heteroaryl groups include the following entities in the form of suitable bonding moieties:
those skilled in the art will recognize that the materials listed or illustrated above are not exhaustive and that other materials within the scope of these defined terms may also be selected.
The term "variable attachment point" means allowing the group to be attached at more than one alternative position in the structure. The connection always replaces a hydrogen atom on one of the ring atoms. In other words, all arrangements of bonding are represented by a single schematic, as shown by the following illustration.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein X is CH.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein X is N.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is CH.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein Y is N.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 Is C 1-4 An alkyl group. By OH or OCH 3 Substituted C 1-4 An alkyl group; c (C) 2-4 Alkenyl groups; c (C) 1-4 A haloalkyl group; by OH or OCH 3 Substituted C 1-4 A haloalkyl group; c (C) 2-4 A haloalkenyl group; n (CH) 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the A cyclopropyl group; quilt C 1-4 An alkyl-substituted cyclopropyl group; or phenyl.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 Is CH 3 ,CH 2 CH 3 ，
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 1 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 2 Is that
Wherein R is b Is made up of OH, halo, CN, OC 1-4 Alkyl, OC 1-4 Haloalkyl or OC 3-6 Cycloalkyl-substituted C 1-4 An alkyl group; and is also provided with
R a Is C 1-4 Alkyl, C 1-4 Haloalkyl or C 3-6 Cycloalkyl groups.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 2 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 H.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 F.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 Is CH 3 。
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 3 Is OCH 3 。
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 4 Is thatWherein the method comprises the steps of
Each R c Independently selected from the group consisting of: h is formed; a halogenated group; c (C) 1-4 An alkyl group; taken by a member selected from the group consisting ofSubstituted C 1- Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-4 A haloalkyl group; c substituted with a member selected from the group consisting of 1-4 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And NO 2 ；
R d Selected from the group consisting of: h is formed; a halogenated group; c (C) 1-4 An alkyl group; by OH, OCH 3 、SCH 3 Or OCF (optical clear) 3 Substituted C 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; by OH or OCH 3 Substituted C 1-4 A haloalkyl group; or OC (alpha) 1-4 An alkyl group; a CN; OC and OC 1-6 An alkyl group; and is also provided with
n is 1 or 2.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 4 Is that
Each R c Independently selected from the group consisting of: H. halo, C 1-4 Alkyl, C 1-4 Haloalkyl, NO 2 、O-CH 2 CH 2 OH and OC 1-4 An alkyl group;
R d selected from the group consisting of: H. halo, C 1-4 Alkyl, CN and OC 1-6 An alkyl group; and is also provided with
n is 1 or 2.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 4 Is that
Wherein the method comprises the steps of
Each R c Independently selected from the group consisting of: h is formed; a halogenated group; c (C) 1-4 An alkyl group; c substituted with a member selected from the group consisting of 1- Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-4 A haloalkyl group; c substituted with a member selected from the group consisting of 1-4 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And R is d Selected from the group consisting of: a halogenated group; c (C) 1-4 An alkyl group; by OH, OCH 3 、SCH 3 Or OCF (optical clear) 3 Substituted C 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; by OH or OCH 3 Substituted C 1-4 A haloalkyl group; or OC (alpha) 1-4 An alkyl group; a CN; and OC 1-6 An alkyl group.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 4 Is that Wherein the method comprises the steps of
Each R c Independently selected from the group consisting of: H. halo, C 1-4 Alkyl, C 1-4 Haloalkyl, OC 1-4 Alkyl and OH;
R d selected from the group consisting of: halo, C 1-4 Alkyl and OC 1-4 An alkyl group; and is also provided with
n is 1 or 2.
In the embodiment of the inventionIn this case, the DHODH inhibitor is a compound of formula (Z), wherein R 4 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 4 Is thatWherein the method comprises the steps of
R c Is H; a halogenated group; c (C) 1-4 An alkyl group; by OH, OCH 3 、SCH 3 Or OCF (optical clear) 3 Substituted C 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; by OH or OCH 3 Substituted C 1-4 A haloalkyl group; or OC (alpha) 1-4 An alkyl group;
R d is a halogenated group; c (C) 1-4 An alkyl group; by OH, OCH 3 、SCH 3 Or OCF (optical clear) 3 Substituted C 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; or by OH or OCH 3 Substituted C 1-4 A haloalkyl group; and is also provided with
R g Is H; c (C) 1-4 An alkyl group; by OH, OCH 3 、SCH 3 Or OCF (optical clear) 3 Substituted C 1-4 An alkyl group; c (C) 1-4 A haloalkyl group; or by OH or OCH 3 Substituted C 1-4 A haloalkyl group.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein
R 4 Is thatWherein the method comprises the steps of
R c Is H or halo；
R d Is C 1-4 An alkyl group; and is also provided with
R g H.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z), wherein R 4 Is that
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z) selected from the group consisting of:
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4-phenylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (3, 3-trifluoroprop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2, 6-dichlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
2- (2, 6-dichlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -4-cyclopropyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) -2- (2- (trifluoromethyl) phenyl) isoquinolin-1 (2H) -one;
2- (6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -1-oxo-4- (prop-1-en-2-yl) isoquinolin-2 (1H) -yl) benzonitrile;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4-isopropylphthalazin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4-isopropylphthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4-isopropylphthalazin-1 (2H) -one;
4-ethyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) phthalazin-1 (2H) -one;
4-ethyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (o-tolyl) phthalazin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-4-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4- (2-hydroxypropan-2-yl) isoquinolin-1 (2H) -one;
4- (dimethylamino) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-methoxy-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
2- (5-chloro-3-methyl-1H-pyrazol-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8- (prop-1-en-2-yl) -6- (o-tolyl) -1, 6-naphthyridin-5 (6H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-methyl-6- (o-tolyl) pyrido [2,3-d ] pyridazin-5 (6H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-tolyl) pyrido [2,3-d ] pyridazin-5 (6H) -one;
6- (2-chloro-6-fluorophenyl) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8- (prop-1-en-2-yl) -1, 6-naphthyridin-5 (6H) -one;
6- (2-chloro-6-fluorophenyl) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-1, 6-naphthyridin-5 (6H) -one;
(S) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-6- (o-tolyl) -8- (1, 1-trifluoropropan-2-yl) -1, 6-naphthyridin-5 (6H) -one;
(R) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-6- (o-tolyl) -8- (1, 1-trifluoropropan-2-yl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylthiazol-5-yl) isoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-tolyl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-tolyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-tolyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-methoxyphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
rac-4- (sec-butyl) -2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoroisoquinolin-1 (2H) -one;
2- (3-chloro-6-methoxypyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-4-methylpyridin-3-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluoro-3-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1 (2H) -one;
rac 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) phthalazin-1 (2H) -one;
(S) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) phthalazin-1 (2H) -one;
(R) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-methoxy-4-methylpyridin-3-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (5-chloro-3-methyl-1H-pyrazol-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (3-chloro-2-methoxy-5-methylpyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-2-methoxy-5-methylpyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-methoxyphenyl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (4-fluoro-2-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-3- (2-hydroxyethoxy) phenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluorophenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2, 5-difluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-6-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-3-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-methoxy-3, 5-dimethylpyridin-4-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2, 5-difluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-6-methylphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (3-fluoro-2-methylphenyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2, 5-xylyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (4-fluoro-2-tolyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluorophenyl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-3, 5-dimethylpyridin-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-methyl-4- (prop-1-en-2-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluoro-3-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (3, 3-trifluoroprop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-tolyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-methoxyphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-methoxypyridin-4-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (3-fluoro-2-methylphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2, 5-xylyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
rac-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (2-ethylphenyl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxypyridin-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-methoxypyridin-4-yl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-5-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2- (methyl-d) 3 ) Phenyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylpyrimidin-5-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxyphenyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (3-fluoro-6-methoxypyridin-2-yl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylpyrazin-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-6- (2-fluoro-5-methylphenyl) -8-isopropyl-1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylpyridazin-3-yl) isoquinolin-1 (2H) -one;
(S) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
(R) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2- (trifluoromethyl) phenyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (5-methylpyrimidin-4-yl) isoquinolin-1 (2H) -one;
2- (2- (difluoromethyl) phenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-2-methoxypyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2-cyclohexyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-6-methylpyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2-cyclopentyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-4-methoxypyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1 r,2 s) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
2- (1, 3-dimethoxyprop-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-5-methylpyridin-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1 s,2 r) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
2- (cyclopropylmethyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (1-methoxybutan-2-yl) isoquinolin-1 (2H) -one;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylpyridin-2-yl) isoquinolin-1 (2H) -one;
rac 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((cis) -3-methoxycyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1R, 2R) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1S, 2S) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (pent-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1R, 2R) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1S, 2S) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1R, 2S) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1S, 2R) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
rac 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((cis) -3-methoxycyclohexyl) isoquinolin-1 (2H) -one;
2- (bicyclo [2.2.1] hept-1-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-3-methylpyridin-4-yl) isoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (2-methoxyphenyl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylisothiazol-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (5-methylisothiazol-4-yl) isoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (2- (trifluoromethyl) phenyl) -1, 6-naphthyridin-5 (6H) -one;
2- (3, 6-dimethylpyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (2, 5-dimethylpyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylpyridin-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylpyridin-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methylpyridin-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-hydroxy-5-methylpyridin-4-yl) -4-isopropylisoquinolin-1 (2H) -one;
6- (2- (difluoromethyl) phenyl) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-hydroxy-3-methylpyridin-4-yl) -4-isopropylisoquinolin-1 (2H) -one; and
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-D) 3 -tolyl) -1, 6-naphthyridin-5 (6H) -one;
and optionally one or more of pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z) selected from the group consisting of:
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4-phenylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (3, 3-trifluoroprop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2, 6-dichlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
2- (2, 6-dichlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -4-cyclopropyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) -2- (2- (trifluoromethyl) phenyl) isoquinolin-1 (2H) -one;
2- (6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -1-oxo-4- (prop-1-en-2-yl) isoquinolin-2 (1H) -yl) benzonitrile;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (prop-1-en-2-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4-isopropylphthalazin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4-isopropylphthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4-isopropylphthalazin-1 (2H) -one;
4-ethyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) phthalazin-1 (2H) -one;
4-ethyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (o-tolyl) phthalazin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-4-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (3-fluorophenyl) -4- (2-hydroxypropan-2-yl) isoquinolin-1 (2H) -one;
4- (dimethylamino) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-methoxy-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
2- (5-chloro-3-methyl-1H-pyrazol-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8- (prop-1-en-2-yl) -6- (o-tolyl) -1, 6-naphthyridin-5 (6H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-methyl-6- (o-tolyl) pyrido [2,3-d ] pyridazin-5 (6H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-tolyl) pyrido [2,3-d ] pyridazin-5 (6H) -one;
6- (2-chloro-6-fluorophenyl) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8- (prop-1-en-2-yl) -1, 6-naphthyridin-5 (6H) -one;
6- (2-chloro-6-fluorophenyl) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-1, 6-naphthyridin-5 (6H) -one;
(S) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-6- (o-tolyl) -8- (1, 1-trifluoropropan-2-yl) -1, 6-naphthyridin-5 (6H) -one;
(R) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-6- (o-tolyl) -8- (1, 1-trifluoropropan-2-yl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylthiazol-5-yl) isoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-tolyl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-tolyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-tolyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-methoxyphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
rac-4- (sec-butyl) -2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoroisoquinolin-1 (2H) -one;
2- (3-chloro-6-methoxypyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-4-methylpyridin-3-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluoro-3-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1 (2H) -one;
Rac 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) phthalazin-1 (2H) -one;
(S) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) phthalazin-1 (2H) -one;
(R) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-methoxy-4-methylpyridin-3-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (5-chloro-3-methyl-1H-pyrazol-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (3-chloro-2-methoxy-5-methylpyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-2-methoxy-5-methylpyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-5-methoxyphenyl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (4-fluoro-2-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-3- (2-hydroxyethoxy) phenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluorophenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2, 5-difluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-6-tolyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-3-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-methoxy-3, 5-dimethylpyridin-4-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2, 5-difluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluoro-6-methylphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (3-fluoro-2-methylphenyl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2, 5-xylyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (4-fluoro-2-tolyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-fluorophenyl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-3, 5-dimethylpyridin-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-methyl-4- (prop-1-en-2-yl) -2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluoro-3-methoxyphenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (3, 3-trifluoroprop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-tolyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-methoxyphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-methoxypyridin-4-yl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (3-fluoro-2-methylphenyl) -4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
2- (2, 5-xylyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) isoquinolin-1 (2H) -one;
rac-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (2-ethylphenyl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxypyridin-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (5-fluoro-2-methoxypyridin-4-yl) -4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-5-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2- (methyl-d) 3 ) Phenyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylpyrimidin-5-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxyphenyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (3-fluoro-6-methoxypyridin-2-yl) -4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylpyrazin-2-yl) isoquinolin-1 (2H) -one;
2- (2-chloro-5-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-6- (2-fluoro-5-methylphenyl) -8-isopropyl-1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylpyridazin-3-yl) isoquinolin-1 (2H) -one;
(S) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
(R) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2- (trifluoromethyl) phenyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (5-methylpyrimidin-4-yl) isoquinolin-1 (2H) -one;
2- (2- (difluoromethyl) phenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-2-methoxypyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2-cyclohexyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-6-methylpyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2-cyclopentyl-6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (3-chloro-4-methoxypyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1 r,2 s) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
2- (1, 3-dimethoxyprop-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-5-methylpyridin-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1 s,2 r) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
2- (cyclopropylmethyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (1-methoxybutan-2-yl) isoquinolin-1 (2H) -one;
2- (2-chlorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylpyridin-2-yl) isoquinolin-1 (2H) -one;
rac 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((cis) -3-methoxycyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1R, 2R) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1S, 2S) -2-methylcyclohexyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (pent-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1R, 2R) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1S, 2S) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1R, 2S) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((1S, 2R) -2-methylcyclopentyl) isoquinolin-1 (2H) -one;
rac 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- ((cis) -3-methoxycyclohexyl) isoquinolin-1 (2H) -one;
2- (bicyclo [2.2.1] hept-1-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methoxy-3-methylpyridin-4-yl) isoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (2-methoxyphenyl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylisothiazol-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (5-methylisothiazol-4-yl) isoquinolin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (2- (trifluoromethyl) phenyl) -1, 6-naphthyridin-5 (6H) -one;
2- (3, 6-dimethylpyridin-2-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (2, 5-dimethylpyridin-4-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (4-methylpyridin-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (3-methylpyridin-4-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2-methylpyridin-3-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-hydroxy-5-methylpyridin-4-yl) -4-isopropylisoquinolin-1 (2H) -one;
6- (2- (difluoromethyl) phenyl) -2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (2-hydroxy-3-methylpyridin-4-yl) -4-isopropylisoquinolin-1 (2H) -one; and
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-D) 3 -tolyl) -1, 6-naphthyridin-5 (6H) -one;
and optionally one or more of pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof; or alternatively
A compound selected from the group consisting of:
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2- (2-fluoro-4-nitrophenyl) -4-iodoisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -7- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -6-fluoro-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -7- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -6-methoxy-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
or a pharmaceutically acceptable salt, N-oxide, solvate or stereoisomer thereof.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z) selected from the group consisting of:
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one;
2- (2-chloro-4-methylpyridin-3-yl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -4- (1-methylcyclopropyl) isoquinolin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4- (prop-1-en-2-yl) phthalazin-1 (2H) -one;
2- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -3-fluoro-8-isopropyl-6- (o-tolyl) -1, 6-naphthyridin-5 (6H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) phthalazin-1 (2H) -one;
2- (2-chloro-6-fluorophenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylphthalazin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2- (methyl-d 3) phenyl) isoquinolin-1 (2H) -one;
(R) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-2- (o-tolyl) -4- (1, 1-trifluoropropan-2-yl) isoquinolin-1 (2H) -one;
6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (2- (trifluoromethyl) phenyl) isoquinolin-1 (2H) -one; and
2- (2- (difluoromethyl) phenyl) -6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropylisoquinolin-1 (2H) -one;
and optionally one or more of pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z) having formula (Za):
wherein the method comprises the steps of
Y is CH or N;
R 1 selected from the group consisting of: c (C) 1-6 An alkyl group; by OH or OCH 3 Substituted C 1-6 An alkyl group; c (C) 2-6 Alkenyl groups; c (C) 1-6 A haloalkyl group; by OH or OCH 3 Substituted C 1-6 A haloalkyl group; c (C) 2-6 A haloalkenyl group; n (CH) 3 ) 2 ；C 3-6 Cycloalkyl; quilt C 1-6 Alkyl substituted C 3-6 Cycloalkyl; a phenyl group;
R 2 is that
R 3 Selected from the group consisting of: H. halo, CH 3 And OCH 3 ；
R 4 Selected from the group consisting of:
C 1-6 an alkyl group; is covered by one or two OCH 3 Substituted C 1-6 An alkyl group; c (C) 3-6 Cycloalkyl; quilt CH 3 Or OCH (optical wavelength) 3 Substituted C 3-6 Cycloalkyl; CH (CH) 2 -C 3-6 Cycloalkyl; and/>
and
Wherein the method comprises the steps of
Each R c Independently selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 ；NO 2 ；OH；O-CH 2 CH 2 OH; OC and OC 1-6 An alkyl group;
R d selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the A CN; OC and OC 1-6 An alkyl group;
R g selected from the group consisting of: h is formed; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; and C substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
n is 1 or 2;
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof.
In an embodiment of the invention, the DHODH inhibitor is a compound of formula (Z) having formula (Zb):
Wherein the method comprises the steps of
Y is CH or N;
R 1 selected from the group consisting of: c (C) 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 Alkenyl groups;
R 2 is that
R 3 Selected from the group consisting of: H. halo and OCH 3 ；
R 4 Selected from the group consisting of:
wherein the method comprises the steps of
R c Selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And NO 2 ；
R d Selected from the group consisting of: h is formed; a halogenated group; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; c substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the A CN; OC and OC 1-6 An alkyl group;
R g selected from the group consisting of: h is formed; c (C) 1-6 An alkyl group; c substituted with a member selected from the group consisting of 1-6 Alkyl: OH, OCH 3 、SCH 3 And OCF (optical fiber) 3 ；C 1-6 A haloalkyl group; and C substituted with a member selected from the group consisting of 1-6 Haloalkyl: OH and OCH 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
n is 1;
or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant or N-oxide thereof.
Exemplary compounds of formula (Z) useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation and examples hereinafter. Those skilled in the art will recognize that to obtain the various compounds herein, the starting materials may be appropriately selected such that the final desired substituents will be carried throughout the reaction scheme with or without protection as desired to give the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can undergo the entire reaction scheme and be replaced with the desired substituent where appropriate. Variables are as defined above for formula (Z) unless otherwise indicated. The reaction may be carried out between the melting point of the solvent and the reflux temperature, and preferably between 0 ℃ and the reflux temperature of the solvent. Conventional heating or microwave heating may be employed to heat the reaction. The reaction may also be carried out in a closed pressure vessel at a temperature above the normal reflux temperature of the solvent.
All abbreviations used in the general schemes and examples for formula (Z) are as defined in table 1A. The variables are as defined in the scope or as specifically defined in the general scheme.
Table 1A: abbreviations (abbreviations)
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Preparation example
Exemplary compounds of formula (Z) useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation and the specific examples that follow.
Scheme 1
According to scheme 1,2, 4-triazol-5 (4H) -one compounds of formula (II) (wherein PG is Bn) are prepared in three steps from ethyl 2- (benzyloxy) acetate. In a first step, ethyl 2- (benzyloxy) acetate is combined with hydrazine hydrate in a suitable solvent (such as EtOH, etc.); reacting at 70-85 deg.c to prepare 2- (benzyloxy) acethydrazide. Hydrazide and R a Isocyanates of NCO (wherein R a Is C 1-6 Alkyl) in a suitable solvent such as water or the like; corresponding semicarbazide is provided. The semicarbazide is then cyclized with a suitable base such as NaOH in a suitable solvent such as water to provide a compound of formula (II) (wherein PG is Bn).
A compound of formula (II) (wherein R a Is C 1-6 Haloalkyl or C 3-6 Cycloalkyl) may be as previously described with formula R a Appropriately substituted compounds of NCO (wherein R a Is C 1-6 Haloalkyl or C 3-6 Cycloalkyl).
Using accepted methods (such as t.w.greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 3 rd edition, john Wiley &Sons press, 1999) implements the exchange of protecting groups of the compound of formula (II), wherein PG is Bn, with the compound of formula (II), wherein PG is TBDPS, in two steps. In the first step, deprotection of the benzyl group is achieved under hydrogen decomposition conditions known to those skilled in the art to provide the alcohol. For example, deprotection is achieved under the following conditions: palladium catalysts (such as Pd/C, etc.) are employed; at H 2 Lower part; in a suitable solvent (such as EtOH, meOH, etOAc or mixtures thereof, preferably EtOH); with or without HCl; for a period of 4 hours to 72 hours. In the second step, protection of the corresponding alcohol as silyl ether is achieved under the following conditions: with t-butyldiphenylsilyl chloride, a suitable base (such as imidazole, dimethylaminopyridine, pyridine, etc.); in a solvent (such as DMF, DCM, etc.); providing a compound of formula (II) wherein PG is TBDPS at a temperature ranging from 0 ℃ to room temperature.
Scheme 2
According to scheme 2, a compound of formula (XIV) (wherein R 3 H) with a halogenating reagent such as N-iodosuccinimide (NIS) or the like; in an aprotic solvent (such as acetonitrile, etc.); the treatment is carried out under heating conditions to provide a halogenated compound of formula (III) wherein HAL is iodide. R is as follows 1 -B(OH) 2 Is reacted with a compound of formula (III) under Suzuki coupling conditions known to those skilled in the art to provide a compound of formula (IV). For example, a compound of formula (III) (wherein HAL is iodide) is reacted with a commercially or synthetically obtainable boric acid (or borate) (such as R 1 -B(OH) 2 (wherein R is 1 Is optionally substituted C as defined herein for formula (Z) 2-6 Alkenyl or aryl)), palladium catalysts (such as bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium, and the like; suitable bases (such as potassium phosphate, cs 2 CO 3 Etc.); in a suitable solvent such as dioxane, water, ethanol or mixtures thereof to provide the compound of formula (IV). Allowing a compound of formula (IV) (wherein R 3 Is H) and formula R 4 -B(OH) 2 Is reacted under copper (II) -mediated Chan-Lam coupling conditions known to those skilled in the art to provide a compound of formula (V) (wherein HAL is bromide, X is CH and R 3 H). For example, reacting a compound of formula (IV) with a compound of formula R 4 -B(OH) 2 Compounds of (wherein R is 4 As defined herein with respect to formula (Z)), a catalyst (such as copper (II) acetate, etc.; bases (such as pyridine, NEt 3 Etc.); in a suitable solvent such as DCM, ACN, dioxane, THF, etc., to provide a compound of formula (V).
Scheme 3
According to scheme 3, a compound of formula (V) (wherein R 1 Is optionally substituted C 2-6 Alkenyl, R 3 Is H, R 4 Is an appropriately substituted phenyl group as described herein with respect to formula (Z), and HAL is Br) with a commercially available or synthetically obtained compound of formula (II) (wherein R a Is C 1-6 Alkyl) such as appropriately protected triazolones (wherein PG is selected from: benzyl, 4-methoxybenzyl or alkyl or aryl silanes, such as TBDPS, TBS, TES or TIPS) are used to catalyze CuI and diamines such as trans-1, 2-diaminocyclohexane and bases such as K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、NaHCO 3 In the presence of triethylamine, etc.; an Ullmann (Ullmann) type aromatic amination reaction occurs in a suitable solvent such as 1, 4-dioxane, DMSO, DMF, THF, ACN, etc.; compounds of formula (VI) are provided wherein X is CH and Y is CH.
Allowing a compound of formula (VI) (wherein PG is Bn and R 1 Is C 2-6 Alkenyl) cyclopropanation bars known to those skilled in the art from Simmons-Smith (Simmons-Smith)Under-piece reaction to provide a compound of formula (VI) (wherein R 1 Is quilt C 1-6 Alkyl substituted C 3-6 Cycloalkyl). For example, reacting a compound of formula (VI) (wherein R 1 Is that) With diiodomethane, diethyl zinc in a suitable solvent such as toluene and the like; reacting at a temperature ranging from 0 ℃ to room temperature for a period of 3 hours to 26 hours to provide a compound of formula (VI) (wherein R 1 Is CH (beta) 3 Substituted cyclopropyl).
Subsequently, accepted methods (such as T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 3 rd edition, john Wiley are employed&Sons press, those described in 1999) to provide compounds of formula (Z) (wherein X and Y are CH). For example, a compound of formula (VI) (wherein R is 3 H and PG is TBDPS). In a preferred method, PG is TBDPS and R a Is C 1-6 An alkyl group. Alternatively, removal of the TBDPS protecting group employs hydrogen fluoride triethylamine (Et 3 N.3hf).
The removal of the Bn protecting group is achieved in the presence of hydrogen in the presence of a catalyst such as palladium on carbon (Pd/C). The removal of the protecting group Bn is also achieved with TFA at a temperature of about 80 ℃.
The compound of formula (Z) (wherein X is CH; Y is CH; R 2 、R 3 、R 4 Each as defined herein with reference to formula (Z); and R is 1 Is C 2-6 Alkenyl) is reduced using hydrogenation conditions known to the person skilled in the art, for example with Pd/C or Wilkinson catalyst [ RhCl (PPh) 3 ) 3 ]At H 2 Reacting in a suitable solvent (such as MeOH, THF, etOAc, etc.); providing a compound of formula (Z), wherein R 1 Is C 2-6 An alkyl group.
Scheme 4
According to scheme 4, compounds of formula (VII) are reacted with α, β -unsaturated aldehydes such as 3-methyl-2-butenal, 3-methylpent-2-enal and the like; by TiCl 4 And a base such as triethylamine in an aprotic solvent such as Dichloromethane (DCM) or the like to provide an enamine intermediate, which is subsequently treated with a reducing agent such as NaBH 4 Etc.) reduction; to provide a compound of formula (VIII) (wherein R 5 Is C 1-4 Alkyl, R 4 As defined herein with respect to formula (Z). The compound of formula (VIII) is coupled with commercially available or synthetically available 4-bromo-2-iodobenzoyl chloride in an anhydrous aprotic solvent such as Dichloromethane (DCM) or the like using a base such as triethylamine and 4-Dimethylaminopyridine (DMAP) to provide the compound of formula (IX). Treatment of a compound of formula (IX) with palladium (II) acetate, tetrabutylammonium bromide and potassium acetate under heating Hertz (Heck) reaction conditions provides an intramolecular cyclized compound of formula (V) (wherein R 1 Is optionally substituted C 2-6 Alkyl, R 3 Is H, X is CH, and HAL is Br) and an intramolecular cyclized compound of formula (Va) (wherein R 1 Is optionally substituted C 2-6 Alkenyl, R 3 Is H, X is CH 2 And HAL is Br).
Scheme 5
According to scheme 5, a commercially available or synthetically obtained compound of formula (X) (wherein HAL is F, R 3 Is F and R 5 Is H or C 1-4 Alkyl) with a commercially available or synthetically obtained nucleophilic compound of formula (II) (wherein R a Is C 1-6 Alkyl) (such as a suitably protected triazolone, wherein PG is selected from: benzyl, 4-methoxybenzyl, or alkyl or aryl silanes, such as TBDPS, TBS, TES or TIPS) in a base such as K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、NaHCO 3 In the presence of triethylamine, etc.; in a suitable solvent (such as DMSO, DMF, THF, ACN, etc.); compounds of formula (XI) are provided. In a preferred method, PG is Bn and R a Is C 1-6 An alkyl group. When R is 5 Is C 1-4 When alkyl, the esters of formula (XI) hydrolyze to their corresponding acids under acidic or basic conditions. For example, treatment of t-butyl ester with TFA (R 5 tertiary-Bu); or alternatively, hydrolysis with a base such as NaOH in an aqueous solvent to provide a compound of formula (XIa) wherein R 5 H. The compound of formula (XIa) is chlorinated using conditions known to those skilled in the art to provide the acid chloride of formula (XII). For example, the compound of formula (XIa) is taken up in SOCl 2 Heating; or with oxalyl chloride in DCM.
Scheme 6
According to scheme 6, a compound of formula (XII) (wherein R 3 Is H or F, PG is Bn, and R a Is C 1-6 Alkyl) with a compound of formula (VIII) (wherein R 5 Is C 1-4 Alkyl) with a base such as a mixture of Triethylamine (TEA) and 4-Dimethylaminopyridine (DMAP) in an anhydrous aprotic solvent such as Dichloromethane (DCM) or the like; to provide a compound of formula (XIII). The compound of formula (VI) (wherein X is CH and Y is CH) is obtained by: treating a compound of formula (XIII) (wherein R is 1 Is optionally substituted C 1-6 Alkyl, as described herein with reference to formula (Z), provides a mixture of intramolecular cyclized compounds, which mixture is then separated to isolate the intermediate compound, wherein R 1 Is C 2-6 Alkyl and R 3 H or F.
Scheme 7
According to scheme 7, a compound of formula (XIV) (wherein R 3 H or F) with a compound of formula (II) such as a suitably protected triazolone (wherein PG is selected from: benzyl, 4-methoxybenzyl or alkyl or aryl silanes such as TBDPS, TBS, TES or TIPS) to afford compounds of formula (XV). In a preferred method, PG is Bn and R a Is C 1-6 An alkyl group. Subjecting the compound of formula (XV) to a halogenating agent such as N-iodosuccinimide (NIS) or the like; in an aprotic solvent (such as acetonitrile, etc.); treatment under heating provides a halo compound of formula (XVI) wherein Y is CH and HAL is iodide.
Scheme 8
According to scheme 8, the compounds of formulae (XVIIa) and (XVIIb) are prepared in two steps from 5-bromoisobenzofuran-1, 3-dione. Reacting 5-bromoisobenzofuran-1, 3-dione with a commercially available or synthetically available appropriately substituted alkyl grignard reagent (such as i-PrMgCl, etMgBr, etc.); in CdCl 2 In the presence of an aprotic solvent (e.g., THF, etc.); subsequently using R 5 Alkylating agents of formula (I) (wherein R 5 Is C 1-4 Alkyl (such as methyl iodide or ethyl iodide)) in a base such as K 2 CO 3 、Cs 2 CO 3 Etc.; treatment in aprotic solvents such as (DMF, DMSO, etc.); providing a mixture of regioisomeric esters of formulae (XVIIa) and (XVIIb) wherein R 1 Is optionally substituted C 1-6 An alkyl group. In a similar manner, aryl grignard reagents can be used to provide compounds of formulas (XVIIa) and (VXIIb) wherein R 1 Is a suitably substituted phenyl group. The regioisomers of formulae (XVIIa) and (XVIIb) are not isolated but are used directly and converted to the corresponding phthalazinones (mixtures). For example, the mixture of formulas (XVIIa) and (XVIIb) is treated with an excess of hydrazine in a suitable solvent such as ethanol or methanolThe treatment is carried out at a temperature ranging from room temperature to 90 ℃ for a period of time ranging from 6 hours to 20 hours. The desired phthalazinone compound of formula (V) may be readily separated from other regioisomers by precipitation, crystallization or purification by flash chromatography. A compound of formula (V) with a suitably protected triazolone of formula (II) (wherein R a Is C 1-6 Alkyl, and PG is selected from: benzyl, 4-methoxybenzyl or alkyl or aryl silanes, such as TBDPS, TBS, TES or TIPS) are used to catalyze CuI and diamines such as trans-1, 2-diaminocyclohexane and bases such as K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、NaHCO 3 In the presence of triethylamine, etc.; an Ullmann (Ullmann) type aromatic amination reaction occurs in a suitable solvent such as 1, 4-dioxane, DMSO, DMF, THF, ACN, etc.; compounds of formula (XVIII) are provided wherein X is N.
Allowing a compound of formula (XVIII) (wherein R 1 Is C 2-6 Alkenyl) under conditions known to those skilled in the art of the cyclopropanation reaction of Simmons-Smith (Simmons-Smith) to provide a compound of formula (XVIII) (wherein R) 1 Is quilt C 1-6 Alkyl substituted C 3-6 Cycloalkyl). For example, a compound of formula (XVIII) (wherein R 1 Is C 2-6 Alkenyl) with diiodomethane, diethyl zinc in a suitable solvent such as toluene and the like; reacting at a temperature ranging from 0 ℃ to room temperature for a period of 24 hours to 26 hours to provide a compound of formula (XVIII) (wherein R 1 Is CH (beta) 3 Substituted cyclopropyl).
