CN115368378A - Substituted macrocyclic compounds, compositions containing the same and uses thereof - Google Patents

Substituted macrocyclic compounds, compositions containing the same and uses thereof Download PDF

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CN115368378A
CN115368378A CN202210543580.3A CN202210543580A CN115368378A CN 115368378 A CN115368378 A CN 115368378A CN 202210543580 A CN202210543580 A CN 202210543580A CN 115368378 A CN115368378 A CN 115368378A
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methyl
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王义汉
李焕银
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Shenzhen Targetrx Inc
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    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract

The invention provides a substituted macrocyclic compound, a composition containing the compound and application of the compound, wherein the substituted macrocyclic compound is a compound shown as a formula (I) or a tautomer, a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The compounds of formula (I) are useful as fourth generation non-covalent EGFR tyrosine kinase inhibitors, capable of inhibiting complex EGFR mutations including T790M and/or C797S, while retaining activity against wild-type EGFR, with high selectivity and good DMPK properties.

Description

Substituted macrocyclic compounds, compositions containing the same and uses thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a substituted macrocyclic compound, a composition containing the compound and application of the compound. More particularly, the inventionInvolving certain deuterium substituted (E) -1 1 ,2 6 7-trimethyl-5 6 - ((4-methylpiperazin-1-yl) methyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]The compound of imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolo-cyclododecen-3-one and derivatives thereof and tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvate compounds thereof. These deuterium substituted compounds and compositions thereof are useful as fourth generation non-covalent bond EGFR tyrosine kinase inhibitors, capable of inhibiting complex EGFR mutations including T790M and/or C797S while retaining activity against EGFR WT, with high selectivity and good DMPK properties.
Background
Epidermal Growth Factor Receptor (EGFR) is a Receptor tyrosine kinase that transduces mitotic signals. EGFR gene mutations are found in Non Small Cell Lung Cancer (NSCLC) tumors in about 12% to 47% of adenocarcinoma histology. The two most common EGFR mutations found in NSCLC tumors are EGFR that lacks amino acids 746 to 750 in the exon 19 region (del 19 mutation) and EGFR that lacks amino acids leucine to arginine in the exon 21 region (L858R mutation), both of which cause ligand-independent activation of EGFR and are collectively referred to as EGFR M+ . The del19 and L858R mutations in EGFR sensitize NSCLC tumors to treatment with EGFR Tyrosine Kinase Inhibitors (TKIs). Clinical experience has shown that EGFR is in first line therapy with the first, second and third generation EGFR inhibitors erlotinib (erlotinib), gefitinib (gefitinib), afatinib (afatinib) and oxitinib (osimertinib) M+ The objective remission rate in NSCLC patients is about 60-85%. These responses indicate that EGFR M+ NSCLC cells and tumors rely on tumorigenic EGFR activity to maintain survival and proliferation, establishing del19 or L858R mutated EGFR as an effective drug target and predictive biomarker for the treatment of NSCLC.
Although the tumor response of patients is accompanied by significant tumor shrinkage, the response is usually not persistent and most patients relapse within 10 to 12 months after treatment with first and second generation EGFR inhibitors. The most prominent molecular mechanism for potential progression is that of the first and second generation EGFR inhibitor treated patients, 50% to 70% of patients acquire the second-order mutation of EGFR, i.e., T790M. Such mutations reduce the inhibitory activity of first and second generation inhibitors in cellular assays.
Mutation selective and covalent third generation EGFR inhibitors, such as oxitinib, have been developed that are effective in inhibiting the first order mutations del19 and L858R of EGFR with and without the second order T790M resistance mutation. Oxitinib on EGFR M+ Efficacy in second line treatment of T790M-positive NSCLC clinically demonstrates that tumor cell survival and proliferation is dependent on the mutated EGFR allele. EGFR previously treated with early EGFR inhibitors M+ Of the T790M positive patients, about 70% responded to second-line oxitinib treatment. However, disease progression will occur after an average of 10 months. The underlying mechanism of acquired resistance to third-generation EGFR inhibitors has been studied in a small subset of patients and has begun to emerge. Existing clinical data indicate that a major resistance mechanism is the acquisition of the third-order mutation C797S of EGFR in about 20-40% of second-line patients with axitinib relapse. A third generation EGFR inhibitor (e.g., oxitinib) is covalently linked to EGFR through residue C797. In the cell model, the C797S mutation abolished the activity of the third-generation EGFR inhibitor tested. In second-line patients, the C797S mutation was found in preference to EGFR del19 genotype binding and was located on the same allele as the T790M mutation (cis configuration) (accounting for 82% of C797S + patients). Importantly, the EGFR del19/L858R T790M C797S cis-mutant kinase variant that appears in second-line patients with progression of axitinib is no longer inhibited by first, second or third generation EGFR inhibitors. Based on the fact that the C797S mutation was detected in the progression of axitinib, tumor cell survival and proliferation in EGFR del19/L858R T790M C797S patients may depend on this mutant allele and may be inhibited by targeting this allele. EGFR with evolution of oxitinib M+ NSCLC second-line patients also found lower levels of other EGFR resistant mutations than C797S: L718Q, L792F/H/Y and C797G/N.
Oxitinib is also approved for the treatment of previously untreated EGFR M+ NSCLC patients, after an average course of 19 months, develop disease progression. Although the EGFR resistance mutation profile after first-line axitinib treatment has not been extensively studied, the first available data indicate that a C797S mutation that abolishes axitinib activity is also present.
The fact that no approved EGFR inhibitors can inhibit the EGFR del19/L858R T790M C797S mutation highlights the medical need for next generation EGFR inhibitors (fourth generation EGFR inhibitors). The fourth generation EGFR TKIs should be effective in inhibiting EGFR del19 and/or L858R regardless of the presence of the two common drug resistant mutations T790M and C797S. The utility of this fourth generation EGFR inhibitor will be enhanced by the activity of the compound against additional drug resistance mutations, such as the potential oxitinib drug resistance mutations C797X (X = S, G, N) and L792F/H/Y. The broad activity of this molecule against EGFR del19/L858R variants that have not been mutated by T790M and/or C797S will ensure that the novel compounds can effectively cope with the expected allelic complexity in patient tumors as monotherapy. Also, another desirable property of fourth generation EGFR inhibitors is the ability to effectively penetrate into the brain (blood brain barrier penetration) in order to facilitate effective dosing and reduce off-target toxicity of the compounds, so as to be able to treat brain metastases and leptomeningeal disease. Finally, the fourth generation EGFR inhibitors have reduced resistance compared to existing EGFR inhibitors to increase the duration of response in patients.
The above-described properties of fourth generation EGFR inhibitors would allow for the treatment of patients who progress after second line therapy with third generation inhibitors, who currently have no targeted treatment regimen. Furthermore, these properties may also allow fourth generation EGFR inhibitors to provide longer response durations in earlier treatment line patients (e.g., patients progressing in first line axitinib treatment with EGFR C797S mutation and first line patients). The activity of fourth generation EGFR inhibitors against resistant mutations such as T790M, C797X (X = S, G, N), and L792X (X = F, H, Y) may delay resistance by mutations within EGFR targets in NSCLC tumors. The properties outlined above define fourth generation EGFR inhibitors as the first EGFR inhibitors that can effectively target NSCLC tumor patients carrying the EGFR del19/L858R T790M C797X/L792X variant. In addition, fourth generation EGFR inhibitors would be the first C797X active compound that also inhibits the T790M positive allele, has EGFR wild type retention activity and efficiently permeates into the brain.