Scheme 9
According to scheme 9, a compound of formula (X) (wherein HAL is Br, R 3 Is H, and R 5 Is CH 3 ) With commercially available or synthetically obtainable formula R 1 Aldehyde of CHO (wherein R 1 Is C 1-6 Alkyl) is coupled in a palladium catalyzed carbonylation reaction to provide the corresponding ketonization of formula (XIX)Compounds (similar transformations have been reported by Suchand et al, J.org.chem.2016,81, 6409-6423). For example, methyl 4-bromo-2-iodobenzoate and isobutyraldehyde in a palladium catalyst such as Pd (OAc) 2 、Ag 2 O, and an oxidizing agent such as t-butyl hydroperoxide (TBHP) at a temperature of about 120 ℃ for a period of 10 hours to 14 hours to provide methyl 4-bromo-2-isobutyrylbenzoate. Reacting a ketone compound of formula (XIX) with hydrazine R 4 -NHNH 2 (wherein R is 4 Is an appropriately substituted aryl group such as 2-chloro-6-fluorophenyl hydrazine) to provide a compound of formula (V) wherein X is N. As previously described, the compound of formula (V) is subjected to an Ullmann aromatic amination reaction with the appropriately protected triazolone (II) to provide the compound of formula (VI) (wherein Y is CH and R 1 Selected from C 1-6 Alkyl).
A compound of formula (VI) (wherein Y is CH and R 1 Is phenyl and X is N) can be prepared in a similar manner to that described previously by reacting methyl 4-bromo-2-iodobenzoate with commercially available or synthetically obtainable compounds of formula R 1 Aldehyde of CHO (wherein R 1 Phenyl) coupling.
Scheme 10
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According to scheme 10, formula R 1 -B(OH) 2 Is reacted with a compound of formula (XVI) under suzuki coupling conditions known to those skilled in the art to provide a compound of formula (XVIII) wherein X is CH. For example, a compound of formula (XVI) wherein Y is CH and HAL is iodide, is reacted with a commercially or synthetically obtainable boric acid (or borate) (such as R 1 -B(OH) 2 (wherein R is 1 Is optionally substituted C as defined herein for formula (Z) 2-6 Alkenyl, C 3-6 Cycloalkyl or aryl)), palladium catalysts (such as bis (triphenylphosphine) palladium (II) dichloride, etc.; suitable bases (such as potassium phosphate, cs 2 CO 3 Etc.). In a suitable solvent (such as dioxane, water, ethyl acetateAlcohols or mixtures thereof) to provide a compound of formula (XVIII) wherein X is CH. It has been noted that during the coupling reaction as described above, the loss of iodide during the reaction conditions provides a compound of formula (XVIII) wherein X is CH and R 1 H. The compound of formula (XVIII), wherein X is CH or N, is reacted with a compound of formula R under copper (II) mediated Chan-Lam coupling conditions known to those skilled in the art or as described previously 4 -B(OH) 2 To provide a compound of formula (VI) wherein X is CH or N, R 1 Is optionally substituted C 2-6 Alkenyl, R 3 Is H or F, and R 4 Is an appropriately substituted phenyl group as described herein with reference to formula (Z).
A compound of formula (XVIII) (wherein R 1 Is N (CH) 3 ) 2 ) From a compound of formula (XVI) wherein HAL is Br and PG is Bn. Compounds of formula (XVI) are reacted with amine bs such as NH (CH) 3 ) 2 Is reacted at a temperature of about 110 ℃ for a period of 96 hours to provide a compound of formula (XVIII) wherein R 1 Is N (CH) 3 ) 2 And R is a Is C 1-6 An alkyl group. The compounds of formula (Z) wherein R are prepared according to the above-described method 1 Is N (CH) 3 ) 2 。
A compound of formula (XVIII) (wherein R 1 Is C substituted by OH 1-6 Alkyl) is derived from a compound of formula (XVIII) (wherein R 1 Is C 2-6 Alkenyl, and PG is Bn) is prepared in two steps. In a first step, a compound of formula (XVIII) (wherein R 1 Is that) Under oxidizing conditions (such as NaIO 4 And K 2 OsO 4 .2H 2 O or OsO 4 ) In a suitable solvent (such as THF/H 2 O) at a temperature in the range of from 0 ℃ to room temperature for a period of from 48 hours to 72 hours to provide a ketone intermediate compound. In a second step, the ketone intermediate compound is reacted with a grignard reagent such as methyl magnesium bromide in a suitable solvent such as diethyl ether at a temperature in the range of 0 ℃ to room temperature, maintainingFor a period of 3 hours to 30 hours, providing a compound of formula (XVIII), wherein R 1 Is C substituted by OH 1-6 An alkyl group.
Scheme 11
According to scheme 11, 4, 5-difluorophthalic anhydride is reacted with a compound of the formula R 4 -NHNH 2 (wherein R is a hydrazine compound 4 Is a suitably substituted phenyl or heteroaryl group such as (2-chloro-6-fluorophenyl) hydrazine hydrochloride in acetic acid at a temperature of about 125 ℃ for a period of about 1.5 hours to provide a compound of formula (XX) wherein R 3 F. Rearranging the compound of formula (XX) under the following conditions provides a ring-expanding compound of formula (XXI): under alkaline conditions (such as sodium ethoxide or sodium methoxide); in a suitable solvent (such as ethanol, methanol, etc.); at room temperature; for a period of about 1.5 hours. By combining in a suitable solvent such as DCM or the like a trifluoromethanesulfonyl agent such as trifluoromethanesulfonic anhydride (Tf 2 O)), a base such as Triethylamine (TEA), pyridine, etc., to effect derivatization of the compound of formula (XXI) with a sulfonate-based leaving group such as triflyl (triflate) to provide the compound of formula (XXII). Milder trifluoromethanesulfonyl agents such as N-phenyl bis (trifluoromethanesulfonyl imide) (TF) in a suitable solvent such as DCM and the like can be used 2 NPh), bases (such as TEA, DIEA, etc.); .
Scheme 12
According to scheme 12, formula R 1 -B(OH) 2 Is reacted with a compound of formula (XXII) under suzuki coupling conditions as previously described to provide a compound of formula (V), wherein X is N. For example, the compound of formula (XXII) is reacted with commercially available or synthetically obtainable boric acids (or esters thereof)For example R 1 -B(OH) 2 (wherein R is 1 Is C as defined herein for formula (Z) 2-6 Alkenyl or C 2-6 Haloalkenyl), palladium catalysts (such as 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride or bis (triphenylphosphine) palladium (II) dichloride, etc.; suitable bases (such as potassium phosphate, cs 2 CO 3 、K 2 CO 3 Etc.); in a suitable solvent such as dioxane, water, ethanol or mixtures thereof to provide the compound of formula (V). A compound of formula (V) (wherein R 1 Is C 2-6 Alkyl or C 2-6 Haloalkyl) is readily prepared by the compounds of formula (V) (wherein R 1 Is C 2-6 Alkenyl or C 2-6 Haloalkenyl) is prepared by selective hydrogenation. For example, a compound of formula (V) (wherein R 1 Is that) Under hydrogenation conditions with a catalyst (such as Pd/C, etc.) in a suitable solvent such as EtOAc, etc.; reacting at room temperature under a hydrogen atmosphere (20 psi-45 psi) for a period of 4 hours to 24 hours provides a compound of formula (V), wherein R 1 Is->The compounds of formula (V) are reacted with appropriately protected triazolones of formula (II) using the conditions previously described to provide a mixture of compounds of formulae (VI) and (VIa) which may be isolated either before or after deprotection of the protecting group.
Scheme 13
According to scheme 13, N-arylation of the compound of formula (XVIII) is effected by reaction of a suitably substituted commercially available or synthetically obtainable fluorine compound of formula (XXIII), wherein R c And R is d As defined herein with respect to formula (Z). Allowing a compound of formula (XVIII) (wherein R 1 H, C of a shape of H, C 2-6 Alkenyl, C 2-6 Haloalkenyl, C 3-6 Cycloalkyl, quilt C 1-6 Alkyl substituted C 3-6 Cycloalkyl, and X is CH or N) with a commercially available or synthetically obtainable fluorine compound of the formula (XXIII) under nucleophilic displacement reaction conditions in a base such as K 2 CO 3 、Cs 2 CO 3 Etc.; in aprotic solvents (such as DMF, DMSO, etc.); reacted at a temperature ranging from 65 ℃ to 100 ℃ to provide the compound of formula (XXIV).
Reduction of the compound of formula (XXIV) with zinc or iron and NH 4 Cl is achieved in a mixed solvent of methanol and water to provide the amino compound of formula (XXV).
With NaNO 2 Diazotizing a compound of formula (XXV) in an acidic aqueous solution or other nitrite reagent in an organic solvent such as EtOH or the like; at a temperature of 0 ℃ and subsequent reduction of the diazo group with zinc at a temperature in the range of 0 ℃ to 85 ℃ or by use of H 3 PO 2 The treatment is carried out; providing a compound of formula (XXVI) wherein R c And R is d As defined herein with respect to formula (Z).
Scheme 14
According to scheme 14, a compound of formula (X) (wherein HAL is F, R 5 Is H and R 3 For F) with a commercially available or synthetically obtainable compound of formula (XXVII) (wherein R 1a And R is 1b Each independently is H or C 1-4 Alkyl groups such as 1-bromo-3-methyl-2-butene) in a base such as K 2 CO 3 、Cs 2 CO 3 Etc.; in a suitable solvent (such as DMSO, DMF, THF, ACN, etc.); to provide an ester compound of the formula (XXVIII), wherein R 3 Is F, and HAL is F. A compound of formula (XXVIII) (wherein R 1a And R is 1b Each independently selected from C 1-4 Haloalkyl or C 3-6 Cycloalkyl) can be prepared in a similar manner. Formula (XXVIII)With a suitably protected triazolone compound of formula (II) in a base such as K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、NaHCO 3 In the presence of triethylamine, etc.; in a suitable solvent (such as 1, 4-dioxane, DMSO, DMF, THF, ACN, etc.); compounds of formula (XXIX) are provided. In a preferred method, PG is Bn and R a Is C 1-6 An alkyl group. A compound of formula (XXIX) (wherein R 3 Intramolecular cyclization for H or F) is carried out under Hegram reaction conditions, such as with a catalyst such as chloro [ (tri-tert-butylphosphine) -2- (2-aminobiphenyl)]Palladium (II) (P (tBu) 3 )PdG 2 ) N-cyclohexyl-N-methyl-cyclohexylamine in a suitable solvent (such as toluene, etc.); at a temperature of about 15 ℃ to 80 ℃; for a period of about 18 hours to 36 hours; to provide isocoumarin compounds of formula (XXX) wherein Y is CH and R 1 Is isopropyl, R 3 Is H or F, R a And PG is defined as described above.
Isocoumarin compounds of formula (XXX) (wherein R 1 Is that) Prepared from a compound of formula (XIa) and methylbutan-1, 2-dien-1-yl acetate. Methyl but-1, 2-dien-1-yl acetate is commercially available or prepared in two steps from 2-methyl-3-butyn-2-ol. Acetic anhydride is reacted with 2-methyl-3-butyn-2-ol in the presence of a catalyst such as Mg (ClO 4 ) 2 ) In the presence of a suitable solvent (such as DCM, etc.); to provide 2-methylbut-3-yn-2-yl acetate. Reacting acetic acid 2-methylbut-3-yn-2-yl ester with a catalytic amount of a Lewis acid (such as AgBF 4 、AgClO 4 、PtCl 2 Etc.) reaction; to provide 3-methylbutan-1, 2-dien-1-yl acetate. Reacting 3-methylbutan-1, 2-dien-1-yl acetate with a compound of formula (XIa) (wherein R 5 For H) intermolecular cyclization under Herck reaction conditions as previously described, such as with catalysts such as Catalcxium A Pd G2 and Cy 2 NMe palladium (II) acetate, a phase transfer agent such as tetrabutylammonium bromide and a base such as potassium acetate in a suitable solvent such as DMF and the like;coupling at a temperature of from 70 ℃ to 90 ℃ for a period of from 10 hours to 16 hours to provide an isocoumarin compound of formula (XXX) wherein Y is CH and R 1 Is->
A compound of formula (XXX) (wherein Y is CH and R 1 Is that) Under hydrogenation conditions using a catalyst such as wilkinson catalyst [ RhCl (PPh) 3 ) 3 ]Etc. in a suitable solvent such as THF etc.; selective reduction at room temperature provides isocoumarin compounds of formula (XXX), wherein R 1 Is isopropyl.
Scheme 15
According to scheme 15, 2-butanone is converted to ethyl 3-methylpent-2-enoate using Wittig reaction (Wittig reaction) conditions known to those skilled in the art. For example, 2-butanone is reacted with a triphenylphosphine ylide such as (ethoxycarbonylmethylene) triphenylphosphine in a suitable solvent such as toluene, with or without additives such as benzoic acid, liCl, sodium Dodecyl Sulfate (SDS), and the like, at a temperature in the range of room temperature to the reflux temperature of the solvent, for a period of 12 hours to 24 hours. The ethyl 3-methylpent-2-enoate is reduced to 3-methylpent-2-en-1-ol using a suitable reducing agent such as DIBAL-H in a suitable solvent such as toluene or the like at a temperature in the range of-78 ℃ to room temperature. Using oxidation conditions known to the person skilled in the art, e.g. DMP (Dess-Martin periodinane), SO 3 Pyridine, swern conditions [ (COCl) 2 、DMSO、Et 3 N]PCC, etc., 3-methylpent-2-en-1-ol in a solvent such as EtOAc, DMSO, DCM, etc., at a temperature in the range of about-78 deg.c to room temperature (about 23 deg.c)3-methylpent-2-enal. In a preferred method, 3-methylpent-2-en-1-ol is oxidized to 3-methylpent-2-enal in DCM with dess-martin oxidant at 25℃for 1 to 4 hours.
Scheme 16
According to scheme 16, isocoumarin of the compound of formula (XXX), wherein Y is CH, is reacted with a commercially available or synthetically obtainable compound of formula R 4 -NH 2 Of (wherein R is 4 As defined herein with respect to formula (Z)), lewis acids (such as AlMe 3 、AlCl 3 Etc.); reaction in a suitable aprotic solvent (such as DCM, toluene, etc.); to provide a compound of formula (XXXI) (wherein Y is CH and R 1 、R 3 、R 4 And R is a Defined as described herein with respect to formula (Z).
Scheme 17
Isocoumarin compounds of formula (XXX) can be prepared according to scheme 17. From a compound of formula (X) (wherein HAL is F, R) in the presence of a catalytic amount of DMF using conditions known to those skilled in the art, such as oxalyl chloride or thionyl chloride 5 Is H and R 3 For F) preparing 4, 5-difluoro-2-iodobenzoyl chloride in a suitable solvent such as an aprotic nonpolar solvent such as Dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile (ACN), toluene, etc., at a temperature ranging from 0 ℃ to room temperature to form 4, 5-difluoro-2-iodobenzoyl chloride. 4, 5-difluoro-2-iodobenzoyl chloride can be reacted with commercially available or synthetically available 2-methylbutan-3-yn-2-ol in the presence of a base such as triethylamine and DMAP in a suitable solvent (such as DCM, etc.); to provide an ester compound of formula (XXXIII). The compound of formula (XXXIII) is reacted with the compound of formula (II) by the method as described above The compounds react to provide a compound of formula (XXXIV). With catalytic amounts of Lewis acids such as AgClO 4 、PtCl 2 And treating the compound of formula (XXXIV); rearranged compounds of formula (XXXV) may be provided. A compound of formula (XXXV) (wherein R 3 H or F) may be in a suitable solvent (such as DMF, etc.) under heck reaction conditions, such as with a catalyst (such as palladium (II) acetate), a phase transfer reagent (such as tetrabutylammonium bromide), and a base (such as potassium acetate); intramolecular cyclization occurs at a temperature of 70 ℃ to 90 ℃ for a period of 1 hour to 3 hours to provide the isocoumarin compound of formula (XXX) wherein Y is CH.
Scheme 18
According to scheme 18, a compound of formula (Xa) (wherein HAL is Cl, R 5 Is CH (CH) 3 ) 2 And R is 3 For F) is commercially available or synthetically obtainable according to the method as described in Chen et al, U.S. patent publication No. US 2016-0176869. Combining a compound of formula (Xa) with a commercially or synthetically obtainable nucleophilic compound of formula (II) (wherein PG is benzyl and R c Is C 1-6 An alkyl group); in a base (such as K 2 CO 3 、Cs 2 CO 3 、NaHCO 3 Triethylamine, etc.) are present; reaction in a suitable solvent such as Dimethylsulfoxide (DMSO), DMF, THF, ACN, etc.; compounds of formula (XXXIX) are provided wherein Y is N. Allowing a compound of formula (XXXIX) or formula (XI) (wherein R 3 Is F and R 5 Is C 1-4 An alkyl group); with commercially available 1-ethoxyethylene-2-boronic acid pinacol esters, palladium catalysts such as bis (triphenylphosphine) palladium (II) dichloride, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride, and the like; suitable bases (such as Cs 2 CO 3 Etc.); in a suitable solvent such as dioxane, water, ethanol or mixtures thereof; the reaction is carried out using conventional or microwave heating to provide a compound of formula (XL) wherein Y is N or CH.
Scheme 19
According to scheme 19, formula R 4 -NH 2 Compounds of (wherein R is 4 As defined herein for formula (Z) with trimethylaluminum in a suitable solvent such as dichloromethane, toluene, or mixtures thereof, and combining the resulting solution with a compound of formula (XL), wherein Y is CH or N, to provide a compound of formula (XLI). The compound of formula (XLI), wherein Y is CH or N, is treated with acetic acid or trifluoroacetic acid under heating conditions between 50 ℃ to 90 ℃ to provide the compound of formula (XLII). Halogenating a compound of formula (XLII) with N-bromosuccinimide in anhydrous dimethylformamide at room temperature to provide a compound of formula (XVI) wherein HAL is Br. Making R 1 -B(OH) 2 Is reacted with a compound of formula (XVI) under suzuki coupling conditions known to those skilled in the art or as previously described to provide a compound of formula (VI) wherein R 1 Is optionally substituted C as defined herein for formula (Z) 2-6 Alkenyl, C 2-6 Haloalkenyl or aryl. Allowing a compound of formula (VI) (wherein R 1 Is optionally substituted C 2-6 Alkenyl or C 2-6 Haloalkenyl) under hydrogenation conditions using wilkinson catalyst ((PPh) 3 ) 3 RhCl) to provide a compound of formula (VI) wherein R 1 Is C 2-6 Alkyl or C 2-6 A haloalkyl group.
Scheme 20
According to scheme 20, 3-methylbutyraldehyde is reacted with a compound of formula (XXXIX) (wherein Y is N and R 5 Is CH (CH) 3 ) 2 ) Using a palladium catalyst (such as allylpalladium (II) chloride dimer, etc.); ligands such as 1,1' -bis (diphenylphosphino) dicyclopentadieneIron (dppf), etc.); suitable bases (such as Cs 2 CO 3 Etc.) in the presence of a water scavenger such as molecular sieve (4A) in a suitable solvent thereof such as dioxane to provide a compound of formula (XXX) (wherein R 1 Is isopropyl). Making R 4 -NH 2 Compounds of (wherein R is 4 As defined herein for formula (Z) with trimethylaluminum in a suitable solvent such as methylene chloride, toluene or mixtures thereof, combining the resulting solution with a compound of formula (XXX) followed by treatment with acetic acid at a heating temperature of 80 ℃ to 100 ℃ for a period of time ranging from 5 hours to 24 hours to provide a compound of formula (VI) wherein X is CH and Y is N, R 1 Is isopropyl, R 3 F.
Scheme 21
According to scheme 21, a compound of formula (XXXIX) or (XI) (wherein R 3 Is F and R 5 Is C 1-4 Alkyl) with a commercially available vinyl boronic acid pinacol ester, a palladium catalyst such as bis (triphenylphosphine) palladium (II) dichloride or 1,1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex, and the like; suitable bases (such as Cs 2 CO 3 Etc.); in a suitable solvent such as dioxane, water, ethanol or mixtures thereof to provide a compound of formula (XLIII) wherein Y is N or CH. Vinyl groups in the compound of formula (XLIII) are selectively converted to aldehyde groups of formula (XLIV) using potassium (VI) osmium dihydrate/sodium periodate or ozonolysis, etc. Contacting a compound of formula (XLIV) with a commercially available or synthetically available appropriately substituted alkyl grignard reagent (such as i-PrMgCl, etc.); reaction in aprotic solvents (such as THF, etc.); followed by treatment with an oxidizing agent (such as dess-martin reagent) or Swern oxidizing conditions, etc.; to provide a ketone compound of formula (XLV).
The compound of formula (XLV) is prepared in two steps from the compound of formula (XXXIX). Allowing a compound of formula (XXXIX)The compound (wherein R 3 Is F and R 5 Is C 1-4 Alkyl) with commercially available tributyl (1-ethoxyvinyl) tin, palladium catalysts such as bis (triphenylphosphine) palladium (II) dichloride, 1' -bis (diphenylphosphino) ferrocene-palladium (II) dichloride, and the like; in a suitable solvent such as dioxane, water, ethanol or mixtures thereof. Subsequent acidic hydrolysis using conditions such as treatment with aqueous HCl at room temperature provides a compound of formula (XLV) (wherein X is N and Y is N or CH, R) 1 Methyl).
Hydrazine R which is commercially available or synthetically available 4 -NHNH 2 (wherein R is 4 As defined herein with respect to formula (Z), such as 2-chloro-6-fluorophenyl hydrazine, o-tolylhydrazine) with a compound of formula (XLV) in the presence of a base such as potassium carbonate and the like; condensation in a suitable solvent such as toluene or mixtures thereof under heating conditions such as 70 ℃ to 120 ℃ provides a compound of formula (VI) wherein X is N, Y is CH or N, and R 4 As defined herein with respect to formula (Z).
Scheme 22
According to scheme 22, methyl 2-bromo-4, 5-difluorobenzoate is reacted with a suitably protected triazolone compound of formula (II) in a base such as K 3 PO 4 、K 2 CO 3 、Cs 2 CO 3 、NaHCO 3 In the presence of triethylamine, etc.; in a suitable solvent (such as 1, 4-dioxane, DMSO, DMF, THF, ACN, etc.); compounds of formula (XLVI) are provided. In a preferred method, PG is Bn and R a Is C 1-6 Alkyl (as previously described in scheme 14). The reaction of 3-methylbutyraldehyde with a compound of formula (XLVI) with a palladium catalyst such as allylpalladium (II) chloride dimer, etc.; ligands such as 1,1' -bis (diphenylphosphino) ferrocene (dppf), etc.; suitable bases (such as Cs 2 CO 3 Etc.); in the absence of water scavengers such as molecular sieves (4A) in a suitable solvent(s) thereforSuch as dioxane) to provide a compound of formula (xlviii). Making R 4 -NH 2 Compounds of (wherein R is 4 As defined herein for formula (Z) with trimethylaluminum in a suitable solvent such as dichloromethane, dichloroethane, toluene or mixtures thereof, combining the resulting solution with a compound of formula (xlviii) followed by treatment with acetic acid at a heating temperature of 80 ℃ to 100 ℃ for a period of time ranging from 5 hours to 24 hours to provide a compound of formula (VI) wherein X is CH, Y is CH, R 1 Is isopropyl, R 3 F. In some cases, formula R 4 -NH 2 Compounds of (e.g., o-toluidine, etc.); directly condensing with a compound of formula (xlviii) in acetic acid at a heating temperature of 80 ℃ to 100 ℃ for a period of time ranging from 10 hours to 24 hours to provide a compound of formula (VI), wherein X, Y, R 1 、R 3 As defined above.
Scheme 23
According to scheme 23, a compound of formula (XXXIX) (wherein R 5 Is C 1-4 Alkyl, Y is N and R 3 F) alkyne protected with silyl groups (such as trimethylsilylacetylene), palladium catalysts (such as bis (triphenylphosphine) palladium (II) dichloride, etc.); copper catalysts (such as copper iodide, etc.) together; the Sonogashira coupling reaction is carried out with a suitable base such as triethylamine in a suitable solvent such as ACN, toluene, etc. Deprotection with TBAF in a suitable solvent such as THF at room temperature; compounds of formula (XLVIII) are provided. Using gold catalysts (preferably AuCl 3 ) The compound of formula (XLIX) is obtained in a suitable solvent mixture, such as MeCN. Marchal, E.et al in Tetrahedron 2007,63,9979-9990 have described the passage through AuCl 3 Catalytic cyclization proceeds with similar transformations. Making R 4 -NH 2 Compounds of (wherein R is 4 As defined herein for formula (Z) with trimethylaluminum in a suitable solvent such as dichloromethane,Dichloroethane, toluene or mixtures thereof), the resulting solution is combined with a compound of formula (XLIX) and subsequently treated with acetic acid at a heating temperature of 80 ℃ to 100 ℃ for a period of time in the range of 5 hours to 24 hours to provide a compound of formula (L). NBS is employed at room temperature in a suitable solvent, preferably DMF, followed by a palladium catalyst, such as bis (triphenylphosphine) palladium (II) dichloride, a base, such as Cs, using conditions known to those skilled in the art 2 CO 3 、Na 2 CO 3 Etc.); cross-coupling in a solvent mixture of 1, 4-dioxane and water at a temperature of 100deg.C provides a compound of formula (VI) (wherein X is CH, Y is N, R 3 Is F and R 1 、R a And PG is defined as previously described).
Scheme 24
According to scheme 24, a compound of formula (VI) (wherein PG is Bn) is deprotected by: using conditions known to those skilled in the art, preferably in neat TFA in a sealed tube, at a temperature of about 60 ℃ to 90 ℃; or BCl is adopted 3 At a temperature of about-78 ℃ in a suitable solvent such as DCM; or with hydrogen in the presence of a catalyst such as palladium on carbon (Pd/C) to provide the compound of formula (Z).
In a similar manner, for the compound of formula (XVIII) (wherein R 1 N-arylation and in situ TBDPS deprotection of I and PG is TBDPS and X is N) are achieved using conditions known to those skilled in the art or as previously described to provide compounds of formula (Z).
Allowing a compound of formula (Z) (wherein R 3 For F) in a nucleophilic aromatic substitution reaction to provide a compound of formula (Z) (wherein R 3 Is OCH 3 ). For example, a compound of formula (Z) (wherein R 3 F) with a suitable base (such as NaOH, etc.) in a suitable solvent (such as MeOH, etc.); to provide a compound of formula (Z) (wherein Y is CH and R 3 Is OCH 3 )。
The compounds of formula (Z) may be converted into their corresponding salts using methods known to those of ordinary skill in the art. For example, an amine of formula (Z) is treated with trifluoroacetic acid, HCl or citric acid in a solvent (such as Et 2 O、CH 2 Cl 2 THF, meOH, chloroform or isopropanol) to provide the corresponding salt forms. Alternatively, trifluoroacetic acid or formate salt is obtained by reverse phase HPLC purification conditions. Crystalline forms of pharmaceutically acceptable salts of the compounds of formula (I) may be obtained by recrystallization with polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or with nonpolar solvents (including mixtures of nonpolar solvents).
If the compounds according to the invention have at least one chiral center, they can accordingly exist in enantiomeric form. If the compounds have two or more chiral centers, they may also exist in diastereomeric form. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The compounds prepared according to the schemes described above may be obtained as single forms, such as single enantiomers, by form-specific synthesis or by resolution. Alternatively, compounds prepared according to the above schemes may be obtained as mixtures in various forms, such as racemic mixtures (1:1) or non-racemic mixtures (non-1:1). In the case of obtaining racemic and non-racemic mixtures of enantiomers, the individual enantiomers may be separated using conventional separation methods known to those of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, bioconversion, or enzymatic conversion. Where a mixture of regioisomers or a mixture of diastereomers is obtained, conventional methods such as chromatography or crystallization may be used to separate the individual isomers, as applicable.
The following specific examples are provided to further illustrate the compounds of formula (Z) and various preferred embodiments.
Examples
In obtaining the compounds of formula (Z) and the corresponding analytical data described in the examples below, the following experimental and analytical protocols were followed, unless indicated otherwise.
Unless otherwise indicated, the reaction mixture was magnetically stirred at room temperature (rt) under nitrogen atmosphere. In the case of solutions that are "dried", they are typically dried (such as Na 2 SO 4 Or MgSO 4 ) Drying is performed. Where the mixtures, solutions and extracts are "concentrated", they are typically concentrated under reduced pressure on a rotary evaporator.
Using a pre-packed column, a silica gel (SiO 2 ) Normal phase silica gel chromatography (FCC) was performed thereon.
Preparative reverse phase high performance liquid chromatography (RP HPLC) was performed on any of the following devices:
method a. Gilson GX-281 semi-preparative HPLC with Phenomenex Synergi C (10 μm,150×25 mm) or Boston Green ODS C (5 μm,150×30 mm) mobile phase 5% -99% acn in water (0.225% fa) for 10 min, then 2 min at 100% acn flow rate 25mL/min; or alternatively
Gilson GX-281 semi-preparative HPLC with Phenomenex Synergi C (10 μm, 150X 25 mm) or Boston Green ODS C (5 μm, 150X 30 mm) mobile phase 5% -99% ACN in water (0.1% TFA) for 10 min, then 2 min at 100% ACN flow rate 25mL/min; or alternatively
Method c. gilson GX-281 semi-preparative HPLC with Phenomenex Synergi C (10 μm,150×25 mm) or Boston Green ODS C (5 μm,150×30 mm) mobile phase 5% -99% acn in water (0.05% hcl) for 10 min, then 2 min at 100% acn flow rate 25mL/min; or alternatively
Gilson GX-281 semi-preparative HPLC with Phenomenex Gemini C (10 μm,150 mm. Times.25 mm), AD (10 μm,250 mm. Times.30 mm) or Waters XB ridge C18 column (5 μm,150 mm. Times.30 mm), aqueous solution with mobile phase 0% -99% ACN (0.05% ammonium hydroxide v/v), for 10 min, then hold at 100% ACN for 2 min at flow rate 25mL/min; or alternatively
Method E.Gilson GX-281 semi-preparative HPLC with Phenomenex Gemini C (10 μm, 150X 25 mM) or Waters XBidge C18 column (5 μm, 150X 30 mM) with 5% -99% ACN aqueous solution (10 mM NH) 4 HCO 3 ) For 10 minutes, then kept at 100% ACN for 2 minutes at a flow rate of 25mL/min.
Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Thar 80 Prep-SFC system or a Waters 80Q Prep-SFC system (from Waters). ABPR is set to 100 bar to maintain CO2 under SF conditions and the flow rate may vary depending on the compound characteristics, with a range of flow rates from 50g/min to 70g/min. The column temperature is ambient temperature.
Mass Spectra (MS) were obtained using electrospray ionization (ESI) in positive ion mode on a SHIMADZU LCMS-2020 MSD or a 1200/g 6110a MSD, unless otherwise indicated. The calculated mass (calculated) corresponds to the exact mass.
Nuclear Magnetic Resonance (NMR) spectra were obtained on a Bruker model AVIII 400 spectrometer. The definition of multiplicity is as follows: s=singlet, d=doublet, t=triplet, q=quartet, dd=doublet, ddd=doublet, td=doublet, td=triplet, dt=doublet, spt=heptadoublet, quin=quin, m=multiplet, br=broad. It will be appreciated that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.
Chemical names were generated using ChemDraw Ultra 12.0,ChemDraw Ultra 14.0 (Cambridge soft corp., cambridge, MA) or ACD/Name version 10.01 (Advanced Chemistry).
The compounds named R or S are enantiomerically pure compounds of undetermined absolute configuration.
Intermediate 1:3- ((benzyloxy) methyl) -4-ethyl-1H-1, 2, 4-triazol-5 (4H) -one。
Step A.2- (benzyloxy) acethydrazide 。
To a solution of ethyl 2- (benzyloxy) acetate (55 g,283.17 mmol) in EtOH (500 mL) was added NH 2 NH 2 πH 2 O (28.3 g,566mmol,27.5 mL). The reaction mixture was heated at 78 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title product (52 g, crude) as a colourless oil, which was used directly in the next step without further purification.
Step B.3- ((benzyloxy) methyl) -4-ethyl-1H-1, 2, 4-triazol-5 (4H) -one。
To 2- (benzyloxy) acetic acid hydrazide (52 g,288 mmol) H at 0deg.C 2 To a solution of O (500 mL) was added ethyl isocyanate (25.1 g,346mmol,27.9 mL) dropwise. After the addition was complete, the mixture was stirred at 25 ℃ for 12 hours. Adding H to the mixture 2 O (20 mL) and NaOH (57.7 g,1.44 mol) in water (120 mL). The mixture was stirred at 95℃for 12 hours. The reaction mixture was cooled to room temperature, then quenched with HCl (12M) at 0 ℃ and adjusted to "pH"6. The solid was filtered and dried under reduced pressure to give the title compound (61 g,91% yield) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ–9.23-9.09(m,1H),–7.41-7.31(m,5H),–4.58-4.53(m,2H),–4.45-4.42(m,2H),–3.82-3.75(m,2H),–1.33-1.29(m,3H)ppm。
Intermediate 2:5- (((tert-butyldiphenylsilyl) oxy) methyl) -4-ethyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one。
Step A.4-Ethyl-5- (hydroxymethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one。
To 5- [ (benzyloxy) methyl ]Pd/C (2 g) was added to a solution of-4-methyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (8 g,34.3mmol,1.0 eq.) in methanol (200 mL). The resulting mixture was kept under hydrogen and stirred at room temperature for 6 hours. The resulting mixture is then mixedThe residue was filtered and the filtrate was concentrated to give 4-ethyl-5- (hydroxymethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (4.3 g,88% yield) as a white solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.52(s,1H),5.55(t,J＝5.50Hz,1H),4.32(d,J＝5.50Hz,2H),3.64(q,J＝6.97Hz,2H),1.18(t,J＝6.97Hz,3H)ppm。
And (B) step (B): 5- (((tert-butyldiphenylsilyl) oxy) methyl) -4-ethyl-2, 4-dihydro-3H-1, 2,4- Triazol-3-ones。
To a solution of 4-ethyl-5- (hydroxymethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (3 g,21mmol,1.0 eq.) in DCM (30 mL) was added tert-butylchlorodiphenylsilane (6.5 mL,25mmol,1.2 eq.) and pyridine (1.86 mL,23mmol,1.1 eq.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (100 mL). The resulting mixture was extracted with DCM (3X 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (SiO 2 50% -80% ethyl acetate/petroleum ether) to afford 5- (((tert-butyldiphenylsilyl) oxy) methyl) -4-ethyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (4.9 g,61% yield) as a white solid. LCMS (ES-API): c (C) 21 H 27 N 3 O 2 The calculated mass of Si is 381.2; found m/z 382.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ9.98(s,1H),7.61-7.72(m,4H),7.32-7.54(m,6H),4.54(s,2H),3.84(q,J＝7.34Hz,2H),1.33(t,J＝7.34Hz,3H),1.07(s,9H)ppm。
Intermediate 3:5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-1-oxo-4- (prop-1-en-2-yl) -1H-iso- Benzopyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one。
Step A.4, 5-difluoro-2-iodobenzoic acid tert-butyl ester。
4, 5-difluoro-2-iodobenzoic acid (3 g,11 mmol) was dissolved in THF (30 mL) and thenDi-tert-butyl dicarbonate (4.6 g,21 mmol) was added followed by DMAP (640 mg,5.3 mmol). The reaction mixture was stirred overnight at 50 ℃ under nitrogen and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc and then washed with brine. The organic layer was separated with Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-5% EtOAc in petroleum ether) to give the title compound (2.9 g, yield: 79%) as a yellow oil. 1 H NMR(400MHz,CDCl 3 )δ7.77(dd,J＝10.2,7.9Hz,1H),7.63(dd,J＝10.2,7.9Hz,1H),1.62(s,9H)ppm； 19 F NMR(376MHz,CDCl 3 )δ-131.55--131.13(m,1F),-136.97--136.65(m,1F)ppm。
Step B.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 5-fluoro-2-iodobenzoic acid tert-butyl ester。
Tert-butyl 4, 5-difluoro-2-iodobenzoate (3.2 g,9.4 mmol), 3- ((benzyloxy) methyl) -4-ethyl-1H-1, 2, 4-triazol-5 (4H) -one (intermediate 1,2.6g,11.2 mmol) and Cs 2 CO 3 A mixture of (6.1 g,18.7 mmol) in anhydrous DMF (30 mL) was stirred at 75deg.C for 1 hour and then cooled to room temperature. Passing the mixture throughThe pad was filtered and the pad was washed with EtOAc. The filtrates were combined, washed with brine, and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-40% EtOAc in petroleum ether) to give the title compound (5 g, yield: 96%) as a colorless amorphous solid. ESI-MS: c (C) 23 H 25 FIN 3 O 4 Is 553.1; found m/z 554.1[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝7.1Hz,1H),7.62(d,J＝10.8Hz,1H),7.29-7.45(m,5H),4.61(s,2H),4.50(s,2H),3.84(q,J＝7.2Hz,2H),1.63(s,9H),1.35(t,J＝7.2Hz,3H)ppm； 19 F NMR(376MHz,CDCl 3 )δ-119.09(dd,J＝10.6,7.0Hz,1F)ppm。
Step C.4- (3-(benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) 5-fluoro-2-iodobenzoic acid。
To a solution of tert-butyl 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -5-fluoro-2-iodobenzoate (5 g,9 mmol) in DCM (50 mL) was slowly added TFA (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue obtained was triturated with petroleum ether at room temperature for 30 minutes. The mixture was filtered and the solid was rinsed with petroleum ether. The precipitate was collected and dried in vacuo to give the title compound (4.1 g, yield: 91%) as a white solid. ESI-MS: c (C) 19 H 17 FIN 3 O 4 Is 497.0; found m/z 498.0[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.16(d,J＝7.3Hz,1H),7.78(d,J＝11.0Hz,1H),7.28-7.43(m,5H),4.60(s,2H),4.57(s,2H),3.74(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H)ppm； 19 F NMR(376MHz,DMSO-d 6 )δ-119.91(s,1F)ppm。
Step D.5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-1-oxo-4- (prop-1-en-2-yl) -1H-isop-henyl) Benzopyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
To acetic acid 3-methylbutan-1, 2-dien-1-yl ester (intermediate 12, 280mg,2.2 mmol), 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -5-fluoro-2-iodobenzoic acid (1.1 g,2.2 mmol) and Cy under nitrogen 2 NMe (867 mg,4.4 mmol) to a mixture of DMF (7 mL) was added Catalcium A Pd G2 (74.2 mg,0.11 mmol). The reaction mixture was stirred under nitrogen at 90 ℃ overnight. The mixture was then cooled to room temperature, diluted with EtOAc and washed with brine. The organic layers were separated and the aqueous layers combined and extracted with EtOAc. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-80% EtOAc in petroleum ether) to give the title compound (240 mg, yield: 25%) as a yellow solid. ESI-MS: c (C) 24 H 22 FN 3 O 4 Is 435.2; m/z 436.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.15(d,J＝10.5Hz,1H),7.86(d,J＝6.8Hz,1H),7.30-7.45(m,5H),7.19(s,1H),5.37-5.39(m,1H),5.18(s,1H),4.62(s,2H),4.53(s,2H),3.87(q,J＝7.1Hz,2H),2.11(s,3H),1.37(t,J＝7.2Hz,3H)ppm。
Intermediate 4:5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-4-isopropyl-1-oxo-1H-isobenzopyr Pyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Method I:
step A.4, 5-difluoro-2-iodobenzoic acid 3-methylbut-2-en-1-yl ester
To 4, 5-difluoro-2-iodobenzoic acid (1.4 g,4.9 mmol) and Cs 2 CO 3 (4.8 g,14.8 mmol) to a mixture of 1-bromo-3-methyl-2-butene (1.5 g,9.9 mmol) in anhydrous DMF (20 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with water and the mixture was extracted with DCM and EtOAc. The combined organic extracts were subjected to Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (SiO 2 Gradient elution: 10% -20% etoac in heptane) to afford the desired product as a colourless oil (1.6 g, yield: 92%). 1 H NMR(400MHz,CDCl 3 )δ7.80(dd,J＝7.58,9.54Hz,1H),7.73(dd,J＝7.83,10.76Hz,1H),5.42-5.52(m,1H),4.82(d,J＝7.34Hz,2H),1.80(s,3H),1.78(s,3H)ppm。
Step B.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 3-methylbut-2-en-1-yl 5-fluoro-2-iodobenzoic acid ester
To 3-methylbut-2-en-1-yl 4, 5-difluoro-2-iodobenzoate (1.6 g,4.5 mmol), 3- ((benzyloxy) methyl) -4-ethyl-1H-1, 2, 4-triazol-5 (4H) -one (intermediate 1,2.1g,9.1 mmol) inCs was added to a mixture in anhydrous DMF (25 mL) 2 CO 3 (2.9 g,9.1 mmol). The reaction mixture was heated at 85 ℃ under nitrogen for 1 hour and then cooled to room temperature. The mixture was diluted with water and extracted with DCM and EtOAc. The combined organic extracts were subjected to Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (SiO 2 Gradient elution: 20% -50% etoac in heptane) to afford the title compound as a white solid (2.4 g, yield: 93%). LCMS (ES-API): c (C) 24 H 25 FIN 3 O 4 Is 565.1; found m/z 566.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.21(d,J＝6.85Hz,1H),7.73(d,J＝11.25Hz,1H),7.29-7.44(m,5H),5.41-5.53(m,1H),4.84(d,J＝7.34Hz,2H),4.60(s,2H),4.50(s,2H),3.84(q,J＝7.22Hz,2H),1.80(s,3H),1.78(d,J＝0.98Hz,3H),1.34(t,J＝7.22Hz,3H)ppm。
Step C.5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-4-isopropyl-1-oxo-1H-isochroman- 6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one。
To a mixture of 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -5-fluoro-2-iodobenzoic acid 3-methylbut-2-en-1-yl ester (4 g,6.86mmol,1 eq.) in toluene (200 mL) was added separately (tBu) 3 P)PdG 2 (351 mg,0.69mmol,0.1 eq.) N-cyclohexyl-N-methyl-cyclohexylamine (1.60 mL,7.54mmol,1.1 eq.). The reaction mixture was degassed three times with nitrogen and then heated at 80 ℃ under nitrogen atmosphere for 18 hours. LCMS analysis showed about 18% starting material residue. The mixture was cooled to 15℃and additional N-cyclohexyl-N-methyl-cyclohexylamine (0.72 mL,3.43mmol,0.5 eq.) and tBu were added 3 PPdG 2 (176 mg,0.34mmol,0.05 eq.). The reaction mixture was degassed with nitrogen and then heated at 80 ℃ for 16 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure, then taken up in H 2 O (200 mL) was diluted and extracted with EtOAc (150 mL. Times.3). The combined organic layers were washed with brine (100 mL. Times.2), dried over anhydrous Na 2 SO 4 Drying, filtering and decompressingConcentrating. The residue was purified by flash chromatography (SiO 2 Petroleum ether/ethyl acetate=5/1 to 3/1) to give the title compound (1.1 g, yield: 35%). ESI-MS: c (C) 24 H 24 FN 3 O 4 Is 437.2; found m/z of 438.5[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝6.6Hz,1H),7.96(d,J＝6.6Hz,1H),7.42-7.34(m,5H),7.13(s,1H),4.63(s,2H),4.54(s,2H),3.88(dd,J＝7.2,14.4Hz,2H),3.13-3.06(m,1H),1.38(t,J＝7.2Hz,3H),1.32(d,J＝6.8Hz,6H)ppm。
Method II：
To a mixture of 5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-1-oxo-4- (prop-1-en-2-yl) -1H-isochroman-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (intermediate 3,5.9g,13.5 mmol) in THF (100 mL) was added wilkinson catalyst [ RhCl (PPh) 3 ) 3 ](3.8 g,4.1 mmol). The mixture was degassed and purged with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (15 Psi) for 12 hours. The mixture was concentrated. The residue was purified by silica column chromatography (elution: 0-25% EtOAc in petroleum ether) to give the title compound (1.5 g, yield: 77%) as a yellow solid. ESI-MS: c (C) 24 H 24 FN 3 O 4 Is 437.2; found m/z of 438.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.10(d,J＝10.5Hz,1H),8.01(d,J＝7.0Hz,1H),7.46(s,1H),7.26-7.42(m,5H),4.61(s,2H),4.59(s,2H),3.77(q,J＝7.3Hz,2H),3.08(dt,J＝13.4,6.8Hz,1H),1.22-1.28(m,9H)ppm； 19 F NMR(376MHz,DMSO-d 6 )δ-118.29(br s,1F)ppm。
Intermediate 5:4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1- Phenyl) -5-fluoro-2-iodobenzoyl chloride
And (A) a step.4, 5-difluoro-2-iodobenzoic acid tert-butyl ester。
4, 5-difluoro-2-iodobenzoic acid (3 g,11 mmol) was dissolved in THF (30 mL) followed by the addition of di-tert-butyl dicarbonate (4.6 g,21 mmol) followed by DMAP (640 mg,5.3 mmol). The reaction mixture was stirred overnight at 50 ℃ under nitrogen and then cooled to room temperature. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc and then washed with brine. The organic layer was separated with Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-5% EtOAc in petroleum ether) to give the title compound (2.9 g, yield: 79%) as a yellow oil. 1 H NMR(400MHz,CDCl 3 )δ7.77(dd,J＝10.2,7.9Hz,1H),7.63(dd,J＝10.2,7.9Hz,1H),1.62(s,9H)ppm； 19 F NMR(376MHz,CDCl 3 )δ-131.55--131.13(m,1F),-136.97--136.65(m,1F)ppm。
Step B.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 5-fluoro-2-iodobenzoic acid tert-butyl ester。
Tert-butyl 4, 5-difluoro-2-iodobenzoate (3.2 g,9.4 mmol), 3- ((benzyloxy) methyl) -4-ethyl-1H-1, 2, 4-triazol-5 (4H) -one (intermediate 1,2.6g,11.2 mmol) and Cs 2 CO 3 A mixture of (6.1 g,18.7 mmol) in anhydrous DMF (30 mL) was stirred at 75deg.C for 1 hour and then cooled to room temperature. Passing the mixture throughThe pad was filtered and the pad was washed with EtOAc. The filtrates were combined, washed with brine, and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-40% EtOAc in petroleum ether) to give the title compound (5 g, yield: 96%) as a colorless amorphous solid. ESI-MS: c (C) 23 H 25 FIN 3 O 4 Is 553.1; found m/z 554.1[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.16(d,J＝7.1Hz,1H),7.62(d,J＝10.8Hz,1H),7.29-7.45(m,5H),4.61(s,2H),4.50(s,2H),3.84(q,J＝7.2Hz,2H),1.63(s,9H),1.35(t,J＝7.2Hz,3H)ppm； 19 F NMR(376MHz,CDCl 3 )δ-119.09(dd,J＝10.6,7.0Hz,1F)ppm。
Step C.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 5-fluoro-2-iodobenzoic acid。
To a solution of tert-butyl 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -5-fluoro-2-iodobenzoate (5 g,9 mmol) in DCM (50 mL) was slowly added TFA (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue obtained was triturated with petroleum ether at room temperature for 30 minutes. The mixture was filtered and the solid was rinsed with petroleum ether. The precipitate was collected and dried in vacuo to give the title compound (4.1 g, yield: 91%) as a white solid. ESI-MS: c (C) 19 H 17 FIN 3 O 4 Is 497.0; found m/z 498.0[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.16(d,J＝7.3Hz,1H),7.78(d,J＝11.0Hz,1H),7.28-7.43(m,5H),4.60(s,2H),4.57(s,2H),3.74(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H)ppm； 19 F NMR(376MHz,DMSO-d 6 )δ-119.91(s,1F)ppm。
Step D.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl 5-fluoro-2-iodobenzoyl chloride
4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -5-fluoro-2-iodobenzoic acid (3.5 g,7 mmol) in SOCl 2 The solution in (14 mL) was heated at reflux for 15 min. The reaction mixture was cooled to room temperature and concentrated. To the residue was added anhydrous toluene, and the mixture was evaporated to give a yellow gel-like crude product (3.6 g) which was used directly in the next step without further purification.
Intermediate 6: 2-chloro-6-fluoro-N- (3-methylpent-2-en-1-yl) aniline
Step A.3-methylpent-2-enoic acid ethyl ester
To a solution of 2-butanone (52 g,717.6 mmol) and (ethoxyformylmethylene) triphenylphosphine (50 g,143.5 mmol) in toluene (65 mL) was added benzoic acid (3.5 g,28.7 mmol). The reaction mixture was heated at reflux for 16 hours. The mixture was diluted with petroleum ether and filtered through a short pad of silica gel. The silica gel was washed with hexane. The filtrate was concentrated under reduced pressure at 0℃to 2 ℃. The residue was purified by silica column chromatography (elution: 0-10% EtOAc in petroleum ether) to give the title compound (23.3 g crude) as a colorless liquid. 1 H NMR(400MHz,CDCl 3 )δ5.58-5.69(m,1H),4.13(qd,J＝7.1,4.9Hz,2H),2.62(q,J＝7.5Hz,1H),2.09-2.20(m,3H),1.86(d,J＝1.2Hz,1H),1.24-1.28(m,3H),1.01-1.09(m,3H)ppm。
Step B.3-methylpent-2-en-1-ol
To a toluene solution (1M) of DIBAL-H (118 mL,118 mmol) was added dropwise a toluene solution (40 mL) of ethyl 3-methylpent-2-enoate (20 g crude) at-78deg.C under nitrogen. The reaction mixture was stirred at-78 ℃ for 2 hours. The mixture was warmed to room temperature and slowly poured into saturated aqueous potassium sodium tartrate solution at 0 ℃. The mixture was stirred for 2 hours and passed shortAnd (5) filtering the pad. The pad was washed with DCM/EtOAc (v/v, 3/1) and the filtrate was extracted with DCM. The organic extracts were separated, taken up in Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (elution: 0-100% DCM in petroleum ether followed by 0-30% EtOAc in DCM) to give the title compound as a colorless liquid (7 g, yield in two steps: 57%). 1 H NMR(400MHz,CDCl 3 )δ5.35-5.46(m,1H),4.11-4.21(m,2H),2.02-2.13(m,2H),1.67-1.76(m,3H),0.98-1.06(m,3H)ppm。
Step C.3-methylpent-2-enal。
To a solution of 3-methylpent-2-en-1-ol (2 g,20.0 mmol) in DCM (20 mL)To this was added dess-Martin oxidant (10 g,24.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. Passing the mixture through a short stageAnd (5) filtering the pad. The pad was washed with DCM. With saturated NaHCO 3 The combined filtrates were washed with aqueous solution. The organic layer was separated over Na 2 SO 4 Drying, filtering and concentrating under reduced pressure at 0-2deg.C. The crude material was purified by silica column chromatography (elution: DCM) to give the title compound (1.5 g, yield: 77%) as a colorless liquid. 1 H NMR(400MHz,CDCl 3 )δ9.91-10.04(m,1H),5.78-5.90(m,1H),2.58(q,J＝7.6Hz,1H),2.23(d,J＝7.3Hz,1H),2.16(s,2H),1.96(d,J＝1.1Hz,1H),1.16(t,J＝7.6Hz,1H),1.09(t,J＝7.4Hz,2H)ppm。
Step D.N- (2-chloro-6-fluorophenyl) -3-methylpent-2-en-1-imine。
To a mixture of 2-chloro-6-fluoroaniline (1.2 g,8.2 mmol) and 3-methylpent-2-enal (0.97 g,9.9 mmol) in DCM (18 mL) was added triethylamine (4.6 mL,33 mmol) under nitrogen at 0deg.C, followed by TiCl dropwise addition 4 (5 mL,5 mmol) in DCM (1M). The resulting mixture was stirred at 0 ℃ for 1 hour, then warmed to room temperature and stirred for 4 hours. Pouring the mixture into saturated NH 4 In aqueous Cl. The mixture became cloudy and passed throughAnd (5) filtering the pad. The pad was washed with EtOAc. The combined filtrates were diluted with DCM and water. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (gradient elution: 0-5% DCM in petroleum ether) to give the title compound (1.3 g, yield: 70%) as a pale yellow oil.
Step E.2-chloro-6-fluoro-N- (3-methylpent-2-en-1-yl) aniline。
To a solution of N- (2-chloro-6-fluorophenyl) -3-methylpent-2-en-1-imine (1.3 g,5.76 mmol) in MeOH (20 mL) was added NaBH 4 (218 mg,5.8 mmol) and 1 hour apart another batch of NaBH was added 4 (218 mg,5.8 mmol). Co-addition of NaBH 4 (1.1 g,29 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated, then diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, and dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by combined flash column chromatography on silica gel (elution: 0-5% DCM in petroleum ether) to give the title compound as a yellow oil (430 mg, yield: 33%). 1 H NMR(400MHz,CDCl 3 )δ6.95-7.02(m,1H),6.84(ddd,J＝12.2,8.3,1.3Hz,1H),6.52-6.63(m,1H),5.17-5.28(m,1H),3.85(d,J＝5.6Hz,2H),3.73(s,1H),1.91-2.07(m,2H),1.58-1.68(m,3H),0.89-0.96(m,3H)。
Intermediate 7: 5-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-amine.
Step A.5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole。
To a solution of 3-methyl-4-nitropyrazole (2 g,15.7 mmol) in EtOAc (20 mL) was added DHP (2 g,23.6 mmol) and TsOH.H at room temperature 2 O (150 mg,0.79 mmol). The mixture was stirred at room temperature overnight. Addition of Et 3 N (0.4 mL) and the mixture was washed with brine. The organic layer was then separated over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was dissolved in THF (45 mL) and the temperature was reduced to-78 ℃. A solution of LiHMDS (10.6 mL,13.8 mmol) in THF (1M) was added to the mixture under nitrogen. After 45 minutes at-78 ℃, a solution of hexachloroethane (8.9 g,37.8 mmol) in THF (20 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred overnight. Pouring the mixture into saturated NH 4 Aqueous Cl and extracted with EtOAc. The organic phase was separated, washed with brine, dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: petroleum ether solution of 0-40% etoac) to afford the title compound as a white solid (1.8 g, yield: 58%). 1 H NMR(400MHz,CDCl 3 )δ5.52(dd,J＝10.0,2.7Hz,1H),4.07-4.15(m,1H),3.70(td,J＝11.3,2.8Hz,1H),2.57(s,3H),2.37-2.47(m,1H),2.11-2.19(m,1H),1.86-1.90(m,1H),1.72-1.75(m,1H),1.64(d,J＝2.0Hz,1H),1.53(d,J＝6.6Hz,1H)ppm。
Step B.5-chloro-3-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-amine。
To 5-chloro-3-methyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (100 mg,0.4 mmol) in MeOH/THF/H 2 Iron powder (114 mg,2.0 mmol) and NH were added to a mixture in O (v/v/v, 1/1,3 mL) 4 Cl (109 mg,2.0 mmol). The mixture was stirred at 70℃for 1.5 hours. The mixture was cooled to room temperature and passed through And (5) filtering the pad. The pad was washed with EtOAc. With saturated NaHCO 3 The combined filtrates were washed with aqueous solution. The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 It was dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0% -50% EtOAc in petroleum ether) to give the title compound (70 mg, yield: 79%) as a yellow oil. ESI-MS: c (C) 9 H 14 ClN 3 The mass calculation value of O is 215.1; m/z found 216.1[ M+H ]] + 。
Intermediate 8:3- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) -2-chloroaniline.
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Step A. Tert-butyl (2- (2-chloro-3-nitrophenoxy) ethoxy) diphenylsilane。
To 2-chloro-3-nitrophenol (200 mg,1.2 mmol), 2- ((tert-butyldiphenylsilyl) under nitrogen at 0deg.C) Oxy) ethan-1-ol (554 mg,1.8 mmol) and PPh 3 (457 mg,1.7 mmol) to a mixture of THF (10 mL) was added DEAD (281mg, 161 mmol). The mixture was warmed to room temperature and stirred at room temperature for 12 hours. Adding saturated NH 4 Aqueous Cl and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0% -10% EtOAc in petroleum ether) to give the title compound (240 mg, yield: 46%) as a yellow oil. 1 H NMR(400MHz,CDCl 3 )δ7.72(dd,J＝7.8,1.5Hz,4H),7.35–7.49(m,7H),7.30(t,J＝8.2Hz,1H),7.12(dd,J＝8.3,1.2Hz,1H),4.20–4.25(m,2H),4.06(t,J＝4.9Hz,2H),1.06(s,9H)ppm。
Step B.3- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) -2-chloroaniline。
To tert-butyl (2- (2-chloro-3-nitrophenoxy) ethoxy) diphenylsilane (220 mg,0.5 mmol), NH 4 To a mixture of Cl (258 mg,4.8 mmol) in THF (3 mL), meOH (3 mL) and H2O (3 mL) was added iron powder (268 mg,4.8 mmol). The reaction mixture was stirred at 70 ℃ for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc, and passed throughAnd (5) filtering the pad. Will->Washed with EtOAc. The combined filtrates were washed with brine, over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0% -11% EtOAc in petroleum ether) to give the title compound (192 mg, yield: 92%) as a yellow solid. ESI-MS: c (C) 24 H 28 ClNO 2 The calculated mass of Si is 425.2; m/z found to be 426.1[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ7.75(dd,J＝7.9,1.6Hz,4H),7.35-7.48(m,6H),6.97(t,J＝8.1Hz,1H),6.42(dd,J＝8.2,1.1Hz,1H),6.33(dd,J＝8.2,1.1Hz,1H),4.13-4.17(m,2H),4.07-4.13(m,2H),4.01-4.06(m,2H),1.06(s,9H)ppm。
Intermediate 9:5- ((benzyloxy) methyl) -4-ethyl-2- (7-methyl-1-oxo-4- (prop-1-en-2-yl) -1H-) Isobenzopyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one。
And (A) a step.2-bromo-4-fluoro-5-methylbenzoic acid tert-butyl ester。
To a solution of 2-bromo-4-fluoro-5-methylbenzoic acid (1 g,4.3 mmol) in THF (10 mL) was added (Boc) 2 O (1.9 g,8.6 mmol) followed by DMAP (262 mg,2.1 mmol). The reaction mixture turned orange and was stirred under nitrogen overnight at 50 ℃. The mixture was cooled to room temperature, diluted with EtOAc, and then washed with brine. The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (elution: 0-3% EtOAc in petroleum ether) to give the title compound (900 mg, yield: 72%) as a colorless oil. 1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝8.1Hz,1H),7.24(d,J＝4.6Hz,1H),2.22(d,J＝1.5Hz,3H),1.58(s,9H)ppm。
Step B.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 2-bromo-5-methylbenzoic acid tert-butyl ester。
Tert-butyl 2-bromo-4-fluoro-5-methylbenzoate (750 mg,2.6 mmol), 5- ((benzyloxy) methyl) -4-ethyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (800 mg,3.4 mmol) and Cs 2 CO 3 A mixture of (1.7 g,5.2 mmol) in DMF (8 mL) was stirred at 90℃for 16 h. By addition of saturated NH 4 The reaction was quenched with aqueous Cl. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, and dried over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by combined flash chromatography (SiO 2 Eluting: petroleum ether solution of 0% -22% etoac) to afford the title compound as a colorless gel (1 g, yield: 71%). ESI-MS: c (C) 24 H 28 BrN 3 O 4 Is 501.1; the m/z observed value is 502.1[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝6.1Hz,2H),7.33-7.43(m,5H),4.61(s,2H),4.50(s,2H),3.85(q,J＝7.3Hz,2H),2.31(s,3H),1.62(s,9H),1.36(t,J＝7.2Hz,3H)ppm。
Step C.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 2-bromo-5-methylbenzoic acid。
To a mixture of tert-butyl 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2-bromo-5-methylbenzoate (500 mg,0.90 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated. The residue was dissolved with DCM and petroleum ether was slowly added. The mixture was stirred at room temperature for 30 minutes. The mixture was filtered and the precipitate was rinsed with petroleum ether. The solid was collected and dried in vacuo to give the title compound as a white solid (360 mg, yield: 86%). ESI-MS: c (C) 20 H 20 BrN 3 O 4 The mass calculation value of (2) is 445.1; found m/z 446.0[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ7.77(s,1H),7.70(s,1H),7.29-7.41(m,5H),4.59(s,2H),4.56(s,2H),3.74(q,J＝7.0Hz,2H),2.24(s,3H),1.23(t,J＝7.2Hz,3H)ppm。
Step D.5- ((benzyloxy) methyl) -4-ethyl-2- (7-methyl-1-oxo-4- (prop-1-en-2-yl) -1H-iso- Benzopyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one。
Pd (OAc) was added to a mixture of 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2-bromo-5-methylbenzoic acid (560 mg,1.26 mmol), acetic acid 3-methylbutan-1, 2-dien-1-yl ester (intermediate 12,1.58g,12.5 mmol), acOK (369 mg,3.76 mmol) and TBAB (809 mg,2.51 mmol) in DMF (3.9 mL) under nitrogen 2 (141 mg,0.63 mmol). The reaction mixture was stirred under nitrogen at 90 ℃ overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The organic layer was separated and the aqueous layer extracted with EtOAc. Combining the organic mattersCombining the layers, passing through Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0% -70% EtOAc in petroleum ether) to give the title compound (410 mg, yield: 73%) as a yellow solid. ESI-MS: c (C) 25 H 25 N 3 O 4 Is 431.2; found m/z 432.1[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.28(s,1H),7.59(s,1H),7.31-7.46(m,5H),7.17(s,1H),5.30-5.37(m,1H),5.15(s,1H),4.63(s,2H),4.52(s,2H),3.87(q,J＝7.1Hz,2H),2.46(s,3H),2.10(s,3H),1.38(t,J＝7.2Hz,3H)ppm。
Intermediate 10:6- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazole-1- Phenyl) -2-chloro-5-fluoro-nicotinic acid isopropyl ester
Step A.2, 6-dichloro-5-fluoronicotinoyl chloride。
To a solution of 2, 6-dichloro-5-fluoronicotinic acid (20 g,95 mmol) in THF (200 mL) at 0deg.C was added dropwise (COCl) 2 (12.7 g,10.0 mmol) and DMF (69.6 mg,0.952 mmol). The mixture was stirred at 0 ℃ for 30 minutes, then warmed to 25 ℃ and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the desired product (21.7 g, crude) as a colourless oil, which was used without further purification.