BI-4020 (chemical name: (R, E) -1 1 ,2 6 7-trimethyl-5 6 - ((4-methylpiperazin-1-yl) methyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-one, of the following structural formula, is a fourth generation, orally active, non-covalent EGFR tyrosine kinase inhibitor developed by Boehringer Invitrogen (Boehringer Ingelheim) pharmaceutical company. Both protein and cell experiments show that it is effective in inhibiting T790M and/or C797S mutant EGFR while retaining activity against wild-type EGFR.
Figure BDA0003651176390000031
Poor absorption, distribution, metabolism and/or excretion (ADME) properties are known to be the major cause of failure in many drug candidate clinical trials. Many drugs currently on the market also have limited their range of application due to poor ADME properties. The rapid metabolism of drugs can result in the difficulty of obtaining many drugs that are otherwise effective in treating disease due to their rapid metabolic clearance from the body. Although frequent or high dose administration may solve the problem of rapid clearance of the drug, this method may cause problems such as poor patient compliance, side effects caused by high dose administration, and increased treatment costs. In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
It is a challenging task to find new potent fourth generation EGFR inhibitors with good oral bioavailability and that are drug-effective. Accordingly, there remains a need in the art to develop compounds having selective inhibitory activity and/or better pharmacodynamics/pharmacokinetics for use as fourth generation EGFR inhibitors, and the present invention provides such compounds.
Disclosure of Invention
In response to the above technical problems, the present invention discloses a novel deuterium substituted macrocyclic compound as a potent fourth generation EGFR inhibitor showing a broad activity against EGFR del19/L858R variants with or without T790M and/or C797S mutations, which ensures that the compounds of the present invention can effectively cope with the expected allelic complexity in patient tumors as a monotherapy. To facilitate effective dose administration and reduce EGFR-mediated on-target toxicity, the compounds of the invention have reduced inhibitory potential for wild-type EGFR, showing higher selectivity across the entire human kinase group. Another property of the compounds of the invention is the potential penetration into the brain (blood brain barrier penetration) for use in the treatment of brain metastases and leptomeningeal diseases. In addition to the inhibitory effect and potency, the compounds of the invention also show good solubility as well as better metabolic stability and/or pharmacokinetic properties.
In contrast, the invention adopts the following technical scheme:
in a first aspect of the invention, there is provided a compound of formula (I):
Figure BDA0003651176390000041
wherein,
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Each independently selected from hydrogen, deuterium or halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient. In a specific embodiment, the compounds of the present invention are provided in an effective amount in the pharmaceutical composition. In a particular embodiment, the compounds of the present invention are provided in a therapeutically effective amount. In particular embodiments, the compounds of the present invention are provided in a prophylactically effective amount. In particular embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.
In another aspect, the present invention provides a method for preparing the pharmaceutical composition as described above, comprising the steps of: a pharmaceutically acceptable excipient is mixed with a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, to form a pharmaceutical composition.
In another aspect, the present invention provides the use of a compound of the present invention, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate compound thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease associated with or mediated by mutant EGFR.
In another aspect, the present invention further provides a method of treating and/or preventing a disease associated with or mediated by mutant EGFR, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of the present invention.
In particular embodiments, the mutant EGFR is selected from EGFR del19, EGFR L858R, EGFR del 19T 790M, EGFR L858R T790M, EGFR del 19T 790M C797X (X = S, G, N), EGFR L858R T790M C797X (X = S, G, N), EGFR del 19T 790M L792X (X = F, H, Y), or EGFR L858R 790M L792X (X = F, H, Y); preferably, the mutant EGFR is selected from EGFR del19, EGFR L858R, EGFR del 19T 790M, EGFR L858R T790M, EGFR del 19T 790M C797S or EGFR L858R T790M C797S.
In particular embodiments, the disease associated with or mediated by mutant EGFR is cancer; preferably, the cancer is selected from lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, stomach cancer, mesothelioma, and metastases thereof (especially brain metastases); preferably, the lung cancer is selected from non-small cell lung cancer, including locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology; more preferably, the lung cancer is NSCLC adenocarcinoma.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description, examples and claims.
Definition of
Herein, "deuterated", unless otherwise specified, means that one or more hydrogens of a compound or group are replaced with deuterium; deuterium substitution can be mono-substitution, di-substitution, multi-substitution or full substitution. The terms "deuterated one or more" and "deuterated one or more" are used interchangeably.
Herein, unless otherwise specified, "non-deuterated compound" means a compound containing deuterium at an atomic ratio of deuterium not higher than the natural deuterium isotope content (0.015%).
As used herein, the term "subject" includes, but is not limited to: a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an older adult)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., a cynomolgus monkey, a rhesus monkey), a cow, a pig, a horse, a sheep, a goat, a rodent, a cat, and/or a dog. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human animal.
"disease," "disorder," and "condition" are used interchangeably herein.
As used herein, unless otherwise specified, the term "treatment" includes the effect that occurs when a subject has a particular disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or delays or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes the effect that occurs before the subject begins to have the particular disease, disorder or condition ("prophylactic treatment").
Generally, an "effective amount" of a compound is an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, disease to be treated, mode of administration, and age health and condition of the subject. An effective amount includes both therapeutically and prophylactically therapeutically effective amounts.
As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.
As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of other prophylactic agents.
"combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the present invention may be administered simultaneously or sequentially with another therapeutic agent in a separate unit dosage form, or simultaneously with another therapeutic agent in a single unit dosage form.
Abbreviations
Mes: mesyl radical
Ts: p-toluenesulfonyl radical
Boc: boc-butoxy group
Cbz: benzyloxycarbonyl group
Fmoc: fmoc group
And (3) Alloc: allyloxycarbonyl radical
Teco:2- (trimethylsilyl) ethyl acetate
Bn: benzyl radical
SEM-Cl:2- (trimethylsilyl) ethoxymethyl chloride
NIS: n-iodosuccinimide
DBBPY:4,4 '-di-tert-butyl-2, 2' -bipyridine
Pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium
Dess-Martin period: 1, 1-tris (acetoxy) -1, 1-dihydro-1, 2-benziodo-3- (1H) -one
NaBH(OAc) 3 : sodium tris (acetoxy) borohydride
TBTU: o- (1H-benzotriazol-3-yl) -N, N, N ', N' -tetramethylhexa-urea tetrafluorophosphate
Cs 2 CO 3 : cesium carbonate
K 2 CO 3 : potassium carbonate
NaH: sodium hydride
DIPEA: n, N-diisopropylethylamine
HCl: hydrochloric acid
Tol: toluene
And (3) MTBE: methyl tert-butyl ether
1,4-dioxane:1, 4-dioxane
i-PrOH: isopropanol (I-propanol)
EA: ethyl acetate
THF: tetrahydrofuran (THF)
DCM: methylene dichloride
DMF: n, N-dimethylformamide
Detailed Description
Compound (I)
Herein, "compound of the present invention" refers to compounds of formula (I) -formula (V) below and subsets thereof (e.g., compounds of formula (IA), formula (IB)), or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates, or solvate compounds thereof.
In one embodiment, the invention relates to compounds of formula (I):
Figure BDA0003651176390000091
wherein,
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Each independently selected from hydrogen, deuterium or halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In a particular embodiment, the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 99%.
Specifically, Y in the present invention 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 The deuterium isotope content of each deuterated position of (a) is at least greater than the natural isotope content by 0.015%, more preferably greater than 1%, more preferably greater than 5%, more preferably greater than 10%, more preferably greater than 15%, more preferably greater than 20%, more preferably greater than 25%, more preferably greater than 30%, more preferably greater than 35%, more preferably greater than 40%, more preferably greater than 45%, more preferably greater than 50%, more preferably greater than 55%, more preferably greater than 60%, more preferably greater than 65%, more preferably greater than 70%, more preferably greater than 75%, more preferably greater than 80%, more preferably greater than 85%, more preferably greater than 90%, more preferably greater than 95%, more preferably greater than 99%.
In another embodiment, the compounds of the present invention contain at least one deuterium atom, preferably two deuterium atoms, more preferably three deuterium atoms, more preferably four deuterium atoms, more preferably five deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably eight deuterium atoms, more preferably nine deuterium atoms, more preferably ten deuterium atoms, more preferably eleven deuterium atoms, more preferably twelve deuterium atoms, more preferably thirteen deuterium atoms, more preferably fourteen deuterium atoms, more preferably fifteen deuterium atoms, more preferably sixteen deuterium atoms, more preferably seventeen deuterium atoms, more preferably eighteen deuterium atoms, more preferably nineteen deuterium atoms, more preferably twenty deuterium atoms, still more preferably twenty-one deuterium atoms, still more preferably twenty-two deuterium atoms, still more preferably twenty-three deuterium atoms, still more preferably twenty-four deuterium atoms, still more preferably twenty-five deuterium atoms, still more preferably twenty-six deuterium atoms, still more preferably twenty-seven deuterium atoms, still more preferably twenty-eight deuterium atoms, still more preferably twenty-nine deuterium atoms, still more preferably thirty-ten deuterium atoms, still more preferably thirty-one deuterium atoms, still more preferably thirty-two deuterium atoms, still more preferably thirty-three deuterium atoms, still more preferably thirty-four deuterium atoms, still more preferably thirty-five deuterium atoms, still more preferably thirty-six deuterium atoms, still more preferably thirty-seven deuterium atoms.
In another specific embodiment, "Y" is 1 、Y 2 、Y 3 、Y 4 、Y 5 And Y 6 Each independently selected from hydrogen, deuterium or halogen "including Y 1 Selected from hydrogen, deuterium or halogen, Y 2 Selected from hydrogen, deuterium or halogen, Y 3 Selected from hydrogen, deuterium or halogen, and so on, up to Y 6 Selected from hydrogen, deuterium or halogen. More specifically, includes Y 1 Is hydrogen, Y 1 Is deuterium or Y 1 Is halogen (F, cl, br or I), Y 2 Is hydrogen, Y 2 Is deuterium or Y 2 Is halogen (F, cl, br or I), Y 3 Is hydrogen, Y 3 Is deuterium or Y 3 Is halogen (F, cl, br or I), and so on, up to Y 6 Is hydrogen, Y 6 Is deuterium or Y 6 Is a technical proposal of halogen (F, cl, br or I).
In another embodiment, "R" is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Each independently selected from hydrogen or deuterium "including R 1 Selected from hydrogen or deuterium, R 2 Selected from hydrogen or deuterium, R 3 Selected from hydrogen or deuterium, and so on, up to R 19 Selected from hydrogen or deuterium. More specifically, includes R 1 Is hydrogen or R 1 Is deuterium, R 2 Is hydrogen or R 2 Is deuterium, R 3 Is hydrogen or R 3 Is deuterium, and so on, R 19 Is hydrogen or R 19 Is a technical scheme of deuterium.
In another embodiment, "X" is 1 、X 2 And X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D' includes X 1 Is selected from CH 3 、CD 3 、CHD 2 Or CH 2 D,X 2 Is selected from CH 3 、CD 3 、CHD 2 Or CH 2 D, and X 3 Is selected from CH 3 、CD 3 、CHD 2 Or CH 2 And D, technical scheme. More specifically, including X 1 Is CH 3 、X 1 Is a CD 3 、X 1 Is CHD 2 Or X 1 Is CH 2 D,X 2 Is CH 3 、X 2 Is a CD 3 、X 2 Is CHD 2 Or X 2 Is CH 2 D, and X 3 Is CH 3 、X 3 Is a CD 3 、X 3 Is CHD 2 Or X 3 Is CH 2 And D, technical scheme.
In another specific embodiment, "X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D' includes X 4 Is H, X 4 Is CH 3 、X 4 Is a CD 3 、X 4 Is CHD 2 Or X 4 Is CH 2 Technical scheme D
In another embodiment, the invention relates to compounds of formula (IA):
Figure BDA0003651176390000111
wherein,
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Each independently selected from hydrogen, deuterium or halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (IB):
Figure BDA0003651176390000121
wherein,
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Each independently selected from hydrogen, deuterium or halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In some embodiments of general formula (I), formula (IA) and formula (IB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 Is a CD 3 ,Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (I), formula (IA) and formula (IB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 Is a CD 3 ,Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (I), formula (IA) and formula (IB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 Is a CD 3 ,Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (I), formula (IA) and formula (IB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 4 Is a CD 3 ,Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 3 As defined above.
In another embodiment, the invention relates to compounds of formula (II):
Figure BDA0003651176390000131
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (IIA):
Figure BDA0003651176390000141
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the present invention relates to compounds of formula (IIB):
Figure BDA0003651176390000151
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 3 And X 4 As defined above.
In the general formula (II),In some embodiments of formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein R is 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R is 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 2 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 And X 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 2 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically thereofAn acceptable salt, hydrate or solvent compound, wherein X 3 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 4 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 4 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, X 1 、X 2 、X 3 And X 4 As defined above.
In some embodiments of formula (II), formula (IIA) and formula (IIB), it is preferred that the present inventionThe invention relates to the compound, or tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent compound thereof, wherein X is 1 、X 2 And X 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 、X 2 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 2 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 2 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 3 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 、X 3 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 2 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 3 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 3 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Is deuterium, R 10 、R 11 、X 2 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 4 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 4 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 2 And X 3 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 、X 3 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 14 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 And X 3 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 And X 3 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 And X 4 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 And X 4 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 2 As defined above.
In some embodiments of general formula (II), formula (IIA) and formula (IIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 And X 4 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 And X 2 As defined above.
In another embodiment, the invention relates to compounds of formula (III):
Figure BDA0003651176390000211
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (IIIA):
Figure BDA0003651176390000212
Figure BDA0003651176390000221
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (IIIB):
Figure BDA0003651176390000222
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 Is a CD 3 ,X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 Is a CD 3 ,X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 3 Is a CD 3 ,X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 4 Is a CD 3 ,X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 2 Is a CD 3 ,X 3 And X 4 As defined above.
In some embodiments of formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above-mentioned compounds, orA tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent compound thereof, wherein X is 1 And X 3 Is a CD 3 ,X 2 And X 4 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 4 Is a CD 3 ,X 2 And X 3 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 And X 3 Is a CD 3 ,X 1 And X 4 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 And X 4 Is a CD 3 ,X 1 And X 3 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 、X 2 And X 3 Is a CD 3 ,X 4 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 、X 2 And X 4 Is a CD 3 ,X 3 As aboveAs defined.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 、X 3 And X 4 Is a CD 3 ,X 2 As defined above.
In some embodiments of general formula (III), formula (IIIA) and formula (IIIB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 、X 3 And X 4 Is a CD 3 ,X 1 As defined above.