Step B.2, 6-dichloro-5-fluoronicotinic acid isopropyl ester
To a mixture of propan-2-ol (8.56 g,142mmol,10.9 mL) and pyridine (9.02 g,114 mmol) in THF (200 mL) was added a solution of 2, 6-dichloro-5-fluoronicotinoyl chloride (21.7 g,96.0 mmol) in THF (50 mL) at 0deg.C. The mixture was stirred at 25℃for 1 hour. The mixture was poured into water (300 mL). The aqueous phase was extracted with ethyl acetate (300 mL). The combined organic phases were treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (SiO 2 Petroleum ether/ethyl acetate=1/1 to 10:1) Purification provided the title compound (21 g,86.82% yield). MS (ESI): c (C) 9 H 8 Cl 2 FNO 2 The calculated mass value of (2) is 250.1; found m/z of 252.0[ M+H ]]+。 1 H NMR(400MHz,CDCl 3 )δ7.97-7.95(d,J＝7.2Hz,1H),5.32-5.25(m,1H),1.58-1.39(m,6H)ppm。
Step C.6- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl) 2-chloro-5-fluoronicotinic acid isopropyl ester。
To a mixture of isopropyl 2, 6-dichloro-5-fluoronicotinate (4 g,15.87 mmol) in DMSO (40 mL) was added 3- ((benzyloxy) methyl) -4-ethyl-1H-1, 2, 4-triazol-5 (4H) -one (3.89 g,16.66 mmol) and K 2 CO 3 (3.29 g,23.80 mmol). The mixture was stirred at 80℃for 3 hours. LCMS showed the starting material had been consumed and the desired quality was detected. The mixture was treated with H 2 O (30 mL) was diluted and extracted with EtOAc (50 mL. Times.3). The combined organic layers were washed with brine (100 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 Petroleum ether/ethyl acetate=1/0 to 1:1) to afford the title compound (5.7 g,79.86% yield). MS (ESI): c (C) 21 H 22 ClFN 4 O 4 Is 448.1; found m/z 449.2[ M+H ]]+。 1 H NMR(400MHz,CDCl 3 )δ8.10(d,J＝8.8Hz,1H),7.43-7.31(m,5H),5.30(td,J＝6.3,12.5Hz,1H),4.61(s,2H),4.54(s,2H),3.85(q,J＝7.2Hz,2H),1.41(d,J＝6.2Hz,6H),1.37-1.31(m,3H)ppm。
Intermediate 11:5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-3-hydroxy-4-isopropyl-1-oxoisobenzo-ne Pyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
Step A.4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl 2-bromo-5-fluorobenzoic acidMethyl ester
To a solution containing methyl 2-bromo-4, 5-difluorobenzoate (100.0 g, 328 mmol), 5- ((benzyloxy) methyl) -4-ethyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (intermediate 1, 113.5g,508 mmol) and K 2 CO 3 A flask (100.0 g, 254 mmol) was charged with anhydrous DMF (1000 mL). The reaction mixture was heated at 50 ℃ under nitrogen for 16 hours, then additional 5- ((benzyloxy) methyl) -4-ethyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one (11 g,51 mmol) was added. The reaction mixture was stirred at 50 ℃. The mixture was cooled to room temperature and stirred for 10 minutes. Water (1000 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration and dried to give a crude product (190 g). The product was stirred in DMF (500 mL) for 30 min, then water (500 mL) was added. The mixture was stirred for 2 hours. The precipitate was collected by filtration and dried to give the title compound (180 g, yield: 90%). 1 H NMR(300MHz,CDCl 3 )δ7.95(d,J＝6.7Hz,1H),7.73(d,J＝10.7Hz,1H),7.44–7.27(m,5H),4.60(s,2H),4.50(s,2H),3.95(s,3H),3.84(q,J＝7.2Hz,2H),1.34(t,J＝7.2Hz,3H)ppm。
Step B.5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-3-hydroxy-4-isopropyl-1-oxoisobenzopyr Pyran-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one
To 4- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -2-bromo-5-fluorobenzoic acid methyl ester (30 g,65.9 mmol), xantphos (4.02 g,6.6 mmol),
[ Pd (allyl) Cl] 2 (1.38g，3.77mmol)、Cs 2 CO 3 To a mixture of (42.6 g,130 mmol) in dimethylacetamide (300 mL) was slowly added 3-methylbutanal (41.4 mL, 383 mmol). The reaction mixture was heated at 80 ℃ under nitrogen for 22 hours. The mixture was filtered and treated with NH 4 The aqueous Cl solution was quenched until the "pH" became 7-8. The mixture was extracted with ethyl acetate (2000 mL. Times.2). The combined organic extracts were concentrated. The residue was purified by column chromatography (SiO 2 Gradient elution: 1% -33% ethyl acetate in petroleum ether) to give the title compound (61.7 g, collected as an oilThe rate is as follows: 56%). 1 H NMR(300MHz,CDCl 3 )δ7.93(d,J＝10.4Hz,1H),7.55(d,J＝6.7Hz,1H),7.44–7.28(m,5H),5.92(s,1H),4.61(s,2H),4.51(s,2H),4.37(br s,1H),3.85(q,J＝7.2Hz,2H),2.80(d,J＝7.1Hz,1H),1.92(spt,J＝6.8Hz,1H),1.35(t,J＝7.2Hz,3H),1.05(d,J＝6.8Hz,3H),0.93(d,J＝6.8Hz,3H)ppm。
Intermediate 12: acetic acid 3-methylbutan-1, 2-dien-1-yl ester
Step A, 2-methylbutan-3-yn-2-yl acetate
At 0 ℃, to Mg (ClO) 4 ) 2 (796 mg,3.6 mmol) to a mixture of acetic anhydride (38 g, 375 mmol) was added dropwise 2-methyl-3-butyn-2-ol (30 g, 317 mmol). The reaction mixture was stirred at 0 ℃ for 10 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was diluted with DCM and then saturated NaHCO 3 Aqueous solution and saturated Na 2 CO 3 Washing with aqueous solution. The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated at 0 ℃. The residue was purified by silica column chromatography (elution: DCM) to give the title compound (35.8 g, yield: 80%) as a pale yellow oil. 1 H NMR(400MHz,CDCl 3 )δ2.54(s,1H),2.03(s,3H),1.67(s,6H)ppm。
Step B3-methylbutan-1, 2-dien-1-yl acetate
To a solution of acetic acid 2-methylbutan-3-yn-2-yl ester (2.5 g,20 mmol) in DCM (20 mL) under nitrogen was added AgBF 4 (117 mg,0.6 mmol). The resulting colorless solution was stirred under nitrogen at 35 ℃ for 2 hours until the mixture became a black solution. The mixture was washed with ammonia (10%). The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica column chromatography (gradient elution: 0-3% EtOAc in petroleum ether),the title compound (650 mg, yield: 26%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl 3 )δ7.20(dt,J＝4.1,2.0Hz,1H),2.11(s,3H),1.81(d,J＝2.0Hz,6H)ppm。
Example 22 of PCT/IB2020/053601 (which is disclosed as WO 2020/212897 at month 22 of 2020) 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl- 2- (o-tolyl) isoquinolin-1 (2H) -one (Compound 22)。
Step A.6- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) propan-yl 7-fluoro-4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one
To a mixture of 5- ((benzyloxy) methyl) -4-ethyl-2- (7-fluoro-3-hydroxy-4-isopropyl-1-oxoisochroman-6-yl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one (intermediate 11, 56g,123 mmol) in AcOH (160 mL) was added o-toluidine (14.8 g,138 mmol). The reaction mixture was heated at 80 ℃ for 16 hours. The mixture was concentrated and then taken up in NaHCO 3 The aqueous solution adjusts the "pH" to 7-8. The mixture was extracted with ethyl acetate (160 mL. Times.2). The combined organic extracts were concentrated. The residue was purified by flash chromatography (SiO 2 0-20% ethyl acetate in DCM) to give the title compound as an oil (32.5 g, yield: 50%). MS (ESI): c (C) 31 H 31 FN 4 O 3 Is 526.2; m/z found 527.4[ M+H ]] + 。 1 H NMR(300MHz,CDCl 3 )δ8.33(d,J＝10.9Hz,1H),8.07(d,J＝6.8Hz,1H),7.44–7.27(m,9H),6.84(s,1H),4.64(s,2H),4.55(s,2H),3.89(q,J＝7.2Hz,2H),3.23(spt,J＝6.8Hz,1H),2.16(s,3H),1.39(t,J＝7.2Hz,3H),1.31(dd,J＝6.8,2.1Hz,6H)ppm。
Step B.6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-) 4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one。
To a stirred solution of 6- (3- ((benzyloxy) methyl) -4-ethyl-5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one (26.5 g,50.3 mmol) in DCM (230 mL) at-78 ℃ under nitrogen was added BCl 3 (290 mL ) of DCM solution (1M). The reaction mixture was stirred at 15 ℃ for 0.5 hours. The reaction was quenched by MeOH (100 mL) at-78deg.C to-20deg.C. The mixture was partitioned between water and DCM. The organic layer was separated and the aqueous layer was extracted with DCM (110 mL. Times.2). The combined organic extracts were washed with brine (30 mL. Times.2), dried over anhydrous Na 2 SO 4 Drying, filtration and concentration gave the crude product (27.5 g). The product was triturated with methyl ethyl ketone (82 mL) and heptane (290 mL) to give the pure product (17.5 g), which was recrystallized from ethanol and water to give the title compound as a white solid (16 g, yield: 73%). MS (ESI): c (C) 24 H 25 FN 4 O 3 Is 436.2; found m/z 437.2[ M+H ]] + 。 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝11.2,1H),8.08(d,J＝6.8,1H),7.39-7.33(m,3H),7.28(s,1H),6.85(s,1H),4.69(br s,2H),3.94(q,J＝7.11Hz,2H),3.27(td,J＝13.66,6.82Hz,1H),2.32(br s,1H),2.17(s,3H),1.45(t,J＝7.11Hz,3H),1.32(dd,J＝6.82,1.83Hz,6H)ppm。
It should be noted that the compounds of formula (Z) described herein are described in PCT/IB2020/053601 (which is disclosed in WO 2020/212897 at month 22 of 2020, which is incorporated herein by reference in its entirety for all purposes).
In some embodiments, combination therapies comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one other anti-neoplastic agent are provided.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a hypomethylation agent.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a hypomethylation agent.
According to an embodiment, the hypomethylation agent is azacytidine, decitabine, or a pharmaceutically acceptable salt or solvate thereof.
According to a particular embodiment, the hypomethylating agent is azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a BCL-2 inhibitor.
In some embodiments, combination therapies are provided that consist of a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a BCL-2 inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and valnemulin, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof and valnemulin or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A1 and valnemulin or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A2 and valnemulin or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A3 and valnemulin or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, or a vitamin A4-b or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4 and valnemulin or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent that is azacitidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent that is azacitidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and azacytidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and azacytidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and azacytidine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and azacytidine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent that is decitabine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is decitabine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is decitabine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is decitabine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is decitabine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is decitabine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is decitabine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is decitabine or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is decitabine, or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a DNA intercalating agent.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a DNA intercalating agent.
According to an embodiment, the DNA intercalator is anthracycline.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an anthracycline.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an anthracycline.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is an anthracycline.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is an anthracycline.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is an anthracycline.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is an anthracycline.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is anthracycline.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is an anthracycline.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is an anthracycline.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a pyrimidine analog.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, wherein the at least one other anti-tumor agent is a pyrimidine analog.
According to an embodiment, the pyrimidine analog is cytarabine.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is cytarabine.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is cytarabine.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is cytarabine.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is cytarabine.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is cytarabine.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is cytarabine.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is cytarabine.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is cytarabine.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is cytarabine.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a purine analog.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, wherein the at least one other anti-neoplastic agent is a purine analog.
According to an embodiment, the purine analog is fludarabine.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is fludarabine.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is fludarabine.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is fludarabine.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is fludarabine.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is fludarabine.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is fludarabine.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is fludarabine.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is fludarabine.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is fludarabine.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an IDH inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an isocitrate dehydrogenase 1 inhibitor (e.g., ai Funi cloth).
According to an embodiment, the IDH inhibitor is Ai Funi cloth.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is Ai Funi cloth.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is Ai Funi.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, the at least one other anti-tumor agent being Ai Funi cloth.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, the at least one other anti-tumor agent being Ai Funi cloth.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, the at least one other anti-tumor agent being Ai Funi cloth.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, the at least one additional antineoplastic agent being Ai Funi.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, the at least one additional antineoplastic agent being Ai Funi.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, the at least one other anti-tumor agent being Ai Funi cloth.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, the at least one other anti-tumor agent being Ai Funi cloth.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an isocitrate dehydrogenase 2 inhibitor (e.g., iranib).
According to an embodiment, the IDH inhibitor is enamiib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is iraonib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is iraonib.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is iraonib.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is iranib.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is iranib.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is iranib.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, the at least one other anti-neoplastic agent being iranib.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent, the at least one other anti-neoplastic agent being iranib.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is iranib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an immunomodulatory antineoplastic agent.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an immunomodulatory antineoplastic agent that is a PD-1 inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an immunomodulatory antineoplastic agent.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is an immunomodulatory antineoplastic agent that is a PD-1 inhibitor.
According to embodiments, the immunomodulatory anti-neoplastic agent is nivolumab, alemtuzumab, pamil bead mab, thalidomide, lenalidomide, pomalidomide, BCG, or levamisole.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional anti-tumor agent, wherein the at least one additional anti-tumor agent is nivolumab.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-tumor agent, wherein the at least one additional anti-tumor agent is nivolumab.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is nivolumab.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-tumor agent that is nivolumab.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is nivolumab.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-tumor agent that is nivolumab.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is nivolumab.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is nivolumab.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-tumor agent that is nivolumab.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional anti-tumor agent, wherein the at least one additional anti-tumor agent is alemtuzumab.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-tumor agent, wherein the at least one additional anti-tumor agent is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional anti-neoplastic agent that is alemtuzumab.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is pamo Li Zhushan resistance.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is pamo Li Zhushan resistance.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is pamphlet Li Zhushan resistant.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is pamoic Li Zhushan anti.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is pamoic Li Zhushan anti.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is pamoic Li Zhushan anti.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is pamoic Li Zhushan resistance.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is pamoic Li Zhushan antibody.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is pamoic Li Zhushan anti.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is thalidomide.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is thalidomide.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is thalidomide.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is thalidomide.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is thalidomide.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is thalidomide.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is thalidomide.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is thalidomide.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is thalidomide.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is lenalidomide.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is lenalidomide.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is lenalidomide.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is lenalidomide.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is lenalidomide.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is lenalidomide.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is lenalidomide.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is lenalidomide.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is lenalidomide.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is pomalidomide.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is pomalidomide.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is pomalidomide.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is pomalidomide.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is pomalidomide.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is pomalidomide.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is pomalidomide.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is pomalidomide.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is pomalidomide.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is BCG.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent, wherein the at least one other anti-tumor agent is BCG.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is BCG.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is BCG.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is BCG.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is BCG.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is BCG.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is BCG.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is BCG.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is levamisole.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is levamisole.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is levamisole.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is levamisole.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is levamisole.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is levamisole.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is levamisole.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is levamisole.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is levamisole.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a DHODH inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a DHODH inhibitor.
According to an embodiment, the DHODH inhibitor is a compound of formula (Z) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent that is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent that is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent that is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a DHODH inhibitor of formula (Z) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other antineoplastic agent that is a DHODH inhibitor of formula (Z), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a kinase inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a kinase inhibitor.
According to an embodiment, the kinase inhibitor is a serine and/or tyrosine kinase inhibitor.
According to embodiments, the kinase inhibitor is an inhibitor of FLT3 and/or BTK.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a FLT3 inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a FLT3 inhibitor.
According to embodiments, the FLT3 inhibitor is sorafenib, sunitinib, midostaurin (PKC 412), letutinib (CEP-701), tandutinib (MLN 518), quinidine (AC 220), gefitinib (ASP 2215), or KW-2449.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is sorafenib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is sorafenib.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is sorafenib.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sorafenib.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sorafenib.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is sorafenib.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is sorafenib.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sorafenib.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sorafenib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is sunitinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is sunitinib.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is sunitinib.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sunitinib.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sunitinib.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is sunitinib.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is sunitinib.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sunitinib.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is sunitinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is midostaurin.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is midostaurin.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is midostaurin.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is midostaurin.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is midostaurin.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is midostaurin.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is midostaurin.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is midostaurin.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is midostaurin.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is rituximab.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is rituximab.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is rituximab.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is rituximab.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is rituximab.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is rituximab.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is rituximab.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is rituximab.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is rituximab.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is tandutinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is tandutinib.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is tandutinib.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is tandutinib.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is tandutinib.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is tandutinib.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent which is tandutinib.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent which is tandutinib.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is tandutinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is AC220.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is AC220.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is AC220.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is AC220.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is AC220.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is AC220.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is AC220.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent which is AC220.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is AC220.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is ASP2215.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is ASP2215.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is ASP2215.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ASP2215.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ASP2215.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ASP2215.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is ASP2215.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is ASP2215.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ASP2215.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is KW-2449.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is KW-2449.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is KW-2449.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent that is a BTK inhibitor.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a BTK inhibitor.
According to an embodiment, the BTK inhibitor is ibrutinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is ibrutinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is ibrutinib.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is ibrutinib.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ibrutinib.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ibrutinib.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ibrutinib.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is ibrutinib.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is ibrutinib.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is ibrutinib.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is a CD20 inhibitor.
According to an embodiment, the CD20 inhibitor is an anti-CD 20 antibody, in particular obbine You Tuozhu mab (GA 101).
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-neoplastic agent which is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is a CD20 inhibitor.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, a BCL-2 inhibitor, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is GA101.
In some embodiments, combination therapies are provided comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent, wherein the at least one additional antineoplastic agent is GA101.
In some embodiments, combination therapies are provided comprising compound a or a pharmaceutically acceptable salt or solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is GA101.
In some embodiments, combination therapies are provided comprising compound A1, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is GA101.
In some embodiments, combination therapies are provided comprising compound A2, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is GA101.
In some embodiments, combination therapies are provided comprising compound A3, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is GA101.
In some embodiments, combination therapies are provided comprising compound A4-a or a solvate thereof, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent which is GA101.
In some embodiments, combination therapies are provided comprising compound A4-b or a hydrate thereof, valnemulin or a pharmaceutically acceptable salt or solvate thereof, and at least one other anti-tumor agent that is GA101.
In some embodiments, combination therapies are provided comprising compound A4, valnemulin, or a pharmaceutically acceptable salt or solvate thereof, and at least one additional antineoplastic agent that is GA101.
All possible combinations of the above embodiments are considered to be included within the scope of the invention.
In some embodiments, methods are provided for treating a subject that has been diagnosed with a hematopoietic disorder. For example, the invention relates to a novel method comprising administering to a subject a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor as described herein; and a therapeutically effective amount of a BCL-2 inhibitor; and optionally a therapeutically effective amount of at least one other antineoplastic agent.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered orally to the subject.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject at a dose of about 1mg/kg to about 50 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject at a dose of about 2.5mg/kg to about 25 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject at a dose of about 7.5mg/kg to about 12.5 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject at a dose of about 8mg/kg to about 10 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject at a dose of about 0.1mg to about 5 mg.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered orally to the subject.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject at a dose of about 1mg/kg to about 50 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject at a dose of about 2.5mg/kg to about 25 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject at a dose of about 7.5mg/kg to about 12.5 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject at a dose of about 8mg/kg to about 10 mg/kg.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject at a dose of about 0.1mg to about 5 mg.
Another embodiment of the invention relates to a method as described herein, wherein at least one other anti-tumor agent is administered to the subject intravenously or subcutaneously.
Another embodiment of the present invention relates to a method as described herein, wherein the at least one additional anti-neoplastic agent is present at about 10mg/m 2 To about 250mg/m 2 Is administered to a subject intravenously or subcutaneously.
Another embodiment of the present invention relates to a method as described herein, wherein the at least one additional anti-neoplastic agent is present at about 50mg/m 2 To about 150mg/m 2 Is administered to a subject intravenously or subcutaneously.
Another embodiment of the present invention relates to a method as described herein, wherein the at least one additional anti-neoplastic agent is present at about 60mg/m 2 To about 100mg/m 2 Is administered to a subject intravenously or subcutaneously.
Another embodiment of the present invention relates to a method as described herein, wherein the at least one additional antineoplastic agent is administered at about 75mg/m 2 Is administered to a subject intravenously or subcutaneously.
Another embodiment of the invention relates to a method as described herein, wherein at least one additional anti-neoplastic agent is orally administered to the subject at a dose of from about 1mg to about 500 mg.
Another embodiment of the invention relates to a method for treating a subject who has been diagnosed with cancer (e.g., wherein the cancer is a hematopoietic disorder such as myelodysplastic syndrome (MDS), acute Myeloid Leukemia (AML), acute Lymphoblastic Leukemia (ALL), small Lymphocytic Lymphoma (SLL), or Chronic Lymphocytic Leukemia (CLL)), wherein the method comprises administering to the subject:
a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor of formula (I), or a tautomer or stereoisomer form thereof, or a pharmaceutically acceptable salt or solvate thereof; and
a therapeutically effective amount of a DHODH inhibitor of formula (Z) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof;
for example, wherein the multiple endocrine oncoprotein-MLL inhibitor and DHODH inhibitor are administered for a period of time according to their dosing regimen, e.g., (i) simultaneously or sequentially in either order on the same day over a period of time (e.g., 21 day period, or 28 day period, or 3 month period, or 6 month period, or one year period, etc.), and/or (ii) on different days over a period of time.
Another embodiment of the invention relates to a method for treating a subject who has been diagnosed with cancer (e.g., wherein the cancer is a hematopoietic disorder such as myelodysplastic syndrome (MDS), acute Myeloid Leukemia (AML), acute Lymphoblastic Leukemia (ALL), small Lymphocytic Lymphoma (SLL), or Chronic Lymphocytic Leukemia (CLL)), wherein the method comprises administering to the subject:
a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor that is compound a or a pharmaceutically acceptable salt or solvate thereof (e.g., compound A1, or compound A2, or compound A3, or compound A4-a, or a solvate thereof, or compound A4-b, or a hydrate thereof, or compound A4); and
a therapeutically effective amount of a DHODH inhibitor that is compound 22 or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof (e.g., 6- (4-ethyl-3- (hydroxymethyl) -5-oxo-4, 5-dihydro-1H-1, 2, 4-triazol-1-yl) -7-fluoro-4-isopropyl-2- (o-tolyl) isoquinolin-1 (2H) -one);
for example, wherein the multiple endocrine oncoprotein-MLL inhibitor and DHODH inhibitor are administered for a period of time according to their dosing regimen, e.g., (i) simultaneously or sequentially in either order on the same day over a period of time (e.g., 21 day period, or 28 day period, or 3 month period, or 6 month period, or one year period, etc.), and/or (ii) on different days over a period of time.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily.
Another embodiment of the invention relates to a method as described herein, wherein the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is administered to the subject daily for at least 7 days.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject daily.
Another embodiment of the invention relates to a method as described herein, wherein the BCL-2 inhibitor is administered to the subject daily for at least 7 days.
Another embodiment of the invention relates to a method as described herein, wherein at least one additional anti-tumor agent is administered to the subject daily.
Another embodiment of the invention relates to a method as described herein, wherein at least one additional anti-neoplastic agent is administered daily to the subject for at least 21 days.
The optimal dosage of any of the therapeutic compounds described herein to be administered can be readily determined and will vary with the particular compound used, the mode of administration, the strength of the formulation, and the progress of the disease, syndrome, condition or disorder. In addition, factors related to the particular subject to be treated (including subject sex, age, weight, diet and time of administration) will result in the need to adjust the dosage to achieve the appropriate level of treatment and desired therapeutic effect.
Thus, the above dosages are examples of general situations. Of course, there may be individual circumstances where higher or lower dosage ranges are beneficial, and such circumstances are within the scope of the invention.
Whenever the use of the therapeutic compounds described herein is administered to a subject in need thereof, the therapeutic compounds described herein may be administered in any of the above-described compositions and dosage regimens, or by means of those compositions and dosage regimens established in the art.
The therapeutic compounds described herein can be administered to a subject simultaneously or sequentially.
When administered sequentially, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) may be administered first. When administered simultaneously, the combination may be administered in the same or different pharmaceutical compositions. For example, the multiple endocrine oncoprotein-MLL inhibitor of formula (I) may be administered prior to, concurrently with, or after the administration of the BCL-2 inhibitor. For example, the BCL-2 inhibitor may be administered prior to, concurrently with, or after administration of the optional other anti-neoplastic agent. Adjuvant therapy (i.e., where one or both agents are used as the primary treatment and the other agent is used to assist the primary treatment) is also an embodiment of the invention.
Embodiments of the present invention relate to a therapeutically effective amount of a multiple endocrine oncoprotein-MLL inhibitor comprising a compound of formula (I) as mentioned in any embodiment and pharmaceutically acceptable salts and solvates thereof or any subgroup thereof, for use in combination with a therapeutically effective amount of a BCL-2 inhibitor, and optionally a therapeutically effective amount of at least one other antineoplastic agent. In certain embodiments, the above-described therapeutically effective amounts are administered in separate dosage forms for use in treating a subject that has been diagnosed with hematopoietic dysfunction.
Embodiments of the present invention relate to pharmaceutical preparations comprising a multiple endocrine oncoprotein-MLL inhibitor of formula (I) as mentioned in any embodiment and pharmaceutically acceptable salts and solvates thereof or any subgroup thereof, and a BCL-2 inhibitor, and optionally at least one other antineoplastic agent, as a combined preparation for simultaneous, separate or sequential use in the treatment of a subject who has been diagnosed with hematopoietic dysfunction.
The following examples are provided to illustrate some concepts described in this disclosure. While the examples are believed to provide embodiments, they should not be considered to limit the more general embodiments described herein.
Examples
General synthetic scheme
Venetolk (Vietnamic)
Venetitolk is commercially available.
Azacytidine
Azacytidine is commercially available.
Compounds of formula I
In this section, as in all other sections, unless the context indicates otherwise, reference to formula (I) also includes all other subgroups and examples thereof as defined herein.
The general preparation of some representative examples of compounds of formula (I) is described below and in the specific examples, and is generally prepared from starting materials that are commercially available or prepared by standard synthetic methods commonly used by those skilled in the art of organic chemistry. The following schemes are intended to represent examples of the present invention only and are not intended to limit the present invention in any way.
Alternatively, the compounds of formula (I) may also be prepared by analogous reaction schemes as described in the general schemes below, in combination with standard synthetic methods commonly used by those skilled in the art.
The skilled artisan will recognize that in the reactions described in the schemes, although not always explicitly shown, it may be desirable to protect the desired reactive functional groups (e.g., hydroxyl, amino, or carboxyl groups) in the final product from their undesired participation in the reaction. In general, conventional Protecting Groups (PG) may be used according to standard practice. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
The skilled artisan will recognize that in the reactions described in the schemes, under an inert atmosphere, e.g., in N 2 The reaction is carried out under the gas atmosphereMay be desirable or necessary.
It will be apparent to the skilled person that it may be necessary to cool the reaction mixture prior to post-reaction treatment (meaning a series of operations required to separate and purify the product of a chemical reaction, such as quenching, column chromatography, extraction).
The skilled artisan will recognize that heating the reaction mixture with agitation may enhance the reaction results. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.
The skilled artisan will recognize that another sequence of chemical reactions, as shown in the schemes below, may also yield the desired compounds of formula (I).
The skilled artisan will recognize that the intermediates and final compounds shown in the schemes below may be further functionalized according to methods well known to those skilled in the art. The intermediates and compounds described herein may be isolated in free form or as salts or solvates thereof. The intermediates and compounds described herein can be synthesized as mixtures of tautomers and stereoisomers, which can be separated from one another according to resolution methods known in the art.
All abbreviations used in the general scheme of formula (I) are defined in the examples below in table 1B. The variables are as defined in the scope or as specifically defined in the general scheme.
Part A) schemes 1a, 1b, 1c, 2a, 2b and 3
In schemes 1a, 1b and 1c, the following reaction conditions apply:
step 1: at a suitable temperature (e.g., -70 ℃) in the presence of a suitable base (e.g., TMEDA) and a suitable organometallic reagent (e.g., isopropyl magnesium bromide) in a suitable solvent (e.g., THF);
step 2: at a suitable temperature (e.g., 0 ℃ to room temperature) in the presence of a suitable oxidizing agent (e.g., DMP) in a suitable solvent (e.g., DCM);
step 3: in a suitable solvent (e.g., THF) at a suitable temperature (e.g., from-20 ℃ to room temperature) in the presence of a suitable organometallic reagent (e.g., isopropyl magnesium bromide);
step 4: at a suitable temperature (e.g., 80 ℃) in the presence of a suitable base (e.g., naOH) in a suitable solvent (e.g., THF and H 2 O);
step 5: in the presence of a suitable amide condensing reagent (e.g., EDCI and HOBt) in the presence of a suitable base (e.g., NMM) in a suitable solvent (e.g., DCM) at a suitable temperature (e.g., room temperature);
Step 6: in the presence of a suitable organometallic reagent (e.g., lithium isopropyl) in a suitable solvent (e.g., THF) at a suitable temperature (e.g., -70 ℃);
step 7: at a suitable temperature (e.g., 90 ℃) over a suitable organometallic catalyst (e.g., pd (dppf) Cl 2 ) In the presence of a suitable base (e.g. Na 2 CO 3 ) In the presence of a suitable solvent (e.g. 1, 4-dioxane and H 2 O);
step 8: at a suitable temperature (e.g. 0 ℃ to room temperature), at a suitable Lewis acid (e.g. BBr) 3 ) In a suitable solvent (e.g., DCM);
step 9: at a suitable temperature (e.g. -78 ℃ to 40 ℃, in particular 0 ℃ to room temperature), in a suitable base (e.g. TEA, DBU or K 2 CO 3 ) In a suitable solvent (e.g., DCM, THF or DMF);
scheme 2a
Scheme 2b
In schemes 2a and 2b, the following reaction conditions apply:
step 9: see step 9 in scheme 1;
step 10: at a suitable temperature (e.g. room temperature) in the presence of a suitable catalyst (e.g. Pd/C) in a suitable reducing agent (e.g. H 2 ) Optionally in the presence of a suitable base (e.g., TEA) in a suitable solvent (e.g., THF); alternatively, at a suitable temperature (such as room temperature), over a suitable catalyst (e.g., pd (dppf) Cl 2 X DCM complex), a suitable reducing agent (such as NaBH 4 ) In the presence of a suitable base (e.g., TMEDA) in a suitable solvent (e.g., THF).
Step 11: for N deprotection, at a suitable temperature (e.g., room temperature), in the presence of a suitable acid (e.g., TFA), in a suitable solvent (e.g., DCM); for O deprotection, at a suitable temperature (e.g., room temperature) in the presence of a suitable acid (e.g., 4-methylbenzenesulfonic acid) in a suitable solvent (e.g., meOH);
step 12: at a suitable temperature (e.g. 80 ℃), optionally at a suitable Lewis acid (e.g. ZnCl) 2 ) In the presence of a suitable reducing agent (e.g. NaBH 3 CN) in a suitable solvent (e.g., meOH);
step 13: at a suitable temperature (e.g. room temperature) in the presence of a suitable organometallic catalyst (e.g. Ag (Phen) 2 OTf) in the presence of a suitable brominating agent (e.g. 1, 3-dibromo-1, 3, 5-triazin-2, 4, 6-trione) in a suitable solvent (e.g. DCE);
step 14: in the presence of a suitable chlorinating agent (e.g. oxalyl chloride) in the presence of DMF in a suitable solvent (e.g. DCM) at a suitable temperature (e.g. room temperature);
scheme 3
In scheme 3, the following reaction conditions are applied:
step 11-12: see steps 11-12 in scheme 2;
step 15: at a suitable temperature (e.g., 80 ℃) in a suitable base (e.g., cs 2 CO 3 ) In a suitable solvent (e.g., DMF);
step 16: in a suitable solvent (e.g., 1, 4-dioxane) in the presence of a suitable base (e.g., ammonia) at a suitable temperature (e.g., 40 ℃).
Part B) schemes 4, 5, 6, 7, 8, 9, 10, 11 and 12
In scheme 4, the following reaction conditions are applied:
step 1: at a suitable temperature (e.g., 90 ℃) over a suitable organometallic catalyst (e.g., pd (dppf) Cl 2 ) In the presence of a suitable base (e.g. Na 2 CO 3 ) In the presence of a suitable solvent (e.g. 1, 4-dioxane and H 2 O);
step 2: in the presence of a suitable amide condensing reagent (e.g., HATU) in the presence of a suitable base (e.g., DIEA) in a suitable solvent (e.g., DCM) at a suitable temperature (e.g., room temperature);
step 3: at a suitable temperature (e.g. -78 ℃ C. To room temperature), at a suitable Lewis acid (e.g. BBr) 3 ) In a suitable solvent (e.g., DCM);
step 4: at a suitable temperature (e.g. -78 ℃ to 40 ℃, in particular 0 ℃ to room temperature), in a suitable base (e.g. TEA, DBU or K 2 CO 3 ) In a suitable solvent (e.g., DCM, THF or DMF);
step 5: at a suitable temperature (e.g. room temperature), in a suitable base (e.g. LiOH X H 2 O) in the presence of a suitable solvent (e.g. THF and H 2 O);
step 6: at a suitable temperature (e.g. room temperature), at a suitable temperatureOrganometallic catalysts (e.g. Ag (Phen) 2 OTf) in the presence of a suitable brominating agent (e.g. 1, 3-dibromo-1, 3, 5-triazin-2, 4, 6-trione) in a suitable solvent (e.g. DCE);
step 7: at a suitable temperature (e.g., room temperature) in the presence of a suitable brominating reagent such as 1, 3-dibromo-1, 3, 5-triazin-2, 4, 6-trione in the presence of 2, 2-trifluoroethan-1-ol as solvent.