In another embodiment, the invention relates to a compound of formula (IV):
Figure BDA0003651176390000241
wherein,
R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (IVA):
Figure BDA0003651176390000251
R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (IVB):
Figure BDA0003651176390000261
R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In the general formula (IV), formula (IVA) andin some embodiments of formula (IVB), preferably, the present invention relates to the above compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 1 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein R is 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein R is 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 2 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 1 And X 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 2 And X 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-mentioned compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, thereof,A hydrate or a solvent compound, wherein X 3 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 2 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 3 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 3 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 4 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the invention relates toAnd the compounds, or tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent compound thereof, wherein X 4 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, X 1 、X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 、X 2 And X 3 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 1 、X 2 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 2 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 2 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 3 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 、X 3 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 2 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 3 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 1 And X 3 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Is deuterium, R 10 、R 11 、X 2 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 4 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 2 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 4 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 2 And X 3 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 2 、X 3 And X 4 Is a CD 3 ,R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 And X 1 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to a compound as described above, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein X is 2 And X 3 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 And X 3 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 And X 4 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-described compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 3 And X 4 Is a CD 3 ,R 10 And R 11 Is deuterium, R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 And X 2 As defined above.
In some embodiments of general formula (IV), formula (IVA) and formula (IVB), preferably, the present invention relates to the above-mentioned compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or thereofA solvent compound of which X 3 And X 4 Is a CD 3 ,R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium, R 10 、R 11 、X 1 And X 2 As defined above.
In another embodiment, the invention relates to compounds of formula (V):
Figure BDA0003651176390000321
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
Or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (VA):
Figure BDA0003651176390000322
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
Or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In another embodiment, the invention relates to compounds of formula (VB):
Figure BDA0003651176390000331
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
Or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 Is a CD 3 ,X 2 、X 3 And X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 Is a CD 3 ,X 1 、X 3 And X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 3 Is a CD 3 ,X 1 、X 2 And X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 4 Is a CD 3 ,X 1 、X 2 And X 3 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 1 And X 2 Is a CD 3 ,X 3 And X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 3 Is a CD 3 ,X 2 And X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 And X 4 Is a CD 3 ,X 2 And X 3 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 And X 3 Is a CD 3 ,X 1 And X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 2 And X 4 Is a CD 3 ,X 1 And X 3 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable thereofA salt, hydrate or solvent compound of formula (I), wherein X 1 、X 2 And X 3 Is a CD 3 ,X 4 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 、X 2 And X 4 Is a CD 3 ,X 3 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, wherein X is 1 、X 3 And X 4 Is a CD 3 ,X 2 As defined above.
In some embodiments of general formula (V), formula (VA) and formula (VB), preferably, the present invention relates to the above compounds, or tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvate thereof, wherein X is 2 、X 3 And X 4 Is a CD 3 ,X 1 As defined above.
As a preferred embodiment of the present invention, the compound, or tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, is selected from any one of the following compounds:
Figure BDA0003651176390000351
Figure BDA0003651176390000361
Figure BDA0003651176390000371
Figure BDA0003651176390000381
Figure BDA0003651176390000391
Figure BDA0003651176390000401
Figure BDA0003651176390000411
Figure BDA0003651176390000421
Figure BDA0003651176390000431
Figure BDA0003651176390000441
Figure BDA0003651176390000451
Figure BDA0003651176390000461
the compounds of the invention may include one or more asymmetric centers and may therefore exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC) and the formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.
One skilled in the art will appreciate that the organic compound may form a complex with the solvent in which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.
The term "solvate" refers to a form of a compound or salt thereof that is combined with a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes a solvate in a solution state and a solvate which can be isolated. Representative solvates include hydrates, ethanolates, and methanolates.
The term "hydrate" refers to a compound that is associated with an aqueous phase. In general, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, hydrates of the compounds can be used, for example, of the formula R.xH 2 O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrates (x is a number greater than 0 and less than 1), e.g., hemihydrate (R0.5H) 2 O)) and polyhydrates (x is a number greater than 1, e.g.Dihydrate of (R.2H) 2 O) and hexahydrate (R.6H) 2 O))。
The compounds of the invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may result in a crystalline form being favored. Various polymorphs of a compound may be prepared by crystallization under different conditions.
The invention also includes isotopically-labeled compounds, which are identical to those recited in the present invention, 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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and 36 and (4) Cl. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, e.g. by incorporation of a radioactive isotope (e.g. by introduction of a radioactive isotope) 3 H and 14 c) Can be used in drug and/or substrate tissue distribution assays. Tritium, i.e. 3 H and carbon-14, i.e. 14 The C isotopes are particularly preferred because of their ease of preparation and detection. Further, by heavier isotopes, e.g. deuterium, i.e. 2 H, can provide therapeutic benefits due to higher metabolic stabilityFor example, to increase in vivo half-life or to reduce dosage requirements and may therefore be preferred in some circumstances. Isotopically labeled compounds of formula (I) and prodrugs thereof of the present invention can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, for example in the blood, into its active form, which has a medicinal effect. Pharmaceutically acceptable Prodrugs are described in t.higuchi and v.stella, prodrugs as Novel Delivery Systems, vol.14 of a.c.s.symposium Series, edward b.roche, ed., bioresorbable Carriers in drugs Design, american Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.barba "Improved organic Delivery: solubility limits are provided for each of the users of the produgs ", advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.
A prodrug is any covalently bonded compound of the present invention that releases the parent compound in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a manner such that the modification is effected by routine manipulation or in vivo cleavage to produce the parent compound. Prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, cleaves to form a hydroxy, amino, or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of hydroxy, mercapto, and amino functional groups of the compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like may be used. The ester itself may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which readily break down in the human body to release the parent acid or salt thereof.
Preparation of the HairMethods of treating cancer
The compounds of the invention (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below. The reaction for preparing the compounds of the present invention may be carried out in a suitable solvent, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reaction is carried out (e.g., temperatures in the range of solvent freezing temperatures to solvent boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. The skilled person can select the solvent for a particular reaction step depending on the particular reaction step.
The preparation of the compounds of the invention may involve the protection and deprotection of different chemical groups. One skilled in the art can readily determine whether protection and deprotection is required and the choice of an appropriate protecting group. The chemistry of protecting Groups can be found, for example, in Wuts and Greene, protective Groups in Organic Synthesis, 4 th edition, john Wiley & Sons: new Jersey, (2006), which is incorporated herein by reference in its entirety.
The compound of the present invention can be prepared by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers thereof, into their individual stereoisomers. Enantiomeric resolution can be carried out using diastereomeric derivatives of the compounds of the invention, preferentially dissociative complexes (e.g., crystalline diastereomeric salts). Diastereomers have significantly different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and can be readily separated by virtue of these dissimilarities. Diastereomers may be separated by chromatography, preferably by separation/resolution techniques based on differences in solubility. The optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not racemize. A more detailed description of techniques suitable for resolution of stereoisomers of compounds starting from racemic mixtures can be found in Jean Jacques, andre Collet, samue1 H.Wilen, "Enantiomers, racemates And resolution" ("Enantiomers, racemes And resolution"), john Wiley And Sons, inc.,1981.
The reaction may be monitored by any suitable method known in the art. For example, it can be determined by spectroscopic means, such as Nuclear Magnetic Resonance (NMR) spectroscopy (e.g. 1 H or 13 C) Infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible light), mass Spectrometry (MS)), or by chromatographic methods such as High Performance Liquid Chromatography (HPLC) or Thin Layer Chromatography (TLC).
General reaction schemes and synthetic schemes
Compound I can be obtained by the synthetic route in scheme 1. Specifically, compound B forms compound a under deprotection agent (e.g., alcoholic solution of inorganic acid) conditions, and then compound a is reacted with a methylating agent (e.g., trideuteroiodomethane, deuterated formaldehyde heavy aqueous solution, and NaBD) 3 CN, deuterated paraformaldehyde, deuterated formic acid, deuterated methanol and bis (triphenylphosphine) cyclopentadienyl ruthenium (II) chloride, methyl iodide, aqueous formaldehyde solution and NaBH 3 CN, paraformaldehyde and formic acid, methanol and bis (triphenylphosphine) cyclopentadienyl ruthenium (II) chloride) to obtain a compound A. Compound a is resolved by chirality to give compounds IA and IB.