In scheme 5, the following reaction conditions are applied:
step 8: at a suitable temperature (e.g. -78 ℃ to 40 ℃, in particular 0 ℃ to room temperature), in a suitable base (e.g. TEA, DBU or K 2 CO 3 ) In a suitable solvent (e.g., DCM, THF or DMF);
step 9: at a suitable temperature (e.g. -78 ℃ to 40 ℃, in particular 0 ℃ to room temperature), in a suitable base (e.g. TEA, DBU or K 2 CO 3 ) In a suitable solvent (e.g., DCM, THF or DMF);
Step 10: at a suitable temperature (e.g., room temperature), in the presence of a suitable organometallic catalyst (e.g., pd/C) and a suitable base (e.g., TEA), in a suitable solvent (e.g., meOH), in H 2 Under the atmosphere;
step 11: when PG is Boc, it is in a suitable solvent (e.g., DCM) at a suitable temperature (e.g., room temperature) in the presence of a suitable acid (e.g., TFA).
Scheme 6
In scheme 6, the following reaction conditions are applied:
step 12: reductive amination conditions at a suitable temperature (e.g., room temperature to 80 ℃) with or without the presence of a suitable Lewis acid (e.gSuch as ZnCl 2 ) Or in the case of acids (e.g., acOH), in the presence of a suitable reducing agent (e.g., naBH 3 CN) in a suitable solvent (e.g., meOH);
step 13: in the presence of a suitable electrophile (e.g., msCl) in a suitable solvent (e.g., DCM) in the presence of a suitable base (e.g., TEA) at a suitable temperature (e.g., 0 ℃);
step 14: at a suitable temperature (e.g., 0 ℃ to room temperature) in the presence of a suitable oxidant (e.g., DMP) in a suitable solvent (e.g., DCM);
step 15: in a suitable solvent (e.g., ACN) in the presence of a suitable acid (e.g., HCl) at a suitable temperature (e.g., 50 ℃);
Step 16: at a suitable temperature (e.g., room temperature) in a suitable solvent (e.g., THF) in the presence or absence of a suitable base (e.g., TEA);
scheme 7
In scheme 7, the following reaction conditions are applied:
step 11: when PG is Boc, it is in a suitable solvent (e.g., DCM) at a suitable temperature (e.g., room temperature) in the presence of a suitable acid (e.g., TFA);
step 12: reductive amination conditions at a suitable temperature (e.g., room temperature to 80 ℃) in the presence or absence of a suitable Lewis acid (e.g., znCl) 2 ) Or in the case of acids (e.g., acOH), in the presence of a suitable reducing agent (e.g., naBH 3 CN) in a suitable solvent (e.g., meOH);
step 17: at a suitable temperature (e.g., room temperature to 80 ℃) in a suitable base (e.g., DIEA or Cs 2 CO 3 ) In a suitable solvent (e.g., DCM or DMF);
step 18: in a suitable solvent, such as 1, 4-dioxane, in the presence of a suitable base, such as ammonia, at a suitable temperature, such as 40 ℃.
Scheme 8
In scheme 8, the following reaction conditions are applied:
step 9: at a suitable temperature (e.g. -78 ℃ to 40 ℃, in particular 0 ℃ to room temperature), in a suitable base (e.g. TEA, DBU or K 2 CO 3 ) In a suitable solvent (e.g., DCM, THF or DMF);
step 10: at a suitable temperature (e.g. room temperature), in the presence of a suitable organometallic catalyst (e.g. Pd/C), optionally in the presence of a suitable base (e.g. TEA), in a suitable solvent (e.g. MeOH), in H 2 Under the atmosphere;
step 19: in the presence of a suitable chlorinating agent (e.g. oxalyl chloride) in the presence of DMF in a suitable solvent (e.g. DCM) at a suitable temperature (e.g. room temperature);
step 20: in a suitable solvent (e.g., etOH) in the presence of a suitable nucleophilic amine at a suitable temperature (e.g., 90 ℃);
step 21: in a suitable solvent (e.g., meOH) in the presence of a suitable acid (e.g., a dioxane solution of HCl) at a suitable temperature (e.g., room temperature);
step 22: in the presence of a suitable boron reagent, such as trimethylboroxine, at a suitable temperature, such as 110 c, in the presence of a suitable organometallic catalyst, such as tetrakis (triphenylphosphine) palladium (0), in the presence of a suitable base, such as K 2 CO 3 ) In a suitable solvent (e.g., 1, 4-dioxane);
scheme 9
In scheme 9, the following reaction conditions were applied:
Step 23: at a suitable temperature (e.g., -78 ℃ to-25 ℃) in the presence of a suitable base (e.g., DIEA) in a suitable solvent (e.g., THF);
step 24: at a suitable temperature (e.g. between-65 ℃ and-55 ℃) in the presence of a suitable reducing agent (e.g. DIBAL-H) in a suitable solvent (e.g. toluene), preferably in a suitable flow chemistry system;
step 25: first in a suitable solvent (e.g., DCM) in the presence of a suitable base (e.g., DMAP) in the presence of a suitable condensing agent (e.g., DCC) at a suitable temperature (e.g., -10 ℃ to 10 ℃); and then at a suitable temperature (e.g., -10 ℃ to 0 ℃) in the presence of a suitable acid (e.g., acOH) in a suitable reducing agent (e.g., naBH 4 ) In a suitable solvent (e.g., DCM);
step 26: in a suitable solvent (e.g., toluene) and heated to reflux;
step 27: at a suitable temperature (e.g., -5 ℃ to 5 ℃) in a suitable reducing agent (e.g., liBH 4 ) In a suitable solvent (e.g., 2-methyltetrahydrofuran);
step 28: at a suitable temperature (e.g., 15 ℃ C. To 25 ℃ C.), in a suitable reducing agent (e.g., naBH (OAc) 3 ) In a suitable solvent (e.g., DCM);
step 29: in a suitable solvent (e.g., IPA) in the presence of a suitable acid (e.g., HCl) at a suitable temperature (e.g., 15 ℃ to 25 ℃);
step 30: at a suitable temperature (e.g. 5 ℃ C. To 30 ℃ C.), in the presence of a suitable base (e.g. TEA), in a suitable reducing agent (e.g. NaBH (OAc) 3 ) In a suitable solvent (e.g., toluene);
step 31: at a suitable temperature (e.g. 50 ℃ to 55 ℃) in a suitable base (e.g. K 2 HPO 4 ) In the presence of a suitable solvent (e.g. H 2 O);
step 32: when PG is Bn, it is in the presence of a suitable catalyst (e.g., palladium hydroxide on carbon) in a suitable solvent (such as EtOH) at a suitable temperature (e.g., from-5 ℃ to 45 ℃) under a hydrogen atmosphere in a suitable pressure range (e.g., from 0.27MPa to 0.40 MPa);
step 33: in a suitable solvent (such as 2-methyltetrahydrofuran) in the presence of a suitable base (e.g., TEA) at a suitable temperature (e.g., -50 ℃ to-40 ℃);
step 34: in a suitable solvent (such as 2-methyltetrahydrofuran) in the presence of a suitable base (e.g., TMG) at a suitable temperature (e.g., 20 ℃ to 30 ℃);
Step 35: in the presence of a suitable catalyst (e.g., palladium on carbon) in a suitable solvent (such as MeOH) under a hydrogen atmosphere at a suitable temperature (e.g., 20 ℃ to 30 ℃) and within a suitable pressure range (e.g., 0.20Mpa to 0.30 Mpa);
alternatively, at a suitable temperature (such as room temperature), in the presence of a suitable catalyst (e.g., 1 '-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex), a suitable reducing agent (such as sodium borohydride), a suitable base (e.g., N' -tetramethyl ethylenediamine), in a suitable solvent (e.g., tetrahydrofuran).
Scheme 10
In general, compounds of formula (I) wherein Y can be prepared according to the following reaction scheme 10 1 Limited to-CH 2 -and R 2 Limited to W 1 Thus, the compound of formula (Ia). In scheme 10, W 1 Represents chlorine, bromine or iodine; all other variables are defined according to the scope of the present invention.
Scheme 10
In scheme 10, the following reaction conditions apply:
step 36: at a suitable temperature in the range of 60 ℃ to 100 ℃ over a suitable catalyst such as palladium acetate (Pd (OAc) 2 ) Or tris (dibenzylideneacetone) dipalladium (0)/(Pd 2 (dba) 3 ) Or tetrakis (triphenylphosphine) palladium (0) in a suitable solvent, for example tetrahydrofuran or dioxane.
The skilled artisan will recognize that similar chemistries as reported in step 10 in scheme 5 and steps 20, 21 and 22 in scheme 8 may be performed starting from compound (Ia).
Scheme 11
In general, compounds of formula (I) wherein Y can be prepared according to the following reaction scheme 11 1 Limited to-CR 5a R 5b -and R 2 Limited to W 1 Thus designated as compound of formula (Ib). In scheme 11, R 5a And R is 5b At least one of which is not hydrogen. All other variables are defined according to the scope of the present invention.
Scheme 11
In scheme 11, the following reaction conditions are applied:
step 37: at a suitable temperature in the range 80 ℃ to 200 ℃ over a suitable catalyst such as palladium acetate (Pd (OAc) 2 ) In the presence of a suitable ligand (e.g. triphenylphosphine or tricyclohexylphosphine) in a suitable solvent (e.g. dioxane), preferably under sealing conditions, optionally under microwave radiation.
The skilled artisan will recognize that similar chemistry as reported in step 10 in scheme 5 and steps 20, 21 and 22 in scheme 8 can be performed starting from compound (Ib).
Scheme 12
Scheme 12
In scheme 12, the following reaction conditions apply:
step 38: at the position ofAt a suitable temperature (e.g., room temperature to 80 ℃) in a suitable base (e.g., DIEA, cs 2 CO 3 Or DBU) in a suitable solvent (e.g., DCM, THF or DMF);
alternatively, the catalyst is prepared in the presence of a suitable catalyst (e.g., pd at a suitable temperature (e.g., room temperature to 100 c 2 dba 3 ) In the presence of a suitable ligand (e.g. Xantphos) in the presence of a suitable base (such as Cs 2 CO 3 Or Na (or) 2 CO 3 ) In a suitable solvent such as dioxane or a mixture of dioxane and water.
The skilled person will appreciate that starting from intermediate Z, it is possible to proceed as in Y 1 Represents a similar chemistry as reported in the case of O.
It will be appreciated that the various compounds of formula (la) or any intermediate used in their preparation, in the presence of suitable functional groups, may be further derivatised by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction or cleavage reactions. Specific substitution methods include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation, and coupling procedures.
The compounds of formula (I) may be synthesized as racemic mixtures of enantiomers, which may be separated from one another according to resolution methods known in the art. The racemic compounds of formula (I) containing a basic nitrogen atom can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by base. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
In the preparation of compounds of formula (I), it may be desirable to protect the terminal functional groups (e.g., primary or secondary amines) of the intermediates. The need for such protection will vary depending on the nature of the terminal functional group and the conditions of the preparation process. Suitable amino protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenyl-methyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by those skilled in the art. For a general description of protecting groups and their use, see t.w. greene and p.g. m.wuts, protective Groups in Organic Synthesis, 4 th edition, wiley, hoboken, new Jersey,2007.
Several methods for preparing the compounds of formula (I) are illustrated in the examples below. Unless otherwise indicated, all starting materials are commercially available from commercial suppliers and may be used without further purification or alternatively may be synthesized by the skilled artisan by using well known methods.
TABLE 1B abbreviations
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As will be appreciated by those of skill in the art, compounds synthesized using the illustrated schemes may exist as solvates (e.g., hydrates) and/or contain residual solvents or small amounts of impurities. The compound or intermediate isolated as a salt may be in integer stoichiometry (integer stoichiometric), i.e., mono-or di-salts, or in intermediate stoichiometry (intermediate stoichiometry). When the intermediates or compounds in the experimental section below are expressed as 'HCl salts' and not as the equivalent number of HCl, this means no There are defined equivalent numbers of HCl. The same principle will also apply to all other salt forms mentioned in the experimental section, such as 'oxalate', 'formate' or
The skilled person will realise that the desired fractions are collected and the solvent evaporated, usually after column chromatography purification, even in cases not explicitly mentioned in the following experimental protocol.
Where stereochemistry is not indicated, this means that it is a mixture of stereoisomers unless otherwise indicated or clear from the context.
Unless otherwise indicated, when a stereocenter is denoted by 'RS', this means that a racemic mixture is obtained at the specified center.
Example 1- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) benzamide (chemical modification Synthesis of Compound A) -preparation method A
Preparation of intermediate tert-butyl 1- (5-methyl-4-oxohexyl) carbamate
To a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (5.0 g,27 mmol) and TMEDA (5.0 mL,33 mmol) in THF (60 mL) cooled to-70℃was slowly added a solution of magnesium isopropylbromide (19 mL,55mmol,2.9M in 2-methyltetrahydrofuran), and the resulting mixture was slowly warmed to room temperature and stirred for 12 hours. Pouring the mixture into saturated NH 4 Aqueous Cl (50 mL) and extracted with EtOAc (50 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a crude product which is further purified by FCC (PE/etoac=1:0 to 100:1) to afford a yellow oilTitle intermediate (3.7 g,60% yield).
Intermediate 13-6- (3, 6-dichloro-1, 2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4]Octane-2-carboxylic acid tert-butyl ester Preparation of butyl esters
To a solution of 3,5, 6-trichloro-1, 2, 4-triazine (10.0 g,54.2 mmol) and TEA (15.2 mL,109 mmol) in DCM (100 mL) cooled at 0deg.C was added 2, 6-diazaspiro [ 3.4)]Tert-butyl octane-2-carboxylate (9.21 g,43.4 mmol), the mixture was warmed to room temperature and stirred for 1 hour. The mixture was diluted with water (20 mL) and extracted with DCM (30 ml×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product which was purified by FCC on silica gel (PE/etoac=1:0 to 3:1) to afford the title intermediate as a yellow solid (12.0 g,58% yield).
Preparation of intermediate 27-N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide
To a mixture of 5-fluoro-2-methoxybenzoic acid (8.00 g,47.0 mmol) and N-ethylpropan-2-amine (8.19 g,94.0 mmol) cooled at 0deg.C in anhydrous DCM (150 mL) was slowly added in portions HATU (21.5 g,56.5 mmol) and DIEA (9.10 g,70.4 mmol). The resulting mixture was slowly warmed to room temperature and stirred for 8 hours. The organic layer was washed with water (20 mL. Times.3) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the solvent was removed under reduced pressure, and the crude product was purified by FCC (EtOAc/pe=0% to 20%) to afford the title intermediate as a white solid (12.0 g,96% yield).
Preparation of intermediate 28-N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide
To a solution of N-ethyl-5-fluoro-N-isopropyl-2-methoxybenzamide (intermediate 27) (12.0 g,50.1 mmol) in anhydrous DCM (100 mL) cooled at-78deg.C was slowly added BBr 3 (14.4 mL,152 mmol) the resulting mixture was slowly warmed to room temperature and stirred for 8 hours. The mixture was cooled again to-78 ℃, meOH (5 mL) was added dropwise to quench the reaction. The resulting mixture was slowly warmed to room temperature and the pH was adjusted to about 8 (by addition of saturated NaHCO 3 An aqueous solution). The aqueous layer was extracted with DCM (50 ml×3) and the combined organic layers were extracted over anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product which was purified by FCC (EtOAc/pe=0% to 20%) to afford the title intermediate as a white solid (9.0 g,78% yield).
Alternative preparation of intermediate 28
A mixture of 5-fluoro-2-hydroxy-benzoic acid (14.0 kg,89.68mol,1.0 eq) in THF (168L, 12 volumes) was adjusted to 15℃to 25℃and 1, 1-carbonyldiimidazole (17.45 kg,107.62mol,1.2 eq) was added over a period of 1 hour. After addition, the mixture was stirred at 15 ℃ to 25 ℃ for 18 hours. Thereafter, N-ethylpropan-2-amine (14.85 kg,170.39mol,1.9 eq.) was added to the mixture over a period of 2 hours at 15℃to 25 ℃. The resulting mixture is further aged at 15-25 ℃ for between 18 hours and 24 hours. pH with 10% H 2 SO 4 The aqueous solution (140 kg,10 volumes) was adjusted to a pH between 4-5 and the layers were separated. The organic phase was concentrated to between 42L-56L, the temperature was kept below 40 ℃, then n-heptane (43 kg,4.5 volumes) was added to the mixture over a period of 3 hours at 15-25 ℃. The mixture was then cooled to 0 ℃ to 10 ℃ and stirred for an additional 6 hours. The resulting slurry was filtered and treated with t-butylMethyl ether (MTBE) n-heptane mixture (25 kg of 2:3 v/v MTBE: n-heptane mixture, 2.5 v) the filter cake was washed. The cake washing was repeated two more times and the resulting solid was dried in vacuo at 50 ℃ to afford intermediate 28 (16.5 kg, purity: 99.1%, yield: 80.4%).
Intermediate 14-6- (3-chloro-6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-tris Oxazin-5-yl) -2, 6-diazaspiro [3.4]Preparation of tert-butyl octane-2-carboxylate
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By reacting 6- (3, 6-dichloro-1, 2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4 ]]A mixture of tert-butyl octane-2-carboxylate (intermediate 13) (12.0 g,33.3 mmol), N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (intermediate 28) (7.5 g,33.3 mmol) and DBU (6.1 g,40.1 mmol) in THF (120 mL) was stirred at 25℃for 8 hours. The mixture was diluted with water (30 mL) and extracted with DCM (30 ml×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product which was purified by FCC (PE/etoac=1:0 to 3:1) to afford the title intermediate as a green solid (14.0 g,73% yield).
Preparation of intermediate 2-6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluoro-phenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
Synthesis method A of intermediate 2：
At N 2 To 6- (3-chloro-6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4] under an atmosphere]Tert-butyl octane-2-carboxylate (intermediate 14) (20 g,36.4 mmol), naBH 4 (2.48 g,65.7 mmol) and TMEDA (8.54 g,73.5 mmol) in THF (500 mL)Pd (dppf) Cl was added to the composition 2 XDCM (1.70 g,2.08 mmol). After the addition, the reaction mixture was stirred at 25 ℃ for 14 hours. The reaction mixture was filtered and the filtrate concentrated, and the residue was purified by FCC (EtOAc) on silica gel to afford the title intermediate as a brown solid (15 g,93% purity, 74% yield).
Synthesis method of intermediate 2B：
To 6- (3-chloro-6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4]To a solution of tert-butyl octane-2-carboxylate (intermediate 14) (22.0 g,40.1 mmol), TEA (15 mL) in MeOH (100 mL) was added Pd/C (wet, 5.0g, 10%). Subjecting the resulting mixture to H 2 Stirring was carried out at 25℃for 8 hours under an atmosphere (30 psi). The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to afford the title intermediate (25.0 g, crude) which was used directly in the next step without further purification.
Intermediate 3-2- ((5- (2, 6-diazaspiro [3.4 ])]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) -N-ethyl Preparation of base-5-fluoro-N-isopropylbenzamide
To 6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4]To a solution of tert-butyl octane-2-carboxylate (intermediate 2) (300 mg,0.583 mmol) in DCM (5 mL) was added TFA (0.5 mL,6.4 mmol) and the resulting mixture was stirred at room temperature for 3 hours. A solution of 10% NaOH (5 mL) was then slowly added to the mixture to adjust the pH to about 12 and the resulting mixture was extracted with DCM (10 mL. Times.3). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the title intermediate as a white solid (220 mg, 90%)Yield).
Compound 61- (4- (6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-e) 5-yl) -2, 6-diazaspiro [3.4]Octyl-2-yl) -5-methylhexyl) carbamic acid tert-butyl ester
2- ((5- (2, 6-diazaspiro [3.4 ])]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (intermediate 3) (1.0 g,2.4 mmol), (5-methyl-4-oxohexyl) carbamic acid tert-butyl ester (intermediate 1) (830 mg,3.62 mmol) and ZnCl 2 A mixture of (660 mg,4.84 mmol) in MeOH (15 mL) was stirred at 80℃for 0.5 h. Then NaBH is added 3 CN (310 mg,4.93 mmol) and the resulting mixture was stirred at 80℃for 6 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC using Waters Xbridge Prep OBD (column: C18150X 40mm 10um; eluent: 45% to 75% v/v ACN/H) 2 O (0.05% ammonia)) to afford the title compound (700 mg,46% yield) as a colorless oil.
Compounds 62 and 63- (R) - (4- (6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1, 2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4]Octyl-2-yl) -5-methylhexyl carbamic acid tert-butyl ester and (S) - (4- (6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4]Octyl-2-yl) -5-methylhexyl) carbamic acid tert-butyl ester
(4-6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [ 3.4) ]Octyl-2-yl) -5-methylhexylcarbamic acid tert-butyl ester(Compound 61) (200 mg,0.319 mmol) was purified by SFC on DAICEL CHIRALPAKIG (column: 250X 30mm 10um; isocratic elution: etOH (containing 0.1% of 25% ammonia): supercritical CO) 2 40%:60% (v/v)) to afford the title compound (compound 62) (85 mg,42% yield) and (compound 63) (80 mg,40% yield), both as pale yellow oils.
Compound 64- (R) -2- ((5- (2- (6-amino-2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4)]Octyl-6- Phenyl) -1,2, 4-triazin-6-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide
To (R) - (4- (6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [ 3.4)]To a solution of tert-butyl oct-2-yl) -5-methylhexyl carbamate (compound 62) (550 mg,0.876 mmol) in DCM (4 mL) was slowly added TFA (4 mL), and the resulting mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted in DCM (40 mL) and the pH was adjusted to about 12 by aqueous NaOH (2 m,16 mL). The aqueous layer was extracted with DCM (10 mL. Times.2). The combined organic layers were dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the title compound (460 mg, crude) as a yellow solid, which was used directly in the next step without further purification.
Compound 11- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) amino) -2-) Methyl hex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
(R) -2- ((5- (2- (6-amino-2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4)]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (Compound 64) (120 mg, crude), 1-bromo-2-methoxyethane (32 mg,0.23 mmol), cs 2 CO 3 A mixture of (222 mg,0.681 mmol), naI (102 mg,0.680 mmol) in DMF (1 mL) was stirred by microwave radiation at 80℃for 1 h. After cooling to room temperature, the mixture was taken up in H 2 O (10 mL) was diluted and extracted with EtOAc (3X 10 mL). The combined organic layers were treated with H 2 O (10 mL) washing, na 2 SO 4 Dried, filtered and concentrated under reduced pressure to provide a crude product which is purified by HPLC on a Phenomenex Gemini-NX (column: 150X 30mm 5 μm; eluent: 51% to 71% (v/v) ACN/H) 2 O(10mM NH 4 HCO 3 ) Purified on DAICEL CHIRALCEL OD-H by SFC (column: 250X 30mm 5um; eluent: supercritical CO 2 Further purification on EtOH (0.1% v/v ammonia) solution 25/25, v/v) provided the title compound (5.13 mg,96% purity) as a yellow solid.
LC-MS (ESI) (method 1): R t =2.997min, found m/z 586.3[ m+h ]] + 。
Compound A- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
(R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4)]A mixture of oct-6-yl) -1,2, 4-triazin-6-yl-oxy) benzamide (compound 11) (40.0 mg,0.068 mmol), formaldehyde (55.4 mg,0.683mol,37% in water) and AcOH (8.2 mg,0.137 mmol) in anhydrous MeOH (2 mL) was stirred at 45℃for 1 hour. Then, naBH is added to the mixture 3 CN (8.6 mg,0.137 mmol) and the resulting mixture was stirred at 45℃for a further 1 hour. After cooling to room temperature, the reaction mixture was taken up with saturated NaHCO 3 (40 mL) aqueous treatment to adjust pHTo about 8 and further extracted with DCM (20 ml×3). The combined organic layers were dried over anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product which was purified by preparative HPLC on Boston Prime (column: C18150X 30mm 5um, mobile phase A: H) 2 O (0.04% ammonia+10 mM NH) 4 HCO 3 ) Mobile phase B: ACN, flow rate: 25mL/min, gradient conditions B/A from 50% to 80% (50% B to 80% B)) to afford the title compound as a yellow oil (9.62 mg,99.10% purity, 23.3% yield).
Example 2- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) benzamide (chemical modification Synthesis of Compound A) Process B
Preparation of intermediate 7-4- ((tert-butoxycarbonyl) (methyl) amino) butanoic acid
To a solution of 4- (methylamino) butyrate (3.0 g,19.5 mmol) and TEA (7.78 mL,58.6 mmol) in MeOH (30 mL) was added Boc dropwise 2 O (4.69 g,21.5 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (100 mL), cooled with 0.1N HCl (70 mL. Times.2), H 2 O (50 mL. Times.2) and brine (50 mL), washed with Na 2 SO 4 Dried, filtered and concentrated to afford the title intermediate (1.80 g, crude) as a colourless oil.
Preparation of intermediate tert-butyl 8- (4- (methoxy (methyl) amino) -4-oxobutyl) (methyl) carbamate
To 4- ((t-Butoxycarbonyl) (methyl) amino) butanoic acid (intermediate7) (1.80 g, crude) in CHCl 3 To a solution of (30 mL) was added N, O-dimethylhydroxylamine hydrochloride (960 mg,9.84 mmol), HOBt (1.24 g,9.18 mmol) and NMM (2.80 mL,25.1 mmol). Furthermore, EDCI (2.23 g,11.6 mmol) was then added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with DCM (100 mL), 1NHCl (30 mL. Times.3), saturated NaHCO 3 Aqueous (30 mL. Times.3) and brine (30 mL) were washed with Na 2 SO 4 Dried, filtered and concentrated in vacuo to afford the title intermediate (1.70 g, crude) as a colourless oil.
Preparation of intermediate tert-butyl 9-methyl (5-methyl-4-oxohexyl) carbamate
To at N 2 To a solution of tert-butyl (4- (methoxy (methyl) amino) -4-oxobutyl) (methyl) carbamate (intermediate 8) (200 mg, crude) cooled at-70℃in THF (5 mL) under an atmosphere was added dropwise lithium isopropyl (3.2 mL,2.24mmol,0.7M in pentane). The resulting mixture was stirred at-70℃for 2 hours. The mixture was treated with saturated NH 4 Aqueous Cl (15 mL) was quenched and extracted with EtOAc (30 mL. Times.2). The combined organic layers were washed with brine (30 mL), and dried over Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave the crude product. The crude product was further purified by FCC (PE/etoac=10:1) to afford the title intermediate (60 mg) as a colourless oil.
The compound 60- (4- (6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-e) 5-yl) -2, 6-diazaspiro [3.4]Preparation of tert-butyl oct-2-yl) -5-methylhexyl) (methyl) carbamate
To 2- ((5- (2, 6-diazaspiro [ 3.4)]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) -N-ethyl-5-fluoro- To a solution of N-isopropylbenzamide (intermediate 3) (600 mg,1.45 mmol) and tert-butyl methyl (5-methyl-4-oxohexyl) carbamate (intermediate 9) (330 mg,1.37 mmol) in MeOH (50 mL) was added ZnCl 2 (789 mg,5.79 mmol). The resulting mixture was stirred at 80℃for 2 hours. Then NaBH is added 3 CN (729 mg,11.6 mmol) and the reaction mixture was stirred at 80℃overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a crude residue, which was diluted with DCM (50 mL) and saturated NH 4 Aqueous Cl (50 mL) was quenched and extracted with DCM (50 mL. Times.3). The combined organic layers were washed with brine (50 mL), and dried over Na 2 SO 4 Drying, filtration and concentration of the filtrate under reduced pressure gave a crude product which was further purified by FCC (DCM/meoh=10:1) to afford the title compound as a white solid (400 mg,42% yield).
Compound 67-N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (2-methyl-6- (methylamino) hex-3-yl)) propan-3-yl) 2, 6-diazaspiro [3.4]]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide hydrochloride
To a solution of tert-butyl (4- (6- (6- (2- (ethyl (isopropyl) carbamoyl) -4-fluorophenoxy) -1,2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4] oct-2-yl) -5-methylhexyl) (methyl) carbamate (compound 60) (1 g,1.56 mmol) in DCM (10 mL) was added a 4M HCl dioxane solution (5 mL,20 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford the title compound (960 mg, crude, HCl salt) which was used directly in the next step without further purification.
Compound A- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide
To N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (2-methyl-6- (methylamino) hex-3-yl) -2, 6-diazaspiro [ 3.4)]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) benzamide hydrochloride (compound 67) (480 mg, crude), K 2 CO 3 To a mixture of (700 mg,5.07 mmol) and NaI (400 mg,2.67 mmol) in DMF (5 mL) was added 1-bromo-2-methoxyethane (230 mg,1.65 mmol). The resulting mixture was stirred at 50 ℃ overnight. After cooling to room temperature, the reaction mixture was taken up with H 2 O (30 mL) was quenched and extracted with DCM (30 mL. Times.3). The combined organic layers were washed with brine (30 mL. Times.3), and dried over Na 2 SO 4 Dried, filtered and concentrated to give a crude residue. The residue was purified by FCC (DCM/meoh=10:1) to provide N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4) as a yellow oil]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy benzamide (compound 68) (250 mg,48% yield).
First, N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4) ]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide (compound 68) (960 mg, combined from several batches obtained by method B) was purified by SFC using DAICEL CHIRALPAKIG (column: 250X 30mm 10um; mobile phase: a: supercritical CO 2 And B: etOH (0.1% ammonia), a: b=40:60, at 60 mL/min) and by preparative HPLC using Boston Prime (column: 150X 30mm 5um, mobile phase A: h 2 O(10mM NH 4 HCO 3 ) Mobile phase B: ACN, flow rate: 25mL/min, gradient conditions B/A from 55% to 85%) to afford the title compound (270 mg) as a colourless oil.
1 H NMR (400 MHz, methanol-d) 4 ):δ＝8.40(s,1H),7.47-7.32(m,1H),7.30-7.10(m,2H),4.24-4.01(m,2H),3.89-3.60(m,3H),3.48(br s,3H),2.63-2.51(m,2H),2.43-2.32(m,2H),2.29-2.07(m,6H),1.86-1.72(m,1H),1.62-1.44(m,2H),1.39-1.02(m,10H),0.99-0.66 (m, 9H). Some protons are hidden by solvent peaks and are not reported.
LCMS (ESI) (method 2): R t =1.965 min, m/z found 600.3[ m+h ]] + 。
SFC (method 11) R t ＝4.904min。
Example 3 Synthesis-preparation of N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide (Compound A) Process C
Intermediate 227- (R) - (1- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl) -3-methyl) Preparation of t-butyl-2-yl) carbamate
A solution of Boc-L-valine (44.9 kg), 2-dimethyl-1, 3-dioxane-4, 6-dione (32.9 kg) and DMAP (35.5 kg) in DCM (607 kg) pre-cooled at-10℃to 0℃was added to a solution of DCM (613 kg) in DMAP (55.5 kg) over 3 hours and aged at-10℃to 0℃for 16 hours. 10% aqueous citric acid (449 kg) was added while maintaining the temperature below 10 ℃. The resulting slurry was aged at 0 ℃ to 10 ℃ for 2 hours, and then filtered. The filter cake was washed with DCM (91 kg). The filtrate was separated, and the organic layer was washed with 10% aqueous citric acid (twice, 450 kg) and 10% aqueous nacl (449 kg). Acetic acid (75.0 kg) was added to the organic phase (1200 kg) while maintaining the temperature between-10 ℃ and 0 ℃. Sodium borohydride (18.0 kg) was added in portions over 5 hours while maintaining the temperature in the range of-10 ℃ to 0 ℃, and the resulting mixture was then aged at-10 ℃ to 0 ℃ for an additional 16 hours. The mixture was warmed to 15 ℃ to 25 ℃ and aged for 2 hours. The mixture was then washed with 14% aqueous NaCl (450 kg), followed by a second wash with 14% aqueous NaCl (432 kg) and finally with water (444 kg). The organic phase was concentrated to 2-4 volumes under reduced pressure. Isopropanol (143 kg) was added to the residue and concentrated under reduced pressure to 4-5 volumes. After cooling to-10 ℃ to 0 ℃ and aging for 8 hours, the resulting slurry was filtered, washed with IPA (38 kg) and dried to provide the title intermediate as a white solid (46.7 kg,69% yield).
Preparation of intermediate 228- (R) -2-isopropyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester
A solution of tert-butyl (R) - (1- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl) -3-methylbutan-2-yl) carbamate (intermediate 227) (46.7 kg) in toluene (333 kg) was heated to reflux and aged for 4 hours. The mixture was cooled to ambient temperature, filtered and washed with toluene (20 kg). The combined filtrates were concentrated to dryness under reduced pressure to afford the desired compound as an oil (31.05 kg,96% yield), which was used without further purification.
Preparation of intermediate 229- (5R) -2-hydroxy-5-isopropyl pyrrolidine-1-carboxylic acid tert-butyl ester
A solution of (R) -2-isopropyl-5-oxopyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 228) (30.9 kg) in 2-MeTHF (26.7 kg) was cooled to-5℃to 5 ℃. LiBH addition over 3 hours 4 A solution in 2-MeTHF (1M, 45.2kg,54.4 mol) was added and the mixture was aged for 4 hours. Cold 5% nahco was added over 3 hours at-5 ℃ to 5 °c 3 Aqueous solution (163 kg) and further aged for 2 hours. The mixture was warmed to ambient temperature and aged for an additional 2 hours. The aqueous layer was separated and the organic layer was washed with 10% aqueous NaCl solution (170 kg) and water (155 kg). During the water wash, an emulsion was formed and solid NaCl (3.1 kg) was added to effect separation. After removal of the aqueous layer, the organic layer was concentrated to dryness under reduced pressure to provide the desired compound as oil (28.5 kg,91% yield), which was used without further purification.
Intermediate 230- (R) - (6- (. About.2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl carbamic acid tert-butyl ester Preparation of butyl esters
A solution of (5R) -2-hydroxy-5-isopropyl-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 229) (28.55 kg) in DCM (344 kg) was treated with 2-methoxy-N-methylethyl-1-amine (12.3 kg,138.0 mol) at 15℃to 25℃and the resulting mixture was aged for 1 hour. Sodium triacetoxyborohydride (40.12 kg) was added in portions over 5 hours while maintaining the temperature between 15 ℃ and 25 ℃ and the resulting mixture was aged for 48 hours. The reaction mixture was quenched by adding 8% aqueous naoh (184 kg) over 2 hours while maintaining the temperature between 15 ℃ and 25 ℃ and the mixture was aged for an additional 2 hours. The aqueous layer was separated and the organic layer was washed with water (169 kg). The organic layer was then concentrated to dryness under reduced pressure to afford the title intermediate as an oil (33.26 kg,88% yield), which was used without further purification.
1 1 Preparation of intermediate 231- (R) -N- (2-methoxyethyl) -N, 5-dimethylhexane-1, 4-diamine, dihydrochloride Preparation method
To a solution of 4 moles of HCl in isopropanol (84.80 kg) was added a solution of tert-butyl (R) - (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) carbamate (intermediate 230) (32.38 kg) in isopropanol (25.6 kg) over 3 hours at ambient temperature and the mixture was aged at ambient temperature for an additional 19 hours. Methyl tert-butyl ether (95.25 kg) was then added over 1 hour and the mixture was aged for 2.5 hours. The resulting slurry was filtered and washed with MTBE (53 kg). The filter cake was dried to afford the title compound as a white solid (23.92 kg,81% yield).
Intermediate 232-1-benzyl-3Preparation of ethyl- (chloromethyl) pyrrolidine-3-carboxylate
To a solution of DIPEA (952 g,1.1 eq.) in THF (6L) cooled to-35 ℃ to-25 ℃ was added n-BuLi (2.33 kg,2.5m in hexane, 1.0 eq.) while maintaining the temperature below-25 ℃. The resulting mixture was aged at-35 ℃ to-25 ℃ for a further 30 minutes and then cooled to a temperature between-78 ℃ and-60 ℃. A solution of ethyl 1-benzyl-pyrrolidine-3-carboxylate (2 kg,1.0 eq) in THF (2L) was added at-78deg.C to-60deg.C and stirred for an additional 30 min. Chloroiodomethane (1.81 kg,1.2 eq.) was then charged at-78 ℃ to-60 ℃. The reaction mixture was aged at-60 ℃ to-40 ℃ for 2 hours. The reaction mixture was added to aqueous citric acid at a temperature between 0℃and 10℃to obtain a mixture (660 g at 6L H) 2 O), and the resulting mixture is aged at 20 ℃ to 30 ℃ for an additional 20 minutes. After separation of the layers, the aqueous layer was extracted with EtOAc (6L) and the combined organic layers were washed with brine (6L) and then warmed to 50 ℃ to 60 ℃. Oxalic acid (2.22 kg) was charged at 50℃to 60 ℃. The resulting mixture was stirred at 50 ℃ to 60 ℃ for 3 hours, then cooled to 20 ℃ to 30 ℃ and aged overnight. The resulting solid was filtered and the filter cake was washed with ethyl acetate (2L). Adding the wet cake to toluene (4L), H 2 O (8L) and K 3 PO 4 (1.5 eq.) and the resulting mixture was aged at 20℃to 30℃for 20 minutes. After separating the layers, the aqueous layer was extracted with toluene (2L). The organic layers were combined and washed twice with water (2L). The organic phase was concentrated under reduced pressure to provide 4.2kg of the desired compound as a toluene solution (by measurement, 46% by weight, yield 80% by measurement).
Preparation of intermediate 233-1-benzyl-3- (chloromethyl) pyrrolidine-3-carbaldehyde
The reaction carried out in a flow chemistry system: a solution of ethyl 1-benzyl-3- (chloromethyl) pyrrolidine-3-carboxylate (intermediate 232) (4.4 kg) in toluene (26L) was pumped at 26.7mL/min and cooled to-60 ℃. After cooling, it was then mixed with a cooling solution of DIBAL-H (28.1 mol) in toluene (28L) at-60℃at a pumping rate of 32.1mL/min. The mixture was passed through a Perfluoroalkoxy (PFA) coil reactor (total flow rate 58.8mL/min, residence time 5 seconds) at-60 ℃. The resulting mixture was mixed with cooled MeOH (-60 ℃) pumped at a rate of 15.2 mL/min. The mixed solution was pumped at-60 ℃ to another PFA coil reactor (total flow rate 74mL/min, residence time 5 seconds). The resulting mixture was collected into a receiver containing 20% by weight of aqueous Rochelle salt (20V). The layers were separated and the organic phase was washed twice with water (2X 44L). The organic phase was combined with another 3.0kg batch prepared in a similar manner and concentrated under reduced pressure to provide 20.8kg of a toluene solution of the desired compound (25.5 wt% as determined by HPLC, giving a determination yield of 85%) which was used without further purification.
1 H NMR (300 MHz, chloroform-d): delta 9.62 (s, 1H), 7.39-7.20 (m, 5H), 3.83-3.57 (m, 4H), 2.96 (d, J=10.2 Hz, 1H), 2.80-2.55 (m, 3H), 2.17 (ddd, J=13.9, 7.9,6.1Hz, 1H), 1.83 (ddd, J=13.4, 7.8,5.5Hz, 1H).
Intermediate 234- (R) -4- (6-benzyl-2, 6-diazaspiro [3.4 ]]Oct-2-yl) -N- (2-methoxyethyl) -N, preparation of 5-dimethylhex-1-amine
At 20℃to 30℃with toluene (30L) and (R) -N 1 - (2-methoxyethyl) -N 1 To a solution of 1-benzyl-3- (chloromethyl) pyrrolidine-3-carbaldehyde (intermediate 233) diluted with 5-dimethylhexane-1, 4-diamine, dihydrochloride (intermediate 231) (3.47 kg) in toluene (3.0 kg,10 wt%) was added triethylamine (2.55 kg,25.2 mol). The resulting mixture was aged at 20℃to 30℃for 2 hours.Sodium triacetoxyborohydride (9.0 kg) was then charged at 20℃to 30℃and the mixture was aged for 12 hours. The reaction mixture was cooled to 5 ℃ to 15 ℃,25 wt% aqueous NaOH (25L, about 16.75 eq.) was added, maintaining the temperature below 35 ℃. The resulting mixture was aged at 20 ℃ to 30 ℃ for 25 minutes and the layers were separated. The organic layer was washed with 15 wt% aqueous NaCl solution (10L) and the layers were separated again and water (18L) was charged into the organic phase. The pH of the aqueous phase was adjusted to 6-7 with 4M HCl aqueous solution while maintaining the internal temperature below 35 ℃. The organic phase is then discarded and the aqueous phase is separated and taken up with K 2 HPO 4 Alkalizing to pH 8-9.
The resulting mixture was warmed to 50 ℃ to 55 ℃ and aged for 3 hours. The reaction mixture was then cooled to ambient temperature and combined with two further batches (2.4kg+3.0kg). The combined streams were washed three times with methyl tert-butyl ether (3X 40L). To the resulting aqueous layer was added additional methyl tert-butyl ether (83L) and the aqueous phase was basified to pH 9-10 using 8 wt% NaOH aqueous solution while maintaining the temperature between 15 ℃ and 35 ℃. The aqueous layer was separated and the organic layer was washed three times with water (3X 30L). The organic layer was then concentrated to about 3 volumes under reduced pressure, then washed three times with methanol (3×30L) and concentrated to dryness to afford the desired intermediate (12.4 kg,90% isolated yield) as a pale yellow oil, which was used without further purification.
Preparation of intermediate 234a (citrate salt of intermediate 234)
EtOH (80 ml) and intermediate 234 (20 g) were added to a round bottom flask. Next, a solution of 0.5M citric acid in EtOH (100 ml;1 eq.) was added to the mixture in the round bottom flask at room temperature. Subsequently, the mixture was evaporated to dryness (Rotavap, 40 ℃). Acetonitrile (200 ml) was added to the residue and the mixture was evaporated to dryness (Rotavap, 40 ℃). Acetonitrile (100 ml) was added to the residue and stirred at room temperature on a magnetic hotplate overnight. Finally, intermediate 234a was filtered off and dried at room temperature.
Preparation of crystalline form of citrate salt of intermediate 234 (intermediate 234 b)
Intermediate 234a (3.72 g) was added to acetonitrile (20 ml) at room temperature and the mixture was stirred. The mixture was heated to 60 ℃ until the reaction mixture became homogeneous (about 10 minutes). The mixture was then cooled to 50 ℃ at a rate of 0.5 ℃/min. Then seed crystals (19 mg intermediate 234a;0.5 w/w%) were added and the mixture was aged during 3 hours 30 minutes while stirring. The mixture was then non-linearly cooled to 20 ℃ over 8 hours at an index of 2, 3. The resulting mixture was stirred overnight and the product was filtered off and dried (overnight at room temperature in a fume hood). After isolation, intermediate 234b (2.75 g; yield 73.9%) was obtained as a crystalline form of citrate salt of intermediate 234. The ratio of intermediate/citric acid obtained was 3/2 (NMR).
The nonlinear cooling mentioned above is performed according to the following formula:
a new linear ramp is started every 30 seconds during a defined cooling duration. The ramp is calculated according to the following formula:
T setting up : setting value of each new slope
T Start value : temperature of mixture measured at the beginning of the cooling trajectory
T Final value : final value of definition of cooling trace
t Action : actual time from start of cooling
Duration of time: defined duration of cooling
n: index number
1 H NMR(400MHz,MeOH-d 4 )δppm 0.91(3H,d,J＝6.88Hz)0.98(3H,d,J＝6.88Hz)1.46-1.57(2H,m)1.67-1.87(2H,m)1.94-2.03(1H,m)2.20-2.29(2H,m)2.62-2.69(2H,m)2.72-2.77(4H,m)2.77-2.82(2H,m)2.90(2H,t,J＝7.32Hz)2.95-3.02(2H,m)3.07-3.16(2H,m)3.16-3.22(2H,m)3.37(3H,s)3.68-3.72(2H,m)3.83-3.89(2H,m)3.90-3.92(2H,m)3.94-4.06(2H,m)7.32-7.43(5H,m)。
Intermediate 224- (R) -N- (2-methoxyethyl) -N, 5-dimethyl-4- (2, 6-diazaspiro [3.4]]Octyl-2- Preparation of base) hex-1-amines
Methanesulfonic acid (MSA) (11 kg), (R) -4- (6-benzyl-2, 6-diazaspiro [3.4] oct-2-yl-N- (2-methoxyethyl) -N, 5-dimethylhex-1-amine (intermediate 234) (10 kg) and EtOH (250L) were added to palladium hydroxide on carbon (1.2 kg) in EtOH (1.47 kg) cooled to-5 ℃ and stirred under a hydrogen atmosphere (0.27 MPa to 0.40 MPa) for 16 hours to 20 hours the mixture was filtered through celite (20 kg) and washed with EtOH (24L) the filtrate was concentrated to 2 to 3 volumes under reduced pressure (< 40 ℃ C.) then washed twice with 2-MeTHF (73 kg and 47 kg) to give a 2 to 3 volumes of solution after dilution with 2-MeTHF (65 kg), 10% aqueous sodium sulfate solution (30 kg) was added and the mixture was cooled to 35 ℃ C. And cooled to 0.27MPa to 0.40MPa for 16 hours to 20 hours, and then concentrated to 50g of aqueous solution was concentrated to 50 to 30 minutes (< 30 kg) with reduced pressure (< 40 ℃ C.) and concentrated to 3 volumes with 2 to 50 kg) of aqueous solution was added to 10% aqueous solution (30 kg) cooled to 10 ℃ C. <40 ℃ C.) (2 to 60 kg) after cooling down to 4), dried over 4A molecular sieve (25 kg) and washed with 2-MeTHF (30 kg). The final solution was concentrated to provide the desired compound (6.7 kg) as an oil, with a measured purity of 90.1% and a corrected yield of 79%.
Intermediate 225- (R) -4- (6- (3, 6-dichloro-1, 2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4]Octyl-2- Preparation of yl) -N- (2-methoxyethyl) -N, 5-dimethylhex-1-amine
To (R) -N- (2-methoxyethyl) -N, 5-dimethyl-4- (2, 6-diazaspiro [ 3.4)]To oct-2-yl) hex-1-amine (intermediate 224) (100 g) were added 2-MeTHF (430 g) and TEA (68 g), and the mixture was cooled to-50℃to-40 ℃. 3,5, 6-trichloro-1, 2, 4-triazine (62 g) in 2-MeTHF (172 g) was added and the mixture stirred for 1 to 3 hours. The resulting mixture was warmed to-20℃to-10℃and 7% NaHCO was added 3 The aqueous solution, the mixture was warmed to 20 ℃ to 30 ℃ and stirred for 30 minutes to 60 minutes. The aqueous layer was removed and the organic layer was taken up with 10% Na 2 SO 4 (500g) And (5) washing. Passing the organic layer throughThe molecular sieve (220 g) was dried and washed with 2-MeTHF (180 g). The title intermediate was provided in 90% assay yield as a 14.8 wt% solution in 2-MeTHF.
Compound 393- (R) -2- ((3-chloro-5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-) Radical) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl-oxy) -N-ethyl-5-fluoro-N-isopropyl-benzyl Amides and their use
Synthesis method A of compound 393：
N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (intermediate 28) (1.10 g,4.88 mmol), (R) -4- (6- (3, 6-dichloro-1, 2, 4-triazin-5-yl) -2, 6-diazaspiro [ 3.4) ]A mixture of oct-2-yl) -N- (2-methoxyethyl) -N, 5-dimethylhex-1-amine (intermediate 225) (1.70 g,3.82 mmol) and DBU (750 mg,4.93 mmol) in dry THF (15 mL) was stirred at 40℃for 8 hours. After cooling to room temperatureAfter concentrating the mixture under reduced pressure, the resulting residue was diluted with DCM (60 mL) and taken up in H 2 O (20 mL. Times.3) was washed. The organic layer was treated with anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product which was purified by FCC (MeOH/dcm=0% to 10%) to give a yellow oil (1.40 g) which was purified by SFC over DAICEL CHIRALPAK AD (column: 250×50mm,10um; mobile phase: a: supercritical CO 2 And B: etOH (0.1% ammonia), a: b=50:50, at 70mL/min; column temperature: 38 ℃; nozzle pressure: 100 bar; nozzle temperature: 60 ℃; evaporator temperature: 20 ℃; potentiometer (Trimmer) temperature: 25 ℃; wavelength: 220 nm) to afford the title compound (1.0 g).
Synthesis method A of compound 393：
At 20 ℃ to 30 ℃, to (R) -4- (6- (3, 6-dichloro-1, 2, 4-triazin-5-yl) -2, 6-diazaspiro [3.4 ]]To a solution of oct-2-yl) -N- (2-methoxyethyl) -N, 5-dimethylhex-1-amine (intermediate 225) in 2-MeTHF-thf (676 g of a 14.8 wt% solution in 2-MeTHF-thf, corrected 100g of intermediate 225) and N-ethyl-5-fluoro-2-hydroxy-N-isopropylbenzamide (intermediate 28) (50.6 g) in 2-MeTHF-thf (40 g) was added tetramethyl guanidine (31 g), and the mixture was stirred for 40 to 48 hours. Addition of 7% NaHCO 3 Aqueous solution (500 g) and the mixture was stirred for 30 to 60 minutes. The aqueous layer was removed and the organic layer was washed twice with 4% aqueous NaOH (2X 500 g) and with 10% Na 2 SO 4 The aqueous solution (500 g) was washed once. Concentrating the organic layer under reduced pressure<40 ℃) to 2.2-3.0 volumes and rinsed three times with MeOH (1X 790g and 2X 395 g) until both 2-MeTHF and water content are ∈1.0%, to provide the desired compound in 86% measured yield (as a 60.1% by weight solution in methanol).
Compound A- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triOxazin-6-yl) oxy) benzamide
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(R-2- ((3-chloro-5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4)]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) -N-ethyl-5-fluoro-N-isopropylbenzamide (compound 393) (163.93 g of a 60.1 wt% solution in MeOH, corrected 100g of compound 393), palladium on carbon (10 g) and MeOH (316 g) in methanol were stirred at 20 ℃ to 30 ℃ under a hydrogen atmosphere (0.20 Mpa to 0.30 Mpa) for 18 hours. The mixture was filtered through celite (75 g) and the filter cake was washed with MeOH (158 g). The filtrate was concentrated under reduced pressure (.ltoreq.40℃) to about 3 volumes, then rinsed with isopropyl acetate (IPAc, 870 g) and concentrated to 3 volumes. The mixture was then diluted with IPAc (696 g) and 20% Na was added 2 CO 3 Aqueous solution (500 g). The mixture was stirred for 30 to 60 minutes. The aqueous layer was removed. The organic layer was washed with water (500 g) and then dried<Concentrated to about 3 volumes at 45 ℃ under reduced pressure. The title intermediate was provided in about 90% assay yield as a 48.1 wt% solution in IPAc.
Example 4- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide grass Synthesis of acid salt (Compound A3)
Compound A3
To a solution of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide (compound A) (270 mg,0.450 mmol) in 20mL of ACN (20 mL) was added oxalic acid (81.0 mg,0.900 mmol). After the addition, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated, the residue redissolved in ACN and deionized water, and lyophilized to provide the title compound (350 mg) as a white solid.
1 H NMR (400 MHz, methanol-d) 4 ):δ＝8.48(s,1H),7.52-7.11(m,3H),4.54-3.64(m,12H),3.40-3.34(m,5H),3.23-3.13(m,2H),2.90(s,3H),2.54-2.27(m,2H),2.19-2.03(m,1H),1.97-1.77(m,2H),1.75-1.50(m,2H),1.35-0.65(m,17H)。
1 H NMR(400MHz,DMSO-d 6 ):δ＝8.51(s,1H),7.51-7.29(m,3H),4.29-3.34(m,12H),3.23-2.84(m,7H),2.70(s,3H),2.35-2.09(m,2H),2.05-1.85(m,1H),1.81-1.58(m,2H),1.56-1.33(m,2H),1.18-0.60(m,17H)。
LCMS (ESI) (method 2): r is R t =1.969 min, m/z found 600.4[ m+h ]] + 。
EXAMPLE 5 Synthesis of Compound A1
To a solution of compound a in IPAc (360 g) (207.90 g of 48 wt% solution in IPAc, 100g of active compound a) was added EtOH (63 g) at 20 ℃ to 25 ℃. The solution was then treated with concentrated HCl (32.9 g) in EtOH (49.5 g) over about 15 minutes. The mixture was seeded with crystalline compound A1 seed (2 g,2% seed loading) and then aged for 18 hours. IPAc (870 g) was slowly added over 4 hours at a temperature between 20℃and 25℃and the slurry was stirred for an additional 18 hours. After cooling to about 5 ℃, the product was filtered, washed with IPAc (522 g) and dried in vacuo at 20 ℃ -30 ℃ to afford weakly crystalline compound A1 (91.0% yield, 115.4 g) as a white solid. ( And (3) injection: the small amount of seed material used in the reaction is obtained on a small scale by a similar reaction scheme. )
And (5) recrystallizing: a solution of weakly crystalline compound A1 (100 g), etOH (166 g), purified water (21.5 g) and IPAc (178 g) was stirred at 20℃to 30℃for 0.5 h-2 h to give a clear solution. Additional IPAc (522 g) was added dropwise over 1-2 hours, and the mixture was then seeded with crystalline compound A1 seed (2 g,2% seed load). The mixture was then aged for 18-20 hours, IPAc (348 g) was slowly added over 12 hours at a temperature between 20℃and 30℃and the slurry was stirred for an additional 55-60 hours. The product was filtered, washed with IPAc (158 g) and dried in vacuo at 20℃to 30℃to afford compound A1 as a white solid (85% yield, 85.0g, net).
1 HNMR(DMSO-d 6 ,400MHz):δ＝11.60(1H,br),10.8(1H,br),8.52(1H,s),7.36(3H,m),3.97-4.20(7H,m),3.64-3.71(4H,m),3.47(7H,m),3.25(2H,m),3.05(3H,m),2.73(3H,s),2.10-2.45(1H,m),1.99(1H,m),1.78(2H,m),1.55(2H,m),0.83-1.12(12H,m),0.70(2H,m)。
LCMS (method 7): R t =0.669 min, m/z found 600.5[ m+h ]] + 。
Example 6- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis Synthesis of form A of benzenesulfonate hydrate (Compound A4) (equivalent amount of water not identified)
Compound A4
43.06g of benzenesulfonic acid (2 equivalents relative to the free base compound A) was added to 840ml of acetone/water 95/5 v/v mixture and dissolved. 192.8g of IPAc solution of Compound A (containing 80g of API) was added. The material was dissolved to give a clear solution. 80ml of IPAc was added and the temperature was adjusted to 25 ℃. 2% seed crystals were added and the mixture was stirred at 25 ℃ for 1 hour. Then 28.8V (2312 ml) IPAc was added over a period of 8 hours. Thereafter, the suspension was stirred at 25 ℃ for 18 hours. The suspension was filtered and washed with 320ml of a mixture of acetone/water/IPAc 23.75/1.75/75 v/v/v. 122.91g of form A bis-benzenesulfonate hydrate (undetermined equivalent amount of water) were obtained.
Those skilled in the art will appreciate that the small amount of initial seed material used in the above reaction can be obtained on a small scale without seeding and awaiting spontaneous nucleation via a similar reaction scheme.
Initial seeds of benzenesulfonate were also obtained during the salt screening experiments. In these experiments, 100mg of the free base was weighed into a 2mL vial, and 200 μl of ethyl acetate or acetone was then added to dissolve the free base. 1 equivalent of counter ion (benzenesulfonic acid) was added to the sample, and the sample was stirred at 25 ℃ for 3 days. The obtained suspension was centrifuged and an initial seed was produced.
The appropriate amount of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [ 3.4)]Crystalline form a of oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate hydrate was dissolved in deuterated DMSO and 1D was recorded 1 H NMR spectrum.
Samples in deuterated DMSO were collected at 300K for a 1-dimensional proton experiment using a Bruker AVANCE NEO-600MHz NMR spectrometer equipped with a Bruker 5mm PA BBO 600S3 BB-H-D-05Z-GRD high resolution probe and running TOPSIN 4.0 software.
1 H NMR(600MHz,DMSO-d 6 )δppm 0.69(br s,2H)0.82-0.98(m,9H)1.07(brs,4H)1.31-1.46(m,1H)1.51(brd,J＝2.91Hz,1H)1.69(brd,J＝3.45Hz,2H)1.98(br s,1H)2.06-2.45(m,2H)2.77(br s,3H)2.87-3.19(m,3H)3.24(br s,1H)3.31(s,6H)3.64(br s,4H)3.71-4.59(m,7H)7.24-7.54(m,9H)7.61(br d,J＝7.27Hz,4H)8.45-8.60(m,1H)9.24(br s,1H)9.44-9.82(m,1H)。
Implement 7- (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl)) am-monia Phenyl) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4]Oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis Alternative synthesis of form a of the besylate hydrate (compound A4) (equivalent amount of water not identified)
A mixture of isopropanol/water 95/5 (24 ml) was charged into the flask and heated to 40 ℃. Benzenesulfonic acid (4.31) was addedg; 98%). Subsequently, 19.3g of a solution of compound a in IPAc (containing 8g of compound a) was added. An additional 16ml of IPAc was added. 2% seed crystals were added and the mixture was stirred at 40 ℃ for 1 hour. IPAc (115.2 ml) was then added dropwise over a period of 8 hours. The mixture was then cooled to 0 ℃ for 15 hours. The suspension was filtered and the wet cake was purified using (IPA/H 2 O95/5)/IPAc 1/6 (32 ml) was washed. The wet cake was dried at 25 ℃ for 16 hours to obtain 11.44g of crystal form a bis-benzenesulfonate hydrate (equivalent water not determined).
Crystal form A
Crystalline form a of (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate hydrate may be characterized by an X-ray powder diffraction pattern.
X-ray powder diffraction (XRPD) analysis was performed on a PANalytical Empyrean diffractometer. The instrument is equipped with a Cu-kαx-ray tube using the iCore and dCore tuning optics for the incident and diffracted beams, respectively. The compound was loaded into the cavity of a 16mm sample holder using a reverse loading technique.
Samples were run on XRPD using the following method:
tube: cu: K-Alpha
The generator comprises: voltage: 45kV; current flow: 40mA
Geometry: bragg-Brentano
Scanning mode: continuous scanning
Scanning range: 3 to 35 DEG
Step size: 0.0131 degree
Counting time: 30s
Rotation time of the rotator: 1 second
Incident beam path (iCore)
Program divergence slit: automatic machine
Irradiation length: 10mm of
A cable pull slit: 0.03rad
Mask 1:14mm of
Mask 2:6mm of
Width: 7.7mm
Diffraction beam path (dCone)
Anti-scatter slit: automatic machine
Irradiation length: 10mm of
A cable pull slit: 0.04rad
A detector: PIXcel3D-Medipix 31 x1
Those skilled in the art will recognize that the diffraction pattern and peak positions are typically substantially independent of the diffractometer used and whether a particular calibration method is used. Typically, peak positions may differ by about + -0.2 deg. 2 theta or less. The intensity (and relative intensity) of each particular diffraction peak may also vary as a function of various factors, including, but not limited to, particle size, orientation, sample purity, and the like.
The X-ray powder diffraction pattern contains peaks at 5.4, 7.2, 11.1, 11.9 and 21.7 °2Θ ± 0.2 °2Θ. The X-ray powder diffraction pattern may further comprise at least one peak selected from the group consisting of: 13.7, 14.5, 14.7, 15.0, 16.5, 17.8, 19.0, 19.4, 20.1 °2θ±0.2 °2θ.
Form a may also be characterized by an X-ray powder diffraction pattern having four, five, six, seven, eight, nine, or more peaks selected from those identified in table 2.
Form a may also be characterized by an X-ray powder diffraction pattern comprising those peaks indicated in table 2, wherein the relative intensity of the peaks is greater than about 2%, preferably greater than about 5%, more preferably greater than about 10%, more preferably greater than about 15%. However, the skilled artisan will recognize that the relative intensities of peaks may vary between different samples and between different measurements on the same sample.
Form a may also be characterized by an X-ray powder diffraction pattern substantially as depicted in figure 1.
Table 2 provides a list of peaks and relative intensities of XPRD for (R) -N-ethyl-5-fluoro-N-isopropyl-2- ((5- (2- (6- ((2-methoxyethyl) (methyl) amino) -2-methylhex-3-yl) -2, 6-diazaspiro [3.4] oct-6-yl) -1,2, 4-triazin-6-yl) oxy) benzamide bis-benzenesulfonate hydrate BSA salt (FIG. 1).
Table 2-peak list and relative intensity of XRPD of form a
Compound A4 described herein is disclosed in PCT/CN2021/100466 (filed 6/17 of 2021), which is incorporated herein by reference in its entirety for all purposes.
Analysis method
Analytical information for the above compounds or in the tables below was generated by using the analytical methods described below.
NMR method
Some NMR experiments were performed at ambient temperature (298.6K) using a Bruker Avance III spectrometer using an internal deuterium lock and equipped with a BBO 400MHz s15mm probe with z gradient and operating at 400MHz for protons and 100MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz.
Some NMR experiments were performed at ambient temperature (298.6K) using a Varian 400-MR spectrometer using an internal deuterium lock and equipped with a Varian 400 nuc PFG probe with z-gradient and operating at 400MHz for protons and 100MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz.
Some NMR experiments were performed at ambient temperature (298.6K) using a Varian 400-VNMRS spectrometer using an internal deuterium lock and equipped with a Varian 400 ASW PFG probe with z gradient and operating at 400MHz for protons and 100MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz.
Some NMR experiments were performed at ambient temperature (298.6K) using a Bruker AVANCE III HD 300 spectrometer using an internal deuterium lock and equipped with a PA BBO 300S1 BBF-H-D-05Z 5mm probe with Z gradient and operating at 300MHz for protons and 75MHz for carbon. Chemical shift (d) is reported in parts per million (ppm). J values are expressed in Hz.
LCMS (liquid chromatography/Mass Spectrometry)
General procedure
High Performance Liquid Chromatography (HPLC) measurements were performed using LC pumps, diode Arrays (DAD) or UV detectors and columns as specified in the corresponding methods. HPLC details are provided in table 3 below. Additional detectors are included if necessary (see tables 3 and 4 below).
The flow from the column is sent to a Mass Spectrometer (MS) configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tuning parameters (e.g. scan range, residence time … …) so as to obtain ions of nominal monoisotopic Molecular Weight (MW) that allow the identification of the compound. Data acquisition is performed with appropriate software.
By experimental retention time (R t ) And ions to describe the compound. If not specified differently in the data table, the reported molecular ion corresponds to [ M+H ]] + (protonated molecule) and/or [ M-H] - (deprotonated molecule). In the case of compounds which are not directly ionizable, the type of adduct is specified (i.e. [ M+NH ] 4 ] + 、[M+HCOO] - Etc.). For molecules with multi-isotopic modes (Br, cl), the reported values are the values obtained for the lowest isotopic mass. All results were obtained with experimental uncertainties generally associated with the methods used.
Hereinafter, "SQD" refers to a single quadrupole detector, "room temperature" refers to room temperature, "BEH" refers to bridging ethyl siloxane/silica mixture, "HSS" refers to high intensity silica, "DAD" refers to a diode array detector.
TABLE 3 LCMS method code
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Flow rate is expressed in mL/min; column temperature (T) is in degrees celsius; run time in minutes
Analysis of SFC
General procedure for SFC method
SFC measurements were performed using an analytical Supercritical Fluid Chromatography (SFC) system, which was used to deliver carbon dioxide (CO) 2 ) And a binary pump of modifier, an autosampler, a cartridge, a diode array detector equipped with a high pressure flow cell up to 400 bar when standing. Analytical SFC details are provided in Table 4 below. If a Mass Spectrometer (MS) is configured, the flow from the column is sent to the MS. It is within the knowledge of the skilled person to set the tuning parameters (e.g. scan range, residence time … …) so as to obtain ions of nominal monoisotopic Molecular Weight (MW) that allow the identification of the compound. Data acquisition is performed with appropriate software.
TABLE 4 analytical SFC detail
Flow rate is expressed in mL/min; column temperature (T) is in degrees celsius; run time is measured in minutes and Back Pressure (BPR) is measured in bars or pounds force per square inch (psi). "ACN" means acetonitrile; "MeOH" means methanol; "EtOH" means ethanol; "DEA" means diethylamine. All other abbreviations used in table 4 above are as previously defined.