Scheme 1
Figure BDA0003651176390000501
Wherein PG 1 Selected from Boc, cbz, fmoc, alloc, teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, bn, p-methoxybenzyl and Ts.
The key intermediate compound B can be prepared by method a/a' of the synthetic route in scheme 2. Compound B can be cyclized from open-chain compound C-a by amide formation. The cyclization reaction can be carried out directly using a strong base (e.g., 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene) to form the amide bond (method A), or by first hydrolyzing the ester functional group in compound C-a and then forming the amide bond by a coupling reagent (e.g., TBTU, HATU) (method A').
Alternatively, compound B may be prepared by method B of the synthetic route in scheme 2. Compound B can be cyclized from the open-chain compound C-B by ether formation. The cyclization reaction can directly form ether bonds through a Mitsonobu reaction, or alcohol energy groups in the compound C-b are firstly converted into halogen or sulfonic acid, and then ether bonds are formed through a nucleophilic substitution reaction.
Scheme 2
Figure BDA0003651176390000511
Wherein R is selected from C 1-6 Alkyl, phenyl, and the like.
The key intermediate C-a can be prepared by the method of the synthetic route in scheme 3. Compound C-a can be prepared from the reduction of compound E and cyanogen bromide mediated cyclization of compound D.
Scheme 3
Figure BDA0003651176390000512
Pharmaceutical compositions, formulations and kits
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.
Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The invention also includes kits (e.g., pharmaceutical packages). The provided kits can include a compound of the invention, an additional therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispensable packages or other suitable containers) containing the compound of the invention, the additional therapeutic agent. In some embodiments, provided kits may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, the compound of the present invention and the additional therapeutic agent provided in the first container and the second container are combined to form one unit dosage form.
The pharmaceutical compositions provided by the present invention may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implant or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebrospinal administration, intralesional administration, and intracranial injection or infusion techniques.
Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by a physician, as the case may be, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
When used to prevent a condition described herein, a subject at risk of developing the condition is administered a compound provided herein, typically based on the recommendations of a physician and under the supervision of a physician, at a dosage level as described above. Subjects at risk of developing a particular disorder, typically include subjects with a family history of the disorder, or those determined to be particularly susceptible to developing the disorder by genetic testing or screening.
The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). By long-term administration is meant administration of the compound or pharmaceutical composition thereof over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue for an indefinite period of time, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within the therapeutic window.
Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to rapidly increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the targeted systemic level of the active ingredient, e.g., an intramuscular or subcutaneous bolus dose results in a slow release of the active ingredient, while a bolus delivered directly to the vein (e.g., by IV intravenous drip) can be delivered more rapidly, allowing the concentration of the active ingredient in the blood to rise rapidly to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV intravenous drip, to provide a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form for convenient accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for the purpose of producing the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful in forming the desired form of administration.
For oral doses, a representative regimen is one to five oral doses per day, in particular two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing about 0.1 to about 10mg/kg, especially about 1 to about 5mg/kg.
In order to provide blood levels similar to, or lower than, those used with the injected dose, transdermal doses are generally selected in amounts of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. In order to obtain sufficient steady state levels, a preload bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.
Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, as well as buffers, suspending and dispersing agents, coloring and flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds with similar properties: a binder, for example, microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example, starch or lactose, disintegrants, for example, alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, e.g., colloidal silicon dioxide; sweetening agents, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with a cream base, for example of the oil-in-water type. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope of the present invention.
The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration may be accomplished using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.
The above components of the compositions for oral, injectable or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceutical Sciences,17th edition,1985, mack Publishing company, easton, pennsylvania, section 8, which is incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitution. In some embodiments, the cyclodextrin is sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, e.g., U.S.5,376,645. In some embodiments, the formulation includes hexapropyl- β -cyclodextrin (e.g., 10-50% in water).
Indications of
In one aspect, the disease treated and/or prevented with a compound of formula (I) (including all individual embodiments and sub-groups of genera disclosed herein) or in a method of medical use, treatment and/or prevention as defined herein is selected from lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer and mesothelial cancer, including metastases (especially brain metastases) of all cancers listed.
In another aspect, the disease treated and/or prevented with a compound of formula (I) or in a method of medical use, treatment and/or prevention as defined herein is lung cancer. Preferably, the lung cancer is non-small cell lung cancer (NSCLC), including, for example, locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology. More preferably, the lung cancer is NSCLC adenocarcinoma.
In another aspect, the disease treated and/or prevented with a compound of formula (I) or in a method for medical use, treatment and/or prevention as defined herein is a disease carrying the EGFR genotype, preferably the disease is a cancer carrying the EGFR genotype. Specifically, the EGFR genotype is selected from the group consisting of EGFR del19, EGFR del 19T 790M, EGFR del 19C 797S, EGFR del 19C 797X (preferably C797G or C797N), EGFR del 19T 790M C797S, EGFR del 19T 790M C797X (preferably C797G or C797N), EGFR del 19L 792X (preferably L792F, L792H or L792Y), EGFR del 19T 790M 792X (preferably L792F, L792H or L792Y), EGFR L858R, EGFR L858R T790M, EGFR L858R C797S, EGFR L858R C797X (preferably C797G or C797N), EGFR L858R T790M C797S, EGFR L858R T790M C797X (preferably C797G or C797N), EGFR L858R L792X (preferably L792F, L792H or L792Y), EGFR L858R 790M 792X (preferably L792F, L792H or L792Y).
Thus, in one aspect, the cancer is a cancer carrying the EGFR del19 genotype. Preferably, cancer patients carrying the EGFR del19 genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a first line therapy, i.e. the patient is initially treated with an EGFR inhibitor.
In another aspect, the cancer is a cancer bearing the EGFR del 19T 790M genotype. Preferably, cancer patients carrying the EGFR del 19T 790M genotype are administered a compound of formula (I), including all individual embodiments and generic subsets disclosed herein, as a second line therapy, i.e. patients who progress after first line treatment with first or second generation EGFR inhibitors (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib).
In another aspect, the cancer is a cancer bearing the EGFR del 19C 797S genotype. Preferably, cancer patients carrying the EGFR del 19C 797S genotype are administered the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second-line therapy, i.e. patients who progress after the first-line therapy with a third-generation EGFR inhibitor (i.e. treatment with ocitinib, amitinib, voretinib).
In another aspect, the cancer is a cancer carrying the EGFR del 19C 797X (preferably C797G or C797N) genotype. Preferably, cancer patients carrying an EGFR del 19C 797X (preferably C797G or C797N) genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second line therapy, i.e. patients who progress after the first line therapy with a third generation EGFR inhibitor (i.e. treatment with ocitinib, amitinib, fulvestrant).
In another aspect, the cancer is a cancer carrying EGFR del 19T 790M C797S genotype. Preferably, cancer patients carrying the EGFR del 19T 790M C797S genotype are administered the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a third line therapy, i.e., patients have progressed on first line therapy with first or second generation EGFR inhibitors (i.e., gefitinib, erlotinib, afatinib, or dacomitinib treatment) after achieving T790M, and patients progress on second line therapy with third generation EGFR inhibitors (i.e., with ocitinib, attetinib, or veertinib) after achieving C797S.