Pharmacological moiety
1) Multi-endocrine oncoproteins/MLL Homogeneous Time Resolved Fluorescence (HTRF) assay
40nL 200 Xtest compound in DMSO and 4. Mu.L of 2 Xterbium chelate labeled multiple endocrine oncoproteins in assay buffer (40 mM Tris-HCl, pH 7.5, 50mM NaCl, 1mM DTT (dithiothreitol) and 0.05% Pluronic F-127) were added to untreated white 384-well microtiter plates (see below for preparation). After incubation of the test compound and terbium chelate labeled multiple endocrine oncoproteins for 30 min at ambient temperature, 4 μl of 2XFITC-MBM1 peptide (FITC- β -alanine-SARWRFPARPGT-NH in assay buffer was added 2 ) ("FITC" means fluorescein isothiocyanate), the microtiter plates were centrifuged at 1000rpm for 1 minute and the assay mixtures were incubated at ambient temperature for 15 minutes. The relative amounts of the multiple endocrine oncoprotein FITC-MBM1 complex present in the assay mixture were determined at ambient temperature by: uniform time resolved fluorescence (HTRF) of terbium/FITC donor/acceptor fluorophore pairs was measured using an EnVision microplate reader (excitation 337 nm/terbium emission 490nm/FITC emission 520 nm). The degree of fluorescence resonance energy transfer (HTRF value) is expressed as the ratio of fluorescence emission intensities of FITC and terbium fluorophores (F em 520nm/F em 490 nm). The final concentrations of reagents in the binding assay were 200pM terbium chelate labeled multiple endocrine oncoprotein, 75nM FITC-MBM1 peptide, and 0.5% DMSO in the assay buffer. Dose-response titration of test compounds was performed using an 11-point, four-fold serial dilution scheme, typically starting at 10 μm.
Compound potency was determined by first calculating% inhibition at each compound concentration according to equation 1:
inhibition% = ((HC-LC) - (HTRF) Compounds of formula (I) -LC))/(HC-LC) 100 (equation 1)
Wherein LC and HC are HTRF values determined in the presence or absence of saturated concentrations of a compound competing with FITC-MBM1 for binding to multiple endocrine oncoproteins, and HTRF Compounds of formula (I) Is the HTRF value measured in the presence of the test compound. HC and LC HTRF values represent the average of at least 10 replicates per plate. For each test compound, the log of% inhibition values relative to test compound concentration and IC derived from fitting these data to equation 2 50 Value mapping:
inhibition% = bottom+ (Top-Bottom)/(1+10 ((log ic) 50 -log[cmpd]) H)) (equation 2)
Wherein Bottom and Top are the lower and upper asymptotes, respectively, of the dose-response curve, IC 50 Is the concentration of the compound that produces 50% inhibition of the signal, h is the Hill coefficient.
Preparation of terbium hole compound label of multiple endocrine oncoproteins: the multiple endocrine oncoproteins (amino acids 1-610-6xhis tag, 2.3mg/mL in 20mM Hepes (2- [4- (2-hydroxyethyl) -1-piperazinyl ] ethanesulfonic acid), 80mM NaCl, 5mM DTT (dithiothreitol) (pH 7.5) were labeled with terbium cryptates as follows. 200 μg of the multiple endocrine oncoprotein buffer was exchanged into 1x Hepes buffer. 6.67. Mu.M of the multiple endocrine oncoprotein was incubated with an 8-fold molar excess of NHS (N-hydroxysuccinimide) -terbium cryptate for 40 minutes at room temperature. Half of the labelled protein was purified from the free label by reaction on NAP5 column with elution buffer (0.1M Hepes (pH 7) +0.1% BSA (bovine serum albumin)). The other half was eluted with 0.1M Phosphate Buffered Saline (PBS) (pH 7). 400 μl of eluate was collected per portion, aliquoted and frozen at-80 ℃. The final concentrations of terbium-labeled multiple endocrine oncoproteins were 115 μg/mL in Hepes buffer and 85 μg/mL in PBS buffer, respectively.
Protein sequence of multiple endocrine oncoproteins (SEQ ID NO: 1):
MGLKAAQKTLFPLRSIDDVVRLFAAELGREEPDLVLLSLVLGFVEHFLAVNRVIPTNVPELTFQPSPAPDPPGGLTYFPVADLSIIAALYARFTAQIRGAVDLSLYPREGGVSSRELVKKVSDVIWNSLSRSYFKDRAHIQSLFSFITGTKLDSSGVAFAVVGACQALGLRDVHLALSEDHAWVVFGPNGEQTAEVTWHGKGNEDRRGQTVNAGVAERSWLYLKGSYMRCDRKMEVAFMVCAINPSIDLHTDSLELLQLQQKLLWLLYDLGHLERYPMALGNLADLEELEPTPGRPDPLTLYHKGIASAKTYYRDEHIYPYMYLAGYHCRNRNVREALQAWADTATVIQDYNYCREDEEIYKEFFEVANDVIPNLLKEAASLLEAGEERPGEQSQGTQSQGSALQDPECFAHLLRFYDGICKWEEGSPTPVLHVGWATFLVQSLGRFEGQVRQKVRIVSREAEAAEAEEPWGEEAREGRRRGPRRESKPEEPPPPKKPALDKGLGTGQGAVSGPPRKPPGTVAGTARGPEGGSTAQVPAPAASPPPEGPVLTFQSEKMKGMKELLVATKINSSAIKLQLTAQSQVQMKKQKVSTPSDYTLSFLKRQRKGLHHHHHH
2a) Proliferation assay
The antiproliferative effect of multiple endocrine oncoproteins/MLL proteins/protein interaction inhibitor test compounds was evaluated in human leukemia cell lines. The cell line MOLM-14 has MLL translocation and expresses the MLL fusion protein MLL-AF9 and the wild-type protein from the second allele, respectively. OCI-AML3 cells carrying mutations in the NPM1c gene were also tested. MLL rearranged cell lines (e.g., MOLM-14) and NPM1c mutated cell lines exhibit stem cell-like elevated HOXA/MEIS1 gene expression signatures. KO-52 was used as a control cell line containing two MLL (KMT 2A) wild-type alleles in order to exclude compounds exhibiting general cytotoxic effects.
MOLM-14 cells were cultured in RPMI-1640 (Sigma Aldrich) supplemented with 10% heat-inactivated fetal bovine serum (HyClone), 2mM L-glutamine (Sigma Aldrich) and 50 μg/ml gentamicin (Gibco). KO-52 and OCI-AML3 cell lines were propagated in alpha-MEM (Sigma Aldrich) supplemented with 20% heat-inactivated fetal bovine serum (HyClone), 2mM L-glutamine (Sigma Aldrich) and 50. Mu.g/ml gentamicin (Gibco). The cells were maintained at 30-250 tens of thousands of cells/ml during the culture and the number of passages did not exceed 20.
To evaluate the antiproliferative effect, 200 MOLM-14 cells, 200 OCI-AML3 cells, or 300 KO-52 cells were seeded in 200. Mu.l of medium/well in 96-well round bottom ultra low adhesion plates (Costar, catalog number 7007). Throughout the experiment, the number of cell inoculations was selected based on the growth curve to ensure linear growth. Test compounds were added at different concentrations and DMSO content was normalized to 0.3%. The cells were incubated at 37℃with 5% CO 2 Incubate for 8 days. Spheroid-like growth was measured in real time by live cell imaging (inticutezoom, essenbio,4x objective) with images taken on day 8. Fusion (%) was determined as a measure of spheroid size using an integrated analytical tool.
To determine the effect of the test compound over time, the fusion in each well was calculated as a measure of spheroid size. The highest dose of fusion of the reference compound was used as baseline for LC (low control) and the fusion of DMSO-treated cells was used as 0% cytotoxicity (high control, HC).
Absolute IC 50 The values were calculated as the percent change in fusion as follows:
lc=low control: cells treated with, for example, 1 μm of the cytotoxic agent staurosporine, or cells treated, for example, with high concentrations of an alternative reference compound;
HC = high control: average fusion (%) (DMSO-treated cells);
effect% = 100- (100 × (sample-LC)/(HC-LC)); and is also provided with
GraphPad Prism (7.00 edition) was used to calculate IC 50 . The dose response equation was used for the plot of% effect versus Log10 compound concentration, with variable slope and fixing the maximum to 100% and the minimum to 0%.
2b) MEIS1 mRNA expression assay
The compound-treated MEIS1 mRNA expression was checked by Quantigene Singleplex assay (Thermo Fisher Scientific). This technique allows direct quantification of mRNA targets using probes that hybridize to a defined target sequence of interest, and detection of signals using a multi-mode (Multimode) plate reader Envision (PerkinElmer). The MOLM-14 cell line was used for this experiment. Cells were seeded in 96-well plates at 3,750 cells/well in the presence of increasing concentrations of the compound. After 48 hours incubation with the compounds, the cells were lysed in lysis buffer and incubated for 45 minutes at 55 ℃. Cell lysates were mixed with human MEIS 1-specific capture probes or human RPL28 (ribosomal protein L28) -specific probes or blocking probes as normalization controls. The cell lysates were then transferred to custom assay hybridization plates (Thermo Fisher Scientific) and incubated at 55 ℃ for 18 to 22 hours. Subsequently, the plate is washed to remove unbound material, followed by sequential addition of pre-amplificate, amplificate and labeled probes. Signal (=gene count) was measured with a multimode plate reader Envision. Calculation of IC by dose response model using appropriate software 50 . For all non-housekeeping gene reactions, the counts corrected for background and relative expression were equal. For each sample, each test gene signal (background subtracted) Divided by normalized gene signal (RPL 28: background subtraction). Fold change was calculated by dividing the normalized value of the treated samples by the normalized value of the DMSO-treated samples. Fold change of each target gene was used to calculate IC 50 。
The results are summarized in table 5 below.
TABLE 5 biological data-HTRF, proliferation and MEIS1 mRNA expression assays
1/2 3) Mouse PK (in vivo T and oral bioavailability)
In vivo Pharmacokinetics (PK) were assessed in fasted male CD-1 mice (6-8 weeks old) following single intravenous (IV, 0.5mg/kg at 2.5ml/kg or 1.0 mg/kg) or oral (PO, 5mg/kg at 10ml solution/kg) administration in 20% (weight: volume) HP-beta-CD solution or test preparation formulated in pyrogen-free water.
Plasma and/or whole blood samples were collected from the dorsal metatarsal vein at the desired time points by continuous capillary microsampling (approximately 0.03 mL) using EDTA as anticoagulant. The concentration of compounds in plasma and blood samples was analyzed using the accepted LC-MS/MS method. Computer simulation analysis of the principal pharmacokinetic parameters was performed using WinNonlin (phoenix (tm), version 6.1) or similar software.
4) Metabolic stability in human/mouse liver microsomes
Experimental procedure
The objective of this study was to measure the in vitro metabolic stability of test compounds in human and mouse liver microsomes and to provide quantitative information about metabolic turnover (i.e., determination of apparent intrinsic clearance of test compounds).
Test articles were prepared at a stock concentration of 10mM in DMSO. To determine metabolic turnover, final working solutions were prepared by adding 2 μl of 10mM DMSO stock solution for test compounds or positive control compounds to 198 μl acetonitrile (100 μΜ final concentration).
Incubation was performed as follows: first, liver microsomes were thawed on ice, and a main solution containing liver microsomes in 100mM PBS (phosphate buffered saline) at pH 7.4 was prepared. Next, the liver microsome solution was added to the incubation plate, and 10mM NADPH (nicotinamide adenine dinucleotide phosphate) (MW: 833.4g/mol; rocheDiagnostics GmbH, germany. Dissolved in phosphate buffer (100 mmol/L, pH 7.4)) was added. The mixture was mixed for 10 seconds and preheated in an incubation plate for 10 minutes at 37 ℃. The metabolic reaction was initiated by adding 5 μl of 100 μΜ working solution for the test compound or positive control compound to the incubation plate (final test article concentration = 1 μΜ). The final reaction mixture should contain 1mM NADPH, 0.5mg/mL microsomal protein and 1. Mu.M test compound or positive control compound in 100mM PBS pH 7.4. The percentage of organic solvent in the incubation mixture was 1%, wherein DMSO was less than or equal to 0.02%.
The reaction was quenched by transferring 50 μl of the incubation mixture to a quenching plate containing 200 μl of cold methanol at selected time points. After sampling at all time points, the quenching plates were centrifuged at 4000rpm for 40 minutes to precipitate the protein. Transfer a total of 90. Mu.L of supernatant to an assay plate and transfer ultrapure H 2 O was added to each well for LC/MS/MS analysis. All incubations and analyses were repeated.
Data analysis
All calculations were performed using Microsoft Excel. The slope value k is determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus the incubation time curve. The results are summarized in table 6 below.
Determination of in vitro half-life from slope values (in vitro t 1/2 )：
In vitro t 1/2 ＝-(0.693/k)
The following equation is used to determine t in vitro 1/2 Conversion to intrinsic clearance in vitro (in minutes) (in vitro CL int In. Mu.L/min/mg protein):
TABLE 6 PK and metabolic stability in mice
"NA" means not analyzed
5) Pharmacodynamic (PD) Activity in subcutaneous (SC or SC) xenografts of MOLM-14 or OCI-AML3 cells Case with a table top
Test reagents and controls
Compound A3 was formulated in 20% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and prepared to a total volume of up to 0.2mL (10 mL/kg) per dose for 20g animals. Dosage was adjusted daily by body weight of the individual. For each study, working stock solutions of compound A3 were prepared once a week and stored at room temperature. Compound A3 was administered orally (PO) daily.
Measurement
The in vivo Pharmacodynamic (PD) activity of the compounds was evaluated in Subcutaneous (SC) xenografts of MOLM-14 cells or OCI-AML3 cells. Naked NMRI mice (Crl: NMRI-Foxn1 nu/-) with MOLM-14 or OCI-AML3 tumors were treated with 3 daily doses of vehicle or compound. Plasma samples were collected 23 hours after the 2 nd day of administration, 0.5 hours after the last administration and 16 hours after the last administration, and tumor samples were collected 16 hours after the last administration. To examine the effect of compounds on the expression of multiple endocrine oncoprotein-KMT 2A target genes (e.g., MEIS1, MEF2C, FLT 3), the QuantiGene Plex technology (Thermo Fisher Scientific) was used. Frozen tumors were homogenized and transferred to individual lysis substrate tubes in lysis buffer and incubated for 30 min at 55 ℃. Cell lysates were mixed with target-specific capture probes, luminex beads and blocking probes, transferred to custom assay hybridization plates (Thermo Fisher Scientific) and incubated at 54 ℃ for 18 to 22 hours. Subsequently, the plates were transferred to magnetic separation plates and washed to remove unbound material from the beads, followed by sequential hybridization of pre-amplicons, amplicons and labeled probes and subsequent streptavidin-phycoerythrin binding. The signal from the beads was measured with a Luminex FlexMap three-dimensional instrument. For all non-housekeeping gene reactions, the counts corrected for background and relative expression were equal. For each sample, each test gene signal (background subtracted) was divided by the normalized gene signal (RPL 19, RPL28, ATP6V1A: background subtracted). Fold change was calculated by dividing the normalized value of the treated samples by the normalized value of the DMSO-treated samples. The results are summarized in tables 7 and 8 below.
TABLE 7 selection of genes
Expression level (in% relative to vehicle) from MOLM-14 SC model (mean and standard deviation)
Compound A3 (mg/kg) MEIS1 FLT3 MEF2C
0 101.30±15.06 104.80±10.07 103.50±11.02
3 83.49±25.48 78.67±20.74 85.50±22.77
10 62.84±4.06 74.91±8.97 68.04±14.43
30 23.16±2.75 52.61±4.51 27.83±2.17
50 14.40±3.39 36.14±3.50 18.75±2.38
100 10.97±3.21 35.82±1.10 14.18±1.56
TABLE 8 selection of genes
Expression levels (in% relative to vehicle) from OCI-AML3 SC model (mean and standard deviation).
Compound A3 (mg/kg) MEIS1
0 100.30±8.53
3 87.90±39.75
10 48.81±15.30
30 32.66±3.71
50 23.83±1.34
100 16.76±1.92
Tables 7a and 8a show the median values based on repeated experiments with fresh tumor samples under optimized conditions.
Table 7 a-expression level of selected genes (in% relative to vehicle) from MOLM-14 SC model (median and standard Deviation of。
Compound A3 (mg/kg) MEIS1 FLT3 MEF2C
0 100.0±13.5 100.0±10.1 100.0±11.0
3 83.7±22.8 89.2±20.7 87.7±22.8
10 49.3±5.9 79.8±9.0 64.6±14.4
30 14.7±3.9 54.5±4.5 28.8±2.2
50 4.7±1.1 37.6±3.5 18.8±2.4
100 3.3±1.4 35.4±1.1 13.6±1.6
Table 8 a-expression level of selected genes from OCI-AML3 SC model (% relative to vehicle) (median and standard Deviation of。
Chemical combinationObject A3 (mg/kg) MEIS1
0 100.0±11.2
3 71.2±15.1
10 26.5±4.3
30 25.1±11.2
50 8.5±2.2
100 9.4±1.2
6) Efficacy study in MOLM-14 subcutaneous model
Test reagents and controls
Compound A3 was formulated in 20% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and prepared to a total volume of up to 0.2mL (10 mL/kg) per dose for 20g animals. Dosage was adjusted daily by body weight of the individual. For each study, working stock solutions of compound A3 were prepared once a week and stored at 25 ℃.
Animals
Female NMRI nude mice (MOLM-14 SC) are used when they are about 6 to 8 weeks old and weigh about 25 g. All animals can be adapted and recovered from any transport-related stress for a minimum of 7 days prior to experimental use. Autoclaved water and irradiated food were provided ad libitum and animals were kept in a 12 hour light and dark cycle. The cages, bedding and water bottles were autoclaved before use and replaced once a week. Further details are provided in table 9 below.
TABLE 9 tissue culture and cell injection reagents
DPBS (Dulbecce phosphate buffered saline)
Heat-inactivated fetal bovine serum
RPMI1640 medium
L-glutamine
Gentamicin
T175 culture bottle
Rolling bottle
Tumor model and cell culture method
Human AML MOLM-14 cells were subjected to 5% CO at 37deg.C 2 The culture was performed in the indicated complete medium (RPMI 1640+10% HI-FBS+2mM L-glutamine+50 ug/ml gentamicin). Cells were harvested while growing logarithmically and resuspended in cold (4 ℃) losv-park souvenir institute (Roswell Park Memorial Institute, RPMI) 1640 in serum-free medium.
Each mouse received 5 x 10 in 50% matrigel on the right flank using a 1cc syringe and 27 gauge needle 6 MOLM-14 cells were used in a total volume of 0.2mL.
Study design
Compound A3 was administered orally (PO) daily.
Day 0 is the day of tumor cell implantation and study initiation.
Mice bearing SCMOLM-14 tumors were randomized on day 16 post tumor implantation and allocated to treatment groups according to tumor volume (average about 130mm 3 The method comprises the steps of carrying out a first treatment on the surface of the n=10/group). Treatment with vehicle or compound A3 (at 30mg/kg and 100 mg/kg) was started on the same day, with oral administration for 21 days per day. Plasma was collected 1 hour, 2 hours, 4 hours, 8 hours and 23 hours (n=4-5/group/time point) after the last dose for PK (pharmacokinetic) analysis.
Animal monitoring
The SC tumor volume was measured 2 to 3 or more times per week for each animal throughout the study.
Calculation of
Tumor volumes were calculated using the formula:
tumor volume (mm) 3 )＝(D×d 2 2) wherein 'D' represents a larger diameter and 'D' represents a smaller diameter tumor, as determined by caliper measurements. Tumor volume data are graphically represented as mean tumor volume±sem.
Δtgi% is defined as the difference between the average tumor burden of the treated and control groups, calculated as Δtgi% = ([ (TV) c TVc 0 )(TV t TV t0 )]/(TV c TVc 0 ) X 100, where' TV) c 'is the average tumor burden of a given control group,' TVc 0 'mean initial tumor burden for a given control group,' TV t 'is the average tumor burden of the treatment group, and' TV t0 ' is the average initial tumor burden of the treatment group. TGI% is defined as the difference between them.
The average tumor volumes of the treatment and control groups were calculated as follows:
TGI％＝((TV c TV t )/TV c ) X 100, where' TV c 'mean tumor volume of control group, and' TV t ' is treatmentAverage tumor volume of treatment group. TGI > 60% is considered biologically significant according to the national cancer institute standard definition.
Tumor Regression (TR)% (which was quantified to reflect treatment-related reduction in tumor volume compared to baseline independent of control) was calculated as follows: TR% = (1-average (TV) t i/TV t0 i) X 100, where' TV) t i 'is tumor burden of individual animals in the treatment group, and' TV t0 i' is the initial tumor burden of the animal.
Data analysis
Tumor volumes were plotted using Prism software (GraphPad version 7 or 8). When 2/3 or more mice remained in each group, the statistical significance of most of the study was evaluated for the compound A3 treated group compared to the HP beta CD vehicle treated control on the last day of the study. When p.ltoreq.0.05, the difference between the groups was considered significant.
Statistical significance of animal tumor volumes was calculated using Linear Mixed Effect (LME) analysis in R software version 3.4.2 (application 4.0 version using Shiny developed inside Janssen's), with treatment and time as fixed effects and animals as random effects. If each longitudinal reaction trajectory is not linear, a logarithmic transformation is performed.
Information derived from this model was used to make pairwise treatment comparisons with the control group or between all treatment groups. The results are shown in fig. 2.
2+ 7) Human pluripotent stem cell derivatives at synchronized beating of test compounds determined using Ca fluorescence assay (CTCM human) Electrocardiographic physiological effects in cardiomyocytes (hSC-CM)
Protocol(s)
Compounds were tested in 96-well plates.
At the position ofOn or in the cardiomyocytes>Compounds were tested on cardiomyocyte 2 at 0.1 μm, 0.2 μm, 0.5 μm, 1 μm, 2.5 μm and 5 μm (n=4/dose).
Alternatively, mainly inCompounds were tested on cardiomyocyte 2 at 0.1 μm, 0.3 μm, 1 μm, 3 μm, 10 μm and 30 μm (n=4/dose).
Positive and negative controls
Vehicle control: dimethyl sulfoxide (DMSO). A solution of the compound in DMSO or a solvent thereof (final concentration 0.1% DMSO; n=8).
Preparation of test articles and controls
Test compounds were dissolved in DMSO at 1000-fold expected concentrations. Compound "master" was prepared containing 1000 times the final concentration of test compound and positive and negative controls. On experimental days, these stock solutions were diluted to 2-fold expected concentrations (in round bottom compound plates) with Tyrode (Sigma) supplemented with 10mM HEPES (Gibco). The final DMSO concentration in the test solutions and vehicle controls was 0.1%.
Cells
Obtaining hSC-CM from CDI (Ncarpia, germany)Cardiomyocytes). Cells were pre-plated and seeded in fibronectin coated 96-well plates at a density suitable for monolayer formation according to the instructions of the cell provider and in a stage incubator (37 ℃,5% co 2 ) Is maintained in culture.
Called asCardiomyocyte 2The secondary hSC-derived cardiomyocytes were purchased from FUJIFILM Cellular Dynamics (united states). After plating the cells on a plate to have a viable beating monolayer of hiPSC-derived cardiomyocytes, the experiment was performed with the test drug for 5 to 7 days. Pulsatile monolayers in 96-well plates are typically taken from 2 vials frozen +.>Cardiomyocyte 2 (. Apprxeq.500 ten thousand cells/vial) was plated on three 96-well plates (. Apprxeq.50K/well).
Before the experiment starts
At least one hour before the start of the experiment, normal cell culture medium was replaced with a Tyrode solution (see below) containing a calcium dye.
Cal520 dye (AAT Bioquest) was dissolved in 11ml of 10mM HEPES-supplemented Wash's solution and heated to 37℃prior to addition to the cells.
Mu.l of cell culture medium was removed from each well, replaced with 35. Mu.l of pre-warmed Cal520 dye solution, and the cell plates were incubated at 37℃C/5% CO 2 Incubate for 45 minutes under. The cells were incubated at 37℃for 5 minutes.
Experiment
Using Cal520 TM (AAT Bioquest) calcium fluorescent dye signaling to record spontaneous electrical activity. The dye integrates the total intracellular calcium activity throughout the well. A bottle of Cal520 dye (50. Mu.g, MW: 1103/mol) was dissolved with 50. Mu.l DMSO as a stock solution of 0.9 mM. To 10ml of the Taiwan solution was added 50. Mu.L of dye stock solution to give a dye concentration of 4.5. Mu.M. Then, 35. Mu.l of the dye solution was added to each well to give a final dye concentration of 1.58. Mu.M. Current dye protocols have recently been established for this CTCM human assay (IvanKopljar et al Journal of Pharmacological and toxicological methods 2018.91.91:80-86; lu et al Tox Sci 2019.170 (2): 345-356).
Fluorescent signal (Ca) 2+ Transient morphology) using a functional drug screening system (FDSS/μcell; hamamatsu, japan) and will then record using appropriate software (e.gNotocord) was analyzed off-line.
Cell plates were loaded into FDSS/μcell for test runs: measurement of Ca 2+ Transient for 4 minutes to check the synchronized pulsation of the myocytes at the center of each well. All 96 wells were measured simultaneously (sampling interval: 0.06s, short exposure time: 10ms; excitation wavelength 480nm; emission wavelength 540nm; FDSS/. Mu.cell warmed to 37 ℃). When all showed synchronized beats, 96-well plates were repeatedly measured 3 times (to verify synchronized beats in all 96 wells at baseline, wells that did not meet the preset criteria were excluded from the study and were not treated with compound):
t=0: control period (-5 min to-1 min) +compound addition, followed by 3 min.
T=30: measurement 29 min to 34 min after addition of compound
During the compound addition step, 100 μl of the corresponding dual concentrated test solution was simultaneously pipetted into each well.
The data was analyzed offline using appropriate software (e.g., notocord-Hem, version 4.3).
Measurement of Ca 2+ The following parameters of the transient morphology:
beat Rate (BR)
-Ca 2+ The amplitude (Amp) of the transient,
-CTD 90 : ca at 90% 2+ Transient duration (90% of time to reach the initial base value).
The presence of various 'arrhythmia-like' activities was also noted during the experimental period. These include:
an early post-depolarization' (EAD-like) event (defined as "extra small peak of the transient waveform after the initial peak of the transient"),
a 'ventricular tachycardia-like' (VT-like) event (defined as a very fast beat rate) or
Ventricular fibrillation-like' (VF-like) events (defined as "small amplitude, fast rate Ca with irregular and unmeasurable transient potentials 2+ Waveform')
Cell 'beating stopped' (no Ca was observed 2+ Transient).
If compound-induced calcium transient signal changes cannot be analyzed by software, these signals are identified as BQL (below the quality analysis level).
Data analysis
Data measured from the FDSS- μcell is replicated for offline analysis and analyzed and uploaded into SPEC-II (our operations management system) for further analysis. Variable values before and after administration of the compounds were collected and transferred to an Excel workbook.
All values (actual units and percent change from baseline) are expressed as median values (minimum and maximum). The changes observed in the compound group relative to the corresponding baseline values (in actual units) were compared to those in the solvent control group using the Wilcoxon-Mann-Whitney test. A two-tailed test with bunafini correction (Bonferroni correction) was performed for multiple adjustment. Since there were 10 treatment groups compared to the solvent group, a level of 0.05/10 (0.005) was considered to reflect a statistically significant difference from the solvent group. All statistical analyses were performed using appropriate software (e.g., R software version 3.5.2).
Quality control of hiPSC-CM in plates:
plates were eliminated if they did not meet the following criteria:
stabilized regular pulsations
Amplitude >500 relative units
-a pulse rate between 25 and 80 pulses per minute
-CTD between 300ms and 800ms 90 。
In this study, the hiPSC-CM in the plate met the criteria described above.
These parameters, in combination with the incidence of arrhythmia or beat arrest, are used to calculate potential risk levels using a weighted scoring method (based on Kopljar et al Stem Cell Reports 2018.11,1365-1377). By being based on CTD 90 This risk score for each concentration is calculated by adding weighting points to the varying Tolerance Interval (TI), beat rate and amplitude (ΔΔ%) and the incidence of beat stopping and early post-depolarization (EAD).Thus, for each concentration, one of four different hazard levels will result. This will be done after 30 minutes incubation with the compound. The risk level is:
no risk: within the level of the vehicle effect or small uncorrelated variations.
Low risk: related effects, but potentially with low risk of cardiac weakness (cardiac liabilities).
High risk: a relatively high risk of cardiac weakness.
Very high risk: very high risk due to arrhythmic Events (EAD).
The 'risk score' results provide identification of potential acute cardiac drug-induced effects at free drug equivalent (as no plasma protein is added to the well). The assessment of risk assessment was performed using a 'Scoring reference book' called ctcm_scoring_version 1 (Kopljar et al Stem Cell Reports 2018.11:1365-1377) and levels were indicated according to the following color schemes of table 10.
TABLE 10 color scheme for hazard verification legend
Green colour No worry about
Yellow colour Low worry
Red color High concern
Black color Very high concerns due to arrhythmic events
According to Ca measured in HiPSc-CM 2+ The test compounds were rated for risk score severity on the transient assay as listed above in the different colors and in the relevant tables.
Results
Using Cardiomyocyte 2 as cell line
Positive and negative controls: in this assay, both positive and negative controls have the expected pharmacological effect. The results are summarized in tables 11 and 12 below.
TABLE 11 Risk score for Compound A3
TABLE 12 Risk score for Compounds A1 and 11
For compound A1: effective dose of 30mg/kg was used in mouse xenograft model, CTCM human concentration and free C max The estimation will be performed as follows:
Marginal CTCM human 10. Mu.M and free Cmax >16 (mouse, human)
Marginal CTCM human 30 μm and free Cmax >45 (mouse, human).
Kr 8) Effect on Membrane Potassium Current I in hERG transfected cell lines
Scheme 1：
Abbreviations (abbreviations)
CHO chinese hamster ovary cell line
DMSO dimethyl sulfoxide
hERG human ether-a-go-go related gene
I Kr Fast active delay rectifier K + Electric current
Method
Experiments were performed using CHO cells stably expressing hERG potassium channels. Cells at 37℃and 5% CO 2 The culture was grown in a culture flask in Hans F12 medium supplemented with 10% heat-inactivated fetal bovine serum, hygromycin B (100. Mu.g/ml) and geneticin (100. Mu.g/ml). For use in an automated patch clamp system QPatch (Sophion), cells are harvested to obtain a single cell suspension.
Solution: the electrolyte contains (in mM) 145NaCl, 4KCl, 10 glucose, 10HEPES ((4- (2-hydroxyethyl) -1-piperazine ethane sulfonic acid), 2CaCl 2 And 1MgCl 2 (pH 7.4 with NaOH). The pipette solution contained (in mM) 120KCl, 10EGTA (ethylene glycol-bis (2-aminoethyl ether) -N, N, N ', N' -tetraacetic acid), 10HEPES, 5.374CaCl 2 And 1.75MgCl 2 (adjustment to pH 7.2 with KOH).
Patch clamp experiments were performed in voltage clamp mode and whole cell currents were recorded using automated patch clamp measurements using the QPatch system (Sophion). The current signal was amplified and digitized, stored and analyzed by using QPatch assay software.
The holding potential was-80 mV. hERG current (K) + Selective outward current) was determined as the maximum tail current at-40 mV after 2 seconds of depolarization to +60 mV. The pulse cycle rate was 15s. A short pulse (90 ms) to-40 mV was used as a baseline step to calculate tail current amplitude. After establishment of the whole cell configuration and stationary phase, a solvent control (0.3% dmso) was applied for 5 minutes followed by 3×10 applications -7 M、3×10 -6 M、10 -5 M and 3X 10 -5 M four increasing concentrations of test substance. The test substance was applied twice for each concentration. The effect of each concentration was determined after 5 minutes as the average current of 3 consecutive voltage pulses. To determine the degree of blocking, the residual current was compared to vehicle pretreatment.
The concentration/response relationship is calculated by a nonlinear least squares fit to the individual data points. The half maximal inhibitory concentration (IC 50) was calculated by fitting routine.