In another aspect, the cancer is a cancer carrying the EGFR del 19T 790M C797X (preferably C797G or C797N) genotype. Preferably, cancer patients carrying the EGFR del 19T 790M C797X (preferably C797G or C797N) genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a third line therapy, i.e., patients progress on the first line therapy with a first or second generation EGFR inhibitor (i.e., gefitinib, erlotinib, afatinib, or dacomitinib treatment) after achieving T790M, and patients progress on the second line therapy with a third generation EGFR inhibitor (i.e., with oxitinib, amitinib, or lumitinib) after achieving C797X (preferably C797G or C797N).
In another aspect, the cancer is a cancer carrying the EGFR del 19L 792X (preferably L792F, L792H or L792Y) genotype. Preferably, cancer patients carrying the EGFR del 19L 792X (preferably L792F, L792H or L792Y) genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second line therapy, i.e. patients who progress after the first line therapy with a third generation EGFR inhibitor (i.e. treatment with ocitinib, amitinib, voretinib).
In another aspect, the cancer is a cancer carrying the EGFR del 19T 790M L792X (preferably L792F, L792H or L792Y) genotype. Preferably, cancer patients carrying the EGFR del 19T 790M L792X (preferably L792F, L792H or L792Y) genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a third line therapy, i.e. patients are progressing on first line therapy with a first or second generation EGFR inhibitor (i.e. gefitinib, erlotinib, afatinib or dacomitinib therapy) after T790M is achieved and patients progress on second line therapy with a third generation EGFR inhibitor (i.e. with axitinib, apitinib or vacetinib) after L792X (preferably L792F, L792H or L792Y) is achieved.
In one aspect, the cancer is a cancer carrying EGFR L858R genotype. Preferably, cancer patients carrying the EGFR L858R genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a first line therapy, i.e. the patient is initially treated with an EGFR inhibitor.
In another aspect, the cancer is a cancer bearing the EGFR L858R T790M genotype. Preferably, cancer patients carrying the EGFR L858R T790M genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second line therapy, i.e. patients who progress after first line therapy with first or second generation EGFR inhibitors (i.e. treatment with gefitinib, erlotinib, afatinib or dacomitinib).
In another aspect, the cancer is a cancer carrying the EGFR L858R C797S genotype. Preferably, cancer patients carrying the EGFR L858R C797S genotype are administered the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second-line therapy, i.e. patients who progress after the first-line therapy with a third-generation EGFR inhibitor (i.e. treatment with oxitinib, almitinib, voretinib).
In another aspect, the cancer is a cancer carrying the EGFR L858R C797X (preferably C797G or C797N) genotype. Preferably, cancer patients carrying the EGFR L858R C797X (preferably C797G or C797N) genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second line therapy, i.e. patients who progress after the first line therapy with a third generation EGFR inhibitor (i.e. treatment with oxitinib, ametinib, vormetinib).
In another aspect, the cancer is a cancer carrying the EGFR L858R T790M C797S genotype. Preferably, cancer patients carrying the EGFR L858R T790M C797S genotype are administered the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a third line therapy, i.e., patients have progressed on first line therapy with first or second generation EGFR inhibitors (i.e., gefitinib, erlotinib, afatinib, or dacomitinib treatment) after achieving T790M, and patients progress on second line therapy with third generation EGFR inhibitors (i.e., with ocitinib, attetinib, or lumitinib) after achieving C797S.
In another aspect, the cancer is a cancer carrying the EGFR L858R T790M C797X (preferably C797G or C797N) genotype. Preferably, cancer patients carrying the EGFR L858R T790M C797X (preferably C797G or C797N) genotype are administered the compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a third line therapy, i.e. patients have progressed on the first line therapy with first or second generation EGFR inhibitors (i.e. gefitinib, erlotinib, afatinib or dacomitinib treatment) after achieving T790M, and patients progress on the second line therapy with third generation EGFR inhibitors (i.e. with oxitinib, amitinib or lumitinib) after achieving C797X (preferably C797G or C797N).
In another aspect, the cancer is a cancer carrying the EGFR L858R L792X (preferably L792F, L792H or L792Y) genotype. Preferably, a cancer patient carrying the EGFR L858R L792X (preferably L792F, L792H or L792Y) genotype is administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a second line therapy, i.e. a patient who progresses after first line therapy with a third generation EGFR inhibitor (i.e. treatment with oxitinib, armetinib, voretinib).
In another aspect, the cancer is a cancer carrying the EGFR L858R T790M L792X (preferably L792F, L792H or L792Y) genotype. Preferably, cancer patients carrying the EGFR L858R T790M L792X (preferably L792F, L792H or L792Y) genotype are administered a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) as a third line therapy, i.e. patients are progressing on first line therapy with a first or second generation EGFR inhibitor (i.e. gefitinib, erlotinib, afatinib or dacomitinib therapy) after achieving T790M, and patients progressing on second line therapy with a third generation EGFR inhibitor (i.e. with axitinib, apitinib or vacetinib) after achieving L792X (preferably L792F, L792H or L792Y).
Combination therapy
In another aspect, the pharmacologically active substance used together/in combination or in a method of medical use, treatment and/or prevention as defined herein, of a compound of formula (I) (including all individual embodiments and generic subsets disclosed herein) may be selected from any one or more of the following (preferably, only one further pharmacologically active substance is used in all these embodiments):
inhibitors of EGFR and/or variants thereof
Egfr inhibitors, e.g., gefitinib, erlotinib, afatinib, dacotinib, lapatinib, oxitinib, amitinib, fulvatinib;
egfr antibodies, e.g., cetuximab, panitumumab, tolituzumab.
Inhibitors of MEK inhibitors and/or variants thereof
For example, trametinib (trametinib), cobinetinib (cobimetinib), bimetinib (binimetinib), semetinib (selumetinib), rifatinib (refametinib).
3.c-MEK inhibitors and/or variant inhibitors thereof
a. For example, voritinib (savolitinib), cabozantinib (cabozantinib), foretinib;
mek antibodies, e.g., amiebuzumab (emibetuzumab).
4. Mitotic inhibitors
For example, CDK4/6 inhibitors, e.g., palbociclib (palbociclib), ribociclib (ribociclib), abercinib (abemacciclib).
5. Immunotherapeutic agent
a. Immune checkpoint inhibitors, e.g., anti-CTLA 4 mAB, anti-PD 1 mAB, anti-PD-L2 mAB, anti-LAG 3 mAB, or anti-TIM 3 mAB; preferably, an anti-PD 1 mAb; preferably, for example, ipilimumab, nivolumab, parbolizumab (pembrolizumab), atelizumab (atezolizumab), avizumab (avelumab), de wauzumab (durvalumab), pidilizumab (pidilizumab), PDR-001 (BAP 049-clone-E, disclosed and used in WO 2017/019896);
b. immunomodulator
For example, a CD73 inhibitor or a CD73 inhibitor antibody.
6. Anti-angiogenic agents
For example, bevacizumab, nintedanib;
7. apoptosis inducer
Bcl-2 inhibitors
For example, venetinib (venetocalax), obacara (obatoclax), navitoclax;
mcl-1 inhibitors
Such as AZD-5991, AMG-176, S-64315.
mTOR inhibitors
Such as rapamitotin, temsirolimus, everolimus, and diphospholimus.
9. Histone deacetylase inhibitors
10.IL6 inhibitors
Inhibitors of JAK
Examples
The invention will be further illustrated by reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Parts and percentages are parts and percentages by weight unless otherwise indicated.