Scheme 2：
Cells
Compounds, vehicle controls and positive controls were tested on hERG transfected HEK293 cells. A human embryonic kidney cell line (HEK 293) stably transfected with hERG was used (Zhou Z et al Biophysical Journal 1998.74,230-241; mcDonald T.V. et al Nature 1997.388,289-292) (university of Wisconsin (University of Wisconsin), madison, USA). Cells were cultured in MEM (minimal essential medium, gibco) supplemented with (the indicated amounts were added to 500ml MEM) using a T175 flask: 5ml of L-glutamine-penicillin-streptomycin (Sigma), 50ml of fetal bovine serum (Bio-Whittaker), 5ml of nonessential amino acids 100x (Gibco), 5ml of sodium pyruvate 100mM (Gibco) and 4ml of geneticin 50mg/ml (Gibco). The cells were incubated at 37℃with 5% CO 2 Incubation in atmosphere (in air).
Cell harvesting for assay
Using accumax TM (Sigma) cells were harvested as dissociating agent as described below. The cells were then resuspended in a mixture of 33% DMEM/F12 (Dulbecco's modified eagle's Medium/nutrient mixture F-12-Sigma)/67% extracellular physiological solution.
The flask was buffered with approximately 5-10ml Phosphate Buffered Saline (PBS) (Gibco) containing 2mM EDTA (ethylenediamine tetraacetic acid) (Sigma) TM ) Careful washing was performed twice. About 3ml accumax was used TM (cell separation solution) cells were dissociated and incubated at 37℃for about 5 minutes to 10 minutes. Cold external physiological solution (2-5 ml) was added and the flask was incubated at about 4℃for 5-10 minutes. The cell suspension in each flask was then gently dissociated with a 5ml pipette. The cell suspension was transferred to a low-binding petri dish (about 10mm diameter). Each flask was washed with another about 5ml of cold external physiological solution and this solution was also added to the petri dish. The dishes are then incubated at about 4℃for a further 5 to 10 minutes. After re-warming and dissociation of the cell suspension in the dish, the cells were transferred to a reservoirThe reservoir was maintained at 16℃on a 200rpm orbital shaker. Cells were recovered for about 20 minutes prior to conducting the experiment.
Compounds of formula (I)
A 10mM solution of the compound was used and plated in 384 well plates. Aliquots of the stock solutions were diluted with recording solutions using automated liquid treatment (Biomek FXP; final DMSO concentration: 0.03% to 0.3%). A standard range of screening concentrations ranging from 1 μm to 30 μm was used.
A positive control (E-4031) was included in each run to evaluate the sensitivity of the assay. Table 13 summarizes the external and intracellular solutions used in the experiments. In Table 13, the composition of the intracellular and external buffer solutions is shown in [ mM ], and "NMDG" means N-methyl-D-glucamine.
TABLE 13 external and intracellular solutions
Study design
Whole cell patch clamp techniques on transfected cells allow ion channels to be studied without interference from other ion channels or with limited interference from other ion channels. The effect of compounds on hERG current was studied using an automated planar patch clamp system SyncroPatch 384PE (Obergrusberger et al Journal of Laboratory Automation 2016.21 (6), 779-793). All cells were recorded in whole cell mode of patch clamp technique. This module was incorporated into the liquid handling pipetting robot system Biomek FXP to administer cells and compounds, vehicle controls and positive controls.
The different concentrations of compound were administered at two cumulative increasing compound concentrations (1 μm and 10 μm, and 3 μm and 30 μm, respectively). hERG current was determined as the maximum tail current at-30 mV and reported as percent inhibition after addition of compound or vehicle and positive control.
Capturing cells to a recording chip using a chip filling solutionAfter single well of (a) with a seal enhancer solution (increased [ Ca ] 2+ ]) Sealing is added; the cells were then washed twice with the recording solution before entering whole cell mode using the pressure protocol.
After the whole cell mode was achieved, the test pulse was administered for about 10 minutes to quantify hERG current in the control conditions. During this control period, vehicle control solution (recording solution containing 0.03% dmso) was added three times to a single well. Vehicle control, compound, or positive control was added at an accumulatively increasing concentration while continuing the pulsing regimen. The effect of vehicle, compound and positive control was measured 5 minutes after drug administration. Each cell was tested for two concentrations of compound.
The use of internal and recording solutions will result in a liquid interfacial potential of about 10mV and commanding a voltage step will take this into account.
Electrophysiological measurement: the membrane current of the cells was measured at different membrane potentials by an automated patch clamp system using patch clamp techniques. The holding potential was-70 mV. hERG current (K) + -selective outward current) is determined as the maximum tail current at-30 mV after 2 seconds depolarization to +70mV (references 1, 4). The pulse cycle rate was 15s.
Data analysis
Leakage corrected hERG current (K + Selective outward current) was determined as the maximum tail current at-30 mV after 2 seconds of depolarization to +70mV measured between 2336.3ms and 3083.6 ms. The median of the three current amplitudes was taken at the end of the control period and at the end of each addition of compound, vehicle and positive control to calculate the percent inhibition.
QC parameters were set in the SyncroPatch 384PE PatchControl384 software so that if the values fall outside this range, the wells were automatically excluded from the analysis. The QC standard depends on the type of recording plate (chip). Typically, recordings were made from hERG transfected HEK293 cells using 4xChip (medium-sized wells). QC criteria 4-6 were set before the first addition of compound; QC standards 4 and 5 were also set at the end of each compound addition.
QC standard and acceptable range:
1. plate inspection: -500pA
2. Contact seal resistance: -100kOhm-10MOhm
3. Bonding potential shift: 0-100mV
4.Rseal≥100MOhm
Rseries: between 1MOhm and 25MOhm
6. hERG tail current ≡0.2nA prior to addition of compound
Each compound was replicated in at least 5 wells on the same plate. The percent inhibition of at least 2-3 replicates per concentration is reported as the median. The results of schemes 1 and 2 are summarized in tables 14 and 15, respectively, below.
50 TABLE 14 hERG IC (μM) from scheme 1
Numbering of compounds hERG-IC 50 (μM)
A >30.2
50 TABLE 15 hERG IC (μM) from scheme 2
Examples numbering hERG IC 50μ M
11 >30.2
9) Efficacy studies in disseminated OCI-AML3 model
Test reagents and controls
Compound A3 was formulated in 20% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and prepared to a total volume of up to 0.2mL (10 mL/kg) per dose for 20g animals. Dosage was adjusted daily by body weight of the individual. For each study, working stock solutions of compound A3 were prepared once a week and stored at 25 ℃.
Animals
Female SCID beige mice (CB17.Cg-PrkdcsccidLystbg-J/Crl/-) are used when they are about 6 to 8 weeks old and weigh about 25 g. All animals can be adapted and recovered from any transport-related stress for a minimum of 7 days prior to experimental use. Autoclaved water and irradiated food were provided ad libitum and animals were kept in a 12 hour light and dark cycle. The cages, bedding and water bottles were autoclaved before use and replaced once a week. Tissue culture and cell injection reagents are summarized in table 16 below.
TABLE 16 tissue culture and cell injection reagents
DPBS (Dulbecce phosphate buffered saline)
Heat-inactivated fetal bovine serum
MEM alpha Medium
L-glutamine
Gentamicin
T175 culture bottle
Rolling bottle
Tumor model and cell culture method
Human AML cell line OCI-AML3 was subjected to 5% CO at 37deg.C 2 The culture was performed in the indicated complete medium (MEMEMEalpha+20% HI-FBS (heat inactivated fetal bovine serum) +2mM L-glutamine+50 ug/ml gentamicin). Cells were harvested while in logarithmic growth and resuspended in cold (4 ℃) MEM (minimum essential medium) alpha in serum-free medium.
For the disseminated OCI-AML3 model, each mouse received 5×10 by intravenous injection using a 26 gauge needle 5 The total volume of each cell was 0.2mL.
Study design
Compound A3 was administered orally (PO) daily.
Day 0 is the day of tumor cell implantation and study initiation.
In efficacy studies, mice bearing IV OCI-AML3 xenograft tumors were randomly assigned to treatment groups 3 days post tumor cell implantation. Treatment with vehicle or compound A3 (at 30mg/kg, 50mg/kg and 100 mg/kg) was started on the same day, with daily dosing for 28 days.
Animal monitoring
Animals were monitored daily for clinical symptoms associated with compound toxicity or tumor burden (i.e., hindlimb paralysis, somnolence, etc.).
Calculation of
For survival assessment, the results are plotted as percent survival versus days after tumor implantation. Negative clinical signs and/or > 20% weight loss were used as surrogate endpoints for death. Median survival was determined using Kaplan-Meier survival analysis. Percent increase In Life (ILS) was calculated as: ((median survival day of treatment group-median survival day of control group)/median survival day of control group) ×100. Animals that failed to reach the surrogate endpoint due to adverse clinical signs (such as ulcerative tumors, weight loss, etc.) or treatment-independent death were examined for survival assessment. ILS.gtoreq.25% is considered biologically significant according to the definition of NCI standard. (JohnsonJI et al Br J cancer.2001.84 (10), 1424-1431).
Data analysis
Survival and weight data are graphically represented using Prism (7 th edition). The statistical significance of body weight was assessed as described above. Statistical significance was assessed in R software version 3.4.2 using a log rank (Mantel-Cox) test against Kaplan-Meier survival curves of the therapeutic treatment group versus a control of appropriate vehicle treatment. When the p value was 0.05 or less, the difference between the groups was considered significant.
Survival of
The Kaplan-Meier survival curve is shown in figure 3. Mice bearing established OCI-AML3 tumors were orally administered 30mg/kg, 50mg/kg, 100mg/kg of compound A3 in a 20% hp- β -CD formulation daily for 28 days (n=9-10/group). For the group treated with compound A3, the median survival days were reached on the following days: this contrasts with the median survival of the vehicle treated control group at day 75.5 for 30mg/kg, day 58.5 for 50mg/kg and day 75 for 100 mg/kg. Compound A3 treatment resulted in statistically significant increases in lifespan of mice bearing OCI-AML3 tumors by 96.1%, 51.9% and 94.8% (at dose levels of 30mg/kg, 50mg/kg and 100 mg/kg) (p.ltoreq.0.001) compared to control mice. This is a biologically significant ILS according to the NCI standard threshold of ≡25% ILS (Johnson JI et al Br J cancer.2001.84 (10), 1424-1431).
10 Multiple endocrine oncoprotein-MLL inhibitors in combination with valnemritox and optionally azacytidine in NSG Efficacy in the mouse OCI-AML3 (NPM 1 c) IV model
The disseminated OCI-AML3 model described above alsoFor examining multiple endocrine oncoprotein-MLL-inhibitors (formulated as described above) and vitamin Natolg (in polyethylene glycol [ PEG ]]-400/Phosal 50/dimethyl sulfoxide [ DMSO ]]Formulated) and optionally azacytidine (formulated in 10% dmso), with the following differences: (i) Instead of female SCID beige, NSG (non-obese diabetes [ NOD]scidγ or NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ), (ii) instead of 5X 10 5 Cells, each mouse received 1X 10 6 Injection of individual cells, (iii) instead of 3 days, treatment with compound was started 5 days after cell injection, and (iv) instead of a total volume of 0.2mL (10 mL/kg) per dose, compound prepared to a volume of 8mL/kg of compound A1 was administered in the morning and valnemulin was administered in the afternoon, at intervals of about 6-8 hours. The treatments for each group using the compounds in this efficacy study are summarized in table 17.
TABLE 17 treatment of OCI-AML3 tumors in mice
The Kaplan-Meier survival curve is shown in figure 4A. The effect of treating mice bearing established OCI-AML3 tumors for 4 weeks on longevity is summarized in table 18.
TABLE 18 Effect on longevity after treatment of OCI-AML3 tumors in mice
P <0.05 compared to vehicle treated control mice except where recorded as insignificant (ns). * P.ltoreq.0.05 relative to Aza and Ven monotherapy and Aza+Ven combination monotherapy.
As reflected in table 18, treatment of mice with the combination of compound A1 and valnemulin resulted in a statistically significant increase in the lifespan (ILS) of mice bearing OCI-AML3 tumors compared to vehicle control treated mice or mice treated with azacytidine or valnemulin alone or with a dual combination of valnemulin. Notably, there is no antagonism with the triple combination (compound A1 plus valnemulin and azacitidine) or the double combination (valnemulin or compound A1), and the efficacy appears to be driven only by compound A1.
11 Multiple endocrine oncoprotein-MLL inhibitors in combination with valnemritox and optionally azacytidine in NSG Efficacy in MOLM-13 (KMT 2A-r) IV model of mice
Methods for examining the efficacy of a combination of a multiple endocrine oncoprotein-MLL-inhibitor with valnemulin and optionally azacytidine similar to the disseminated OCI-AML3 model described herein were employed using MOLM-13 cells instead of OCI-AML3 cells.
Tumor model and cell culture method
At 37℃in 5% CO2 in the indicated complete medium (RPMI, rockwell-Parker souvenir institute (Roswell ParkMemorial Institute) [ RPMI)]1640+10% HIFBS+2mM L-Glutamine+50. Mu.g/ml gentamicin). Cells were harvested while growing logarithmically and resuspended in cold (4 ℃) serum-free RPMI 1640 medium. Each mouse received 1X 10 5 Injection of individual MOLM-13 cells, and all other parameters were performed as described for experiment (10).
The treatments for each group using the compounds in this efficacy study are summarized in table 19.
TABLE 19 treatment of MOLM-13 tumors in mice
The Kaplan-Meier survival curve is shown in fig. 4B. The effect of treating mice bearing established MOLM-13 tumors for 4 weeks on longevity is summarized in Table 20.
TABLE 20-in miceEffect on longevity after treatment of MOLM-13 tumors
P <0.05 compared to vehicle treated control mice except where recorded as insignificant (ns). * P.ltoreq.0.05 relative to Aza and Ven monotherapy. * P.ltoreq.0.05 relative to compound A1, aza and Ven monotherapy and aza+ven combination monotherapy.
As reflected in table 20, treatment of mice with the combination of compound A1 with valnemulin or valnemulin resulted in a statistically significant increase in the longevity (ILS) of mice bearing the MOLM-13 tumor, as compared to mice treated with valnemulin alone or with a dual combination of valnemulin.
(12) In vitro proliferation protocol
(A) Combination of a multiple endocrine oncoprotein-MLL inhibitor with valnemulin and optionally azacitidine
The effect of compound A3 in combination with valnemulin or in combination with valnemulin and azacytidine was determined in proliferation assays using the MOLM-13 (KMT 2A-r) cell line. MOLM-13 cells were seeded at 500 cells/well in 96-well plates and exposed to specified drugs alone or in combination at the specified concentrations detailed in tables 21A and 21B. In particular, for the combination of compound A3 with valnemulin (without azacitidine), a range of concentrations of compound A3 (7-point, 4-fold serial dilutions starting at an initial concentration of 1 μm) was combined with valnemulin (6-point, 5-fold serial dilutions starting at an initial concentration of 1 μm). For the combination of compound A3 with valnemulin and azacitidine, a range of concentrations of compound A3 (6-point, 4-fold serial dilutions starting at an initial concentration of 1 μm) was mixed with a combination of azacitidine (7-point, 5-fold serial dilutions starting at an initial concentration of 25 μm) and valnemulin (7-point, 5-fold serial dilutions starting at an initial concentration of 1 μm) at a ratio of 25:1. Treatment with compound A3 and azacytidine (when added) on day 0 and addition on day 4 Ganciclovir. MOLM-13 cells were incubated at 37℃with 5% CO 2 The following incubations were performed in quadruplicate for 8 days (compound A3 and azacytidine) and 4 days (valnemulin) with the indicated drug combination concentrations.
Spheroid-like growth was monitored in real time by non-invasive live cell imaging using a 4x objective lens of the Incucyte ZOOM live cell imaging system (Essen BioScience) and image acquisition on day 8. The percent fusion, which is a measure of spheroid size, was determined using an integrated analysis tool that is part of the Incucyte ZOOM software "Incucyte ZOOM 2016B" (Essen BioScience). DMSO content was normalized to 0.3% and percent fusion from DMSO wells was used as baseline response.
The potential combined effects were evaluated on day 8 and synergy was analyzed using an R-based Biochemically Intuitive Generalized Loewe (BIGL) model implemented with the Highest Single Agent (HSA) null model (Van der borgo 2017). Data from 2 independent experiments were pooled and analyzed.
Results
The dual combination of compound A3 with valnemulin resulted in significantly increased inhibition of cell proliferation compared to compound A3 or valnemulin monotherapy (see figure 5A). Strong synergy was observed in a range of concentrations in MOLM-13 cells, as reflected in the contour plots (fig. 5A) and detailed in table 21A below, where the effect size is expressed as the difference between the observed and expected results for the combination therapy, with 95% confidence intervals shown in brackets.
The triple combination of compound A3 with valnemulin and azacytidine resulted in significantly increased inhibition of cell proliferation compared to compound A3 monotherapy or the double combination of valnemulin and azacytidine (see fig. 5B). Strong synergy was observed in a range of concentrations in MOLM-13 cells, as reflected in the contour plots (fig. 5B) and detailed in table 21B below, where the effect size is expressed as the difference between the observed and expected results for the combination therapy, with 95% confidence intervals shown in brackets.
Table 21A-combination of Compound A3 and Winetatox for MOLM-13 cell proliferationEffect of the germ。
Note that the absence of any asterisks indicates additive effects, antagonism is indicated by "×", and synergy is indicated by "×". Antagonism and synergy result from significant modulation based on the maxR test and the numbers associated therewith, which are interpreted as antagonism or synergy, respectively.
Table 21B-Effect of Compound A3 in combination with Venezucchine and azacitidine on MOLM-13 cell proliferation。
Note that the absence of any asterisks indicates additive effects, antagonism is indicated by "×", and synergy is indicated by "×". Antagonism and synergy result from significant modulation based on the maxR test and the numbers associated therewith, which are interpreted as antagonism or synergy, respectively.
(B) Combination of a multiple endocrine oncoprotein-MLL inhibitor, decitabine and valnemulin
The effect of the combination of compound A4 with decitabine was determined in proliferation assays using the MOLM-13 (KMT 2A-r) and OCI-AML3 (NPM 1 c) cell lines, as compared to the combination of decitabine and valnemulin.
Cell lines
AML cell lines MOLM-13 and OCI-AML3 were purchased from DSMZ. MOLM-13 was grown in RPMI medium supplemented with 10% Fetal Bovine Serum (FBS) and 1% penicillin/streptomycin. OCI-AML3 cells were cultured in 80% -90% alpha-MEM (containing ribose and deoxyribose nucleosides) +10% -20% fbs. All cell lines were cultured at 37℃in a 5% CO2 atmosphere.
Cell Titer Glo assay
AML cell linesMOLM-13 and OCI-AML3 (5×10) 3 Individual cells/well) were seeded in 96-well plates and grown in the presence or absence of the indicated concentrations detailed in tables 22A and 22B below in medium containing serum (10%) for 6 days. Proliferation was analyzed by CellTiter Glo assay using CellTiter 96 Aqueous One Solution cell proliferation assay (Promega, madison, WI, usa) according to the manufacturer's instructions. The data are the mean and standard deviation of two to four independent experiments in triplicate of the technique. Compound A4 and decitabine were added on day 0, and valnemulin (when added) was added on day 4.
Synergistic calculation
An R-based Biochemically Intuitive Generalized Loewe (BIGL) model implemented with the Highest Single Agent (HSA) null model. Specifically, the BIGL method was applied to calculate drug-drug interactions (Van der Borgo, K., tourny, A., bagdzinas, R.et al. BIGL: biochemically Intuitive Generalized Loewe null model for prediction of the expected combined effect compatible with partial agonism and antagonish. Sci Rep 7,17935 (2017); thas, O., tourny, A., verbest, B., hawinkel, S., nazarov, M., mutabtangwe, K, and Bijnens, L.statistical detection of synergy: new methods and a comparative sty. Pharmaceutical Statistics (2021)).
The synergy matrix results of the BIGL analysis of Cell line data using HSA as an average model were calculated based on Cell metabolic activity using the Cell Titer-Glo assay. Bootstrap confidence intervals are indicated. The effect size and its confidence interval are shown. Notably, each data point is based on the p-value and the sign of the corresponding maxR statistic, where the size of the point reflects the degree of synergy or antagonism corresponding to the hierarchical scale. If 0 is included in the interval, there is no significant averaging effect.
Results
The paired matrix combination of decitabine and compound A4 with or without valnemulin was evaluated in MOLM-13 (KMT 2A-AF9; FLT 3-ITD) and OCI-AML3 (NPM 1c AML) cells using the 6 day CellTiter-Glo assay format. Notably, the combination of decitabine and compound A4 (with or without valnemulin) had synergistic cytotoxicity in MOLM-13 (KMT 2A-aF9; FLT 3-ITD) cells, as reflected in the contour plots (fig. 6A and 6B) and as detailed in tables 22A and 22B, respectively, below.
TABLE 22 Effect of combination of Compound A4 and Decitabine on MOLM-13 cell proliferation。
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Note that the absence of any asterisks indicates additive effects, antagonism is indicated by "×", and synergy is indicated by "×". Antagonism and synergy result from significant modulation based on the maxR test and the numbers associated therewith, which are interpreted as antagonism or synergy, respectively.
TABLE 22 effect of combination of Compound A4 with valnemtock and decitabine on MOLM-13 cell proliferation。
Note that the absence of any asterisks indicates additive effects, antagonism is indicated by "×", and synergy is indicated by "×". Antagonism and synergy result from significant modulation based on the maxR test and the numbers associated therewith, which are interpreted as antagonism or synergy, respectively.
Antagonism in OCI-AML3 (NPM 1c AML) cells was observed at low doses of decitabine (15 nM) with or without valnemulin, as reflected in the contour plots (fig. 7A and 7B) and detailed in tables 23A and 23B, respectively, below.
TABLE 23 effects of combination of Compound A4 and Decitabine on OCI-AML3 cell proliferation。
Note that the absence of any asterisks indicates additive effects, antagonism is indicated by "×", and synergy is indicated by "×". Antagonism and synergy result from significant modulation based on the maxR test and the numbers associated therewith, which are interpreted as antagonism or synergy, respectively.
TABLE 23 effects of combination of Compound A4 with Venezuostat and Decitabine on OCI-AML3 cell proliferation。
Note that the absence of any asterisks indicates additive effects, antagonism is indicated by "×", and synergy is indicated by "×". Antagonism and synergy result from significant modulation based on the maxR test and the numbers associated therewith, which are interpreted as antagonism or synergy, respectively.
<110> Janssen Pharmaceutica NV
<120> combination therapy
<130> P2022TC2023
<150> PCT/CN2021/093036
<151> 2021-05-11
<150> PCT/CN2021/100523
<151> 2021-06-17
<150> PCT/CN2022/086004
<151> 2022-04-11
<160> 1
<170> patent In 3.5 version
<210> 1
<211> 616
<212> PRT
<213> artificial sequence
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Met Gly Leu Lys Ala Ala Gln Lys Thr Leu Phe Pro Leu Arg Ser Ile
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Asp Leu Val Leu Leu Ser Leu Val Leu Gly Phe Val Glu His Phe Leu
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Ala Val Asn Arg Val Ile Pro Thr Asn Val Pro Glu Leu Thr Phe Gln
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Pro Ser Pro Ala Pro Asp Pro Pro Gly Gly Leu Thr Tyr Phe Pro Val
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Ala Asp Leu Ser Ile Ile Ala Ala Leu Tyr Ala Arg Phe Thr Ala Gln
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Ile Arg Gly Ala Val Asp Leu Ser Leu Tyr Pro Arg Glu Gly Gly Val
100 105 110
Ser Ser Arg Glu Leu Val Lys Lys Val Ser Asp Val Ile Trp Asn Ser
115 120 125
Leu Ser Arg Ser Tyr Phe Lys Asp Arg Ala His Ile Gln Ser Leu Phe
130 135 140
Ser Phe Ile Thr Gly Thr Lys Leu Asp Ser Ser Gly Val Ala Phe Ala
145 150 155 160
Val Val Gly Ala Cys Gln Ala Leu Gly Leu Arg Asp Val His Leu Ala
165 170 175
Leu Ser Glu Asp His Ala Trp Val Val Phe Gly Pro Asn Gly Glu Gln
180 185 190
Thr Ala Glu Val Thr Trp His Gly Lys Gly Asn Glu Asp Arg Arg Gly
195 200 205
Gln Thr Val Asn Ala Gly Val Ala Glu Arg Ser Trp Leu Tyr Leu Lys
210 215 220
Gly Ser Tyr Met Arg Cys Asp Arg Lys Met Glu Val Ala Phe Met Val
225 230 235 240
Cys Ala Ile Asn Pro Ser Ile Asp Leu His Thr Asp Ser Leu Glu Leu
245 250 255
Leu Gln Leu Gln Gln Lys Leu Leu Trp Leu Leu Tyr Asp Leu Gly His
260 265 270
Leu Glu Arg Tyr Pro Met Ala Leu Gly Asn Leu Ala Asp Leu Glu Glu
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Leu Glu Pro Thr Pro Gly Arg Pro Asp Pro Leu Thr Leu Tyr His Lys
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Gly Ile Ala Ser Ala Lys Thr Tyr Tyr Arg Asp Glu His Ile Tyr Pro
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Tyr Met Tyr Leu Ala Gly Tyr His Cys Arg Asn Arg Asn Val Arg Glu
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Ala Gly Glu Glu Arg Pro Gly Glu Gln Ser Gln Gly Thr Gln Ser Gln
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Gly Ser Ala Leu Gln Asp Pro Glu Cys Phe Ala His Leu Leu Arg Phe
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Leu Gln Leu Thr Ala Gln Ser Gln Val Gln Met Lys Lys Gln Lys Val
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Claims (25)

1. A combination, comprising:
● A therapeutically effective amount of a multiple endocrine oncoprotein-mixed lineage leukemia 1 (MLL) inhibitor of formula (I), or a tautomer or stereoisomer form thereof, or a pharmaceutically acceptable salt or solvate thereof;
● A therapeutically effective amount of a B cell lymphoma 2 (BCL-2) inhibitor; and
● Optionally, a therapeutically effective amount of at least one other antineoplastic agent;
wherein the multiple endocrine oncoprotein-MLL inhibitor of formula (I) has the structure:
wherein the method comprises the steps of
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group; wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl group, said oneEach of the two or three substituents is independently selected from the group consisting of: -OH, cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 11 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group.
2. The combination of claim 1, wherein the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is compound a:
or a pharmaceutically acceptable salt or solvate thereof.
3. The combination of claim 1, wherein the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is compound A4-a:
Or a solvate thereof.
4. The combination according to any one of claims 1-3, wherein the BCL-2 inhibitor is selected from the group consisting of obatuk, HA14-1, nanotuk, ABT-737, TW-37, AT101, sha Butuo grams, gambogic acid, valnemtuk, and pharmaceutically acceptable salts or solvates thereof.
5. The combination according to claim 4, wherein the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt or solvate thereof.
6. The combination according to any one of claims 1-5, wherein the at least one other anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory anti-neoplastic agent, or a dihydroorotate dehydrogenase inhibitor.
7. The combination of claim 6, wherein the at least one other anti-neoplastic agent is a hypomethylation agent.
8. The combination according to claim 7, wherein the hypomethylating agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.
9. The combination of claim 1, wherein the multiple endocrine oncoprotein-MLL inhibitor is compound a or a pharmaceutically acceptable salt or solvate thereof, the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt or solvate thereof, and the at least one other anti-tumor agent is a hypomethylation agent.
10. The combination according to claim 9, wherein the hypomethylating agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.
11. A pharmaceutical composition comprising a combination according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.
12. A combination according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use as a medicament.
13. The combination according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 for use in the prevention or treatment of hematopoietic disorders, in particular in the treatment of hematopoietic disorders.
14. The combination or pharmaceutical composition for use according to claim 13, wherein the hematopoietic dysfunction is a nuclear phosphoprotein 1 (NPM 1) mutated leukemia or a MLL rearranged leukemia.
15. The combination or pharmaceutical composition for use according to claim 13, wherein the hematopoietic dysfunction is Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL).
16. A method for treating a subject who has been diagnosed with hematopoietic dysfunction, comprising administering to the subject:
● A therapeutically effective amount of a multiple endocrine oncoprotein-mixed lineage leukemia 1 (MLL) inhibitor of formula (I), or a tautomer or stereoisomer form thereof, or a pharmaceutically acceptable salt or solvate thereof;
● A therapeutically effective amount of a BCL-2 inhibitor; and
● Optionally a therapeutically effective amount of at least one other antineoplastic agent;
wherein the multiple endocrine oncoprotein-MLL inhibitor of formula (I) has the structure:
wherein the method comprises the steps of
R 1a represents-C (=O) -NR xa R xb The method comprises the steps of carrying out a first treatment on the surface of the Het; or (b)
Het represents a 5-or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety; wherein the 5-or 6-membered monocyclic aromatic ring is optionally selected from C 3-6 Cycloalkyl and C 1-4 One or two substituents of the group consisting of alkyl are substituted;
R xa and R is xb Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 1b represents F or Cl;
Y 1 representation-CR 5a R 5b -, -O-or-NR 5c -；
R 2 Selected from the group consisting of: hydrogen, halo, C 1-4 Alkyl, -O-C 1-4 Alkyl and-NR 7a R 7b ；
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X 1 represents CH, and X 2 Represents N;
R 4 represents isopropyl;
R 5a 、R 5b 、R 5c 、R 7a and R is 7b Each independently selected from the group consisting of: hydrogen, C 1-4 Alkyl and C 3-6 Cycloalkyl;
R 3 representation-C 1-6 alkyl-NR 8a R 8b 、-C 1-6 alkyl-C (=O) -NR 9a R 9b 、-C 1-6 alkyl-OH, or-C 1-6 alkyl-NR 11 -C(＝O)-O-C 1-4 alkyl-O-C (=o) -C 1-4 An alkyl group; wherein R is 3 Each C in the definition 1-4 Alkyl or C 1-6 The alkyl moieties may be substituted independently of each other with one, two or three substituents each independently selected from the group consisting of: cyano, halo, -OH and-O-C 1-4 An alkyl group;
R 8a and R is 8b Each independently selected from the group consisting of: hydrogen; c (C) 1-6 An alkyl group; -C (=o) -C 1-4 An alkyl group; -C (=o) -O-C 1-4 An alkyl group; -C (=o) -NR 12a R 12b The method comprises the steps of carrying out a first treatment on the surface of the And C substituted with one, two or three substituents 1-6 Alkyl, said one, two or three substituents each being independently selected from the group consisting of: -OH,Cyano, halo, -S (=o) 2 -C 1-4 Alkyl, -O-C 1-4 Alkyl, -C (=O) -NR 10a R 10b and-NR 10c -C(＝O)-C 1-4 An alkyl group; and is also provided with
R 9a 、R 9b 、R 10a 、R 10b 、R 10c 、R 11 、R 12a And R is 12b Each independently selected from the group consisting of: hydrogen and C 1-6 An alkyl group.
17. The method of claim 16, wherein the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is compound a:
or a pharmaceutically acceptable salt or solvate thereof.
18. The method of claim 11, wherein the multiple endocrine oncoprotein-MLL inhibitor of formula (I) is compound A4-a:
Or a solvate thereof.
19. The method of any one of claims 16-18, wherein the BCL-2 inhibitor is selected from the group consisting of valnemulin, obatoxin, HA14-1, nanotrope, ABT-737, TW-37, AT101, sha Butuo grams, gambogic acid, and pharmaceutically acceptable salts or solvates thereof.
20. The method of claim 19, wherein the BCL-2 inhibitor is valnemulin or a pharmaceutically acceptable salt or solvate thereof.
21. The method of any one of claims 16-20, wherein the at least one additional anti-neoplastic agent is a hypomethylating agent, a DNA intercalating agent, a pyrimidine analog, a purine analog, a kinase inhibitor, a CD20 inhibitor, an isocitrate dehydrogenase inhibitor, an immunomodulatory anti-neoplastic agent, or a dihydroorotate dehydrogenase inhibitor.
22. The method of claim 21, wherein the at least one other anti-neoplastic agent is a hypomethylation agent.
23. The method of claim 22, wherein the hypomethylating agent is azacitidine or a pharmaceutically acceptable salt or solvate thereof.
24. The method of any one of claims 16-23, wherein the hematopoietic disorder is a nuclear phosphoprotein 1 (NPM 1) mutated leukemia or a MLL rearranged leukemia.
25. The method of any one of claims 16-23, wherein the hematopoietic disorder is Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL).
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