Preparation of intermediate F-1- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6-methyl isonicotinate methyl ester hydrochloride
Figure BDA0003651176390000601
The following synthetic route is adopted
Figure BDA0003651176390000602
Step 1 Synthesis of Compound 2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one
1-methyl-1H-pyrazol-5-ol (49.0 g,0.5 mol) and acetonitrile (1.5L) were sequentially added to a 3L single-neck flask equipped with magnetic stirring, the mixture was stirred to dissolve, potassium carbonate (138.0 g,1.0 mmol) was added, the mixture was stirred at room temperature for half an hour, SEM-Cl (124.5 g, 0.75mol) was slowly added dropwise, and the reaction was stirred at room temperature under nitrogen overnight. Insoluble solids were filtered off, washed with acetonitrile (100 mL), the filtrate was concentrated to dryness, water (200 mL) was added, MTBE extracted (300 mLx 3), dried over anhydrous sodium sulfate, filtered, concentrated until a solid precipitated, the concentration was stopped, petroleum ether (1.5L) was added with stirring to precipitate a large amount of white solid, filtered, washed with petroleum ether (100 mL), and the filter cake was dried under vacuum to give 70.5g of this white solid in 61.84% yield. LC-MS (APCI) M/z =229.2 (M + 1) + . 1 H NMR(500MHz,CDCl 3 )δ(ppm):7.29(d,J=3.5Hz,1H),5.49(d,J=3.5Hz,1H),4.99(s,2H),3.47-3.43(m,5H),0.89-0.86(m,2H),0.00(s,9H).
Step 2 Synthesis of Compound 4-iodo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one
2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one (45.6 g,0.2 mol) and acetonitrile (1.0L) are added into a 3L single-neck bottle with magnetic stirring, stirred to be dissolved clearly, cooled in an ice-water bath, NIS (44.8g, 0.2 mol) is slowly added, after the addition, the ice-water bath is removed, and the reaction is stirred at room temperature under nitrogen for 2 hours. Concentrating under reduced pressure, adding ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate (200 mL) into the residue, stirring for 10 min, separating out the organic phase, extracting the aqueous phase with ethyl acetate (200 mL), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating until a solid is separated out, stopping concentrating, adding petroleum ether (600 mL) with stirring to separate out a large amount of yellow solid, filtering, washing with petroleum ether (50 mL), and drying the filter cake under vacuum to obtain 60.5g of the yellow solid with the yield of 85.5%. LC-MS (APCI) M/z =355.1 (M + 1) + . 1 H NMR(500MHz,CDCl 3 )δ(ppm):7.43(s,1H),4.98(s,1H),3.49-3.43(m,5H),0.89-0.84(m,2H),0.89-0.86(m,2H),0.00(s,9H).
Step 3 Synthesis of methyl 2-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isonicotinate, compound
Methyl 2-chloroisonicotinate (80g, 0.47mol) was added to a 3L three-necked flask equipped with magnetic stirring, evacuated and replaced with nitrogen three times under nitrogen for further use.
To another 3L three-necked flask equipped with magnetic stirring, pinacol diboron (142g, 0.56mol), methoxy (cyclooctadiene) iridium dimer (5.5g, 8.3 mmol), and DBBPY (4.5g, 16.8 mmol) were added in this order, evacuated and replaced with nitrogen three times, and dry MTBE (1.2L) was pumped in, and stirred under nitrogen for 15 minutes to give a brownish red solution. The solution was pumped into a reaction flask of methyl 2-chloroisonicotinate under nitrogen and the reaction stirred at room temperature under nitrogen for 64 hours. Insoluble solids are filtered, the filtrate is concentrated to dryness under reduced pressure, petroleum ether (200 mL) is added into the residue, stirring is carried out for 20 minutes, a large amount of off-white solids are separated out, filtering is carried out, petroleum ether is used for washing (20 mL), and vacuum drying is carried out to obtain 61.5g of off-white solids with the yield of 44.0%. LC-MS (APCI) M/z =298.1 (M + 1) + . 1 H NMR(400MHz,CDCl 3 )8.24(s,1H),7.88(s,1H),3.95(s,3H),1.37(s,12H).
Step 4 Synthesis of Compound methyl 2-chloro-6- (2-methyl-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate
To a 1L single-neck flask equipped with a magnetic stirring and condensing tube were added 4-iodo-2-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one (35.4 g, 0.1mol), methyl 2-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isonicotinate (35.6 g, 0.12mol), pd in that order 2 (dba) 3 (2.28g, 2.5 mmol), n-butylbis (1-adamantyl) phosphine (2.87g, 8 mmol), cesium carbonate (97.7g, 0.3mol), toluene (250 mL) and water (80 mL), evacuated and replaced with nitrogen three times, heated to 50 ℃ and stirred for 2 hours with heat. Cooling to room temperature, filtering to remove insoluble solid, separating organic phase, extracting with water phase ethyl acetate (100 mLx 2), combining organic phases, drying with anhydrous sodium sulfate,filtration, concentration and passage through a silica gel column gave 28.5g of off-white solid in 71.8% yield. LC-MS (APCI) M/z =398.1 (M + 1) + . 1 H NMR(500MHz,CDCl 3 )δ(ppm):8.84(d,J=1.5Hz,1H),8.15(s,1H),7.64(d,J=1.5Hz,1H),5.16(s,2H),3.94(s,3H),3.55(s,3H),3.51(t,J=8.0Hz,2H),0.90(t,J=8.0Hz,2H),0.01(s,9H).
Step 5 Synthesis of Compound methyl 2-methyl-6- (2-methyl-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate
To a 1L single-necked flask equipped with a magnetic stirring and condenser tube were added in sequence methyl 2-chloro-6- (2-methyl-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate (27.8g, 70mmol), pd 2 (dba) 3 (1.95g, 2.13mmol), n-butylbis (1-adamantyl) phosphine (2.28g, 6.36mmol), cesium carbonate (68.3g, 210mmol) and 1,4-dioxane (350 mL), evacuated and nitrogen replaced 3 times, trimethylcyclotriboroxane (40mL, 140mmol,3.5M tetrahydrofuran solution) was added dropwise under nitrogen atmosphere, and after dropwise addition, the reaction mixture was heated to 80 ℃ and stirred overnight with heat. Cool to room temperature, filter off insoluble solids, wash with ethyl acetate (20 mL), concentrate the filtrate to dryness, add water (150 mL) and ethyl acetate (150 mL), stir for 10 minutes, separate the organic phase, extract the aqueous phase with ethyl acetate (100 mLx 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate and pass through a silica gel column to give 20.5g of a yellow solid in 77.7% yield. LC-MS (APCI) M/z =378.1 (M + 1) + .
Step 5 Synthesis of intermediate Compound F-1
To a 250mL single-neck flask equipped with magnetic stirring were added methyl 2-methyl-6- (2-methyl-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate (20g, 53.1mmol) and ethyl acetate (100 mL) in this order, the solution was stirred, 5M HCl isopropanol solution (60 mL) was added dropwise, and the reaction was stirred under nitrogen for 3 hours. A large amount of yellow solid precipitated, which was diluted with ethyl acetate (100 mL), filtered, washed with ethyl acetate (30 mL) and dried in vacuo to give 14.5g of the yellow solid in 96.6% yield. LC-MS (APCI) M/z =248.1 (M + 1) + .
3 Intermediate F-2- (5-hydroxy-1- (methyl-d) -1H-pyrazol-4-yl) -6-methyl isonicotinic acid methyl ester hydrochloride Preparation of salts
Figure BDA0003651176390000631
The following synthetic route is adopted
Figure BDA0003651176390000632
Step 1 Synthesis of Compound 2-Benzylidene hydrazine-1-carboxylic acid tert-butyl ester
A500 mL single-neck flask equipped with magnetic stirring was charged with t-butoxycarbonylhydrazine (26.4 g,0.2 mol) and anhydrous THF (200 mL), stirred to dissolve, benzaldehyde (27.6 g, 0.26mol) was added, and the reaction was stirred at room temperature under nitrogen overnight. A large amount of white solid was precipitated, and petroleum ether (200 mL) was added thereto, followed by stirring for 10 minutes, filtration, washing with petroleum ether (20 mL) and vacuum drying to obtain 37.6g of the white solid in 85.5% yield.
Step 2 Compound 2-Benzylidene-1- (methyl-d) 3 ) Synthesis of hydrazine-1-carboxylic acid tert-butyl ester
To a 500mL three-necked flask equipped with magnetic stirring was added sodium hydride (7.1g, 177.3mmol, w/w 60%), evacuated and replaced with nitrogen three times, cooled in an ice-water bath, charged with anhydrous THF (250 mL), added dropwise with stirring an anhydrous THF solution of tert-butyl 2-benzylidenehydrazine-1-carboxylate (30g, 136.4mmol, 50mL), stirred for 10 minutes, and added dropwise iodomethane-d 3 (23.7 g,163.7 mmol) was added dropwise thereto, the ice bath was removed, and the reaction was stirred at room temperature under nitrogen for 3 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride (100 mL), the organic phase separated, extracted with aqueous ethyl acetate (100 mLx 2), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a pale yellow solid 26.3g, 81.3% yield. 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.68-7.74(m,2H),7.65(s,1H),7.29-7.44(m,3H),1.59(s,9H).
Step 3 Compound 1- (methyl-d) 3 ) Hydrazine-1-carboxylic acidSynthesis of tert-butyl ester
2-benzylidene-1- (methyl-d) was added simultaneously to 5 250mL single-neck flasks equipped with magnetic stirring 3 ) Hydrazine-1-formic acid tert-butyl ester (5.0 g, 21mol) and methanol (100 mL), stirring to dissolve, adding Pd/C (0.6 g, w/w 10%), vacuumizing and replacing with hydrogen for 3 times, heating to 50 ℃ under hydrogen atmosphere, and keeping the temperature and stirring for reaction overnight. Cooled to room temperature, combined treatments filtered off catalyst, the filter cake washed with methanol (30 mL) and the filtrate concentrated to dryness to give 15.7g of brown oil in 100% yield which was used directly in the next reaction.
Step 4 Compound (methyl-d) 3 ) Synthesis of hydrazine dihydrochloride
To the flask is charged with 1- (methyl-d) 3 ) A250 mL single-neck flask containing tert-butyl hydrazine-1-carboxylate (15.7g, 105mmol) was charged with a 5M isopropanol hydrochloride solution (150 mL) and the reaction was stirred at room temperature under nitrogen overnight. The solvent was distilled off under reduced pressure to give 12.8g of a brown solid in 100% yield, which was used directly in the next reaction.
Step 5 Compound 1- (methyl-d) 3 ) Synthesis of (E) -1H-pyrazol-5-ol
To be filled with (methyl-d) 3 ) Hydrazine dihydrochloride (12.8 g, 105mmol) is added with water (75 mL) in a 250mL single-neck flask, adjusted to pH 9.5 with 50% NaOH aqueous solution by using precision pH paper, heated to 40 ℃, slowly added with 3-methoxy methyl acrylate (111g, 94.5 mmol), added after 1 hour, 50% NaOH aqueous solution is adjusted to pH 9.0-9.5 after the addition is finished, monitored by TLC, when the 3-methoxy methyl acrylate point disappears, the mixture is kept warm and stirred for reaction for 3 hours, during which the mixture is controlled to pH 9.0-9.5, cooled to room temperature and then cooled in ice-water bath, adjusted to pH 3-4 with 6M hydrochloric acid aqueous solution, extracted with dichloromethane (60 mLx 5), the organic phase is combined, dried with anhydrous sodium sulfate, filtered, concentrated to dry to obtain white solid 5.2g, the yield is 49.0%, and the solid is directly used in the next step.
Step 6 Compound 2- (methyl-d 3 ) Synthesis of (E) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one
To the charge with 1- (methyl-d) 3 ) Acetonitrile (100 mL) was added to a 250mL single-neck flask of (E) -1H-pyrazol-5-ol (5.2g, 51.4 mmol), and the mixture was stirred until clear, potassium carbonate (10.6g, 77.1mmol) was added thereto, and the mixture was stirred at room temperature for half an hourSEM-Cl (11.2g, 66.8 mol) was added slowly dropwise thereto, and the reaction was stirred at room temperature under nitrogen overnight. Adding ethyl acetate (100 mL) to dilute the reaction solution, filtering out insoluble solids, washing with ethyl acetate (10 mL), concentrating the filtrate to dryness, adding water (200 mL), extracting with ethyl acetate (60 mLx 3), drying with anhydrous sodium sulfate, filtering, concentrating until solids are precipitated, stopping concentrating, adding petroleum ether (50 mL) under stirring to precipitate a large amount of white solids, filtering, washing with petroleum ether (5 mL), and vacuum-drying the filter cake to obtain 6.56g of the white solids with a yield of 55.2%. LC-MS (APCI) M/z =232.2 (M + 1) + .
Step 7 Compound 4-iodo-2- (methyl-d) 3 ) Synthesis of (E) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one
Adding 2- (methyl-d) to a 250-neck flask equipped with magnetic stirring 3 ) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one (6.5 g, 28.1mmol) and acetonitrile (100L), stirring and dissolving, cooling in an ice-water bath, slowly adding NIS (6.32g, 28.1mol), removing the ice-water bath after addition, and stirring at room temperature under nitrogen for 2 hours. Concentrating under reduced pressure, adding ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL) into the residue, stirring for 10 min, separating out an organic phase, extracting with ethyl acetate in an aqueous phase (50 mL), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating until a solid is separated out, stopping concentrating, adding petroleum ether (60 mL) under stirring to separate out a large amount of yellow solid, filtering, washing with petroleum ether (5 mL), and drying the filter cake in vacuum to obtain 8.43g of yellow solid with the yield of 84.0%. LC-MS (APCI) M/z =358.1 (M + 1) + .
Step 8 Compound 2-chloro-6- (2- (methyl-d) 3 ) Synthesis of methyl (E) -3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate
4-iodo-2- (methyl-d) was added sequentially to a 250mL single-neck flask equipped with a magnetic stir and condenser tube 3 ) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 2-dihydro-3H-pyrazol-3-one (7.16g, 20mmol), 2-chloro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isonicotinoyl acid methyl ester (7.12g, 24mmol), pd 2 (dba) 3 (0.46g, 0.5 mmol), n-butylbis (1-adamantane)Yl) phosphine (0.57g, 1.6 mmol), cesium carbonate (19.5g, 60mmol), toluene (60 mL) and water (20 mL), evacuated and replaced with nitrogen three times, warmed to 50 ℃ and stirred for 2 hours. Cooling to room temperature, filtering off insoluble solids, separating the organic phase, extracting the aqueous phase with ethyl acetate (50 ml x 2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating and passing through a silica gel column to give an off-white solid 5.80g, yield 72.3%. LC-MS (APCI) M/z =401.1 (M + 1) + .
Step 9 Compound 2-methyl-6- (2- (methyl-d) 3 ) Synthesis of methyl (E) -3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate
2-chloro-6- (2- (methyl-d) was added sequentially to a 250L single-neck flask equipped with a magnetic stirring and condensing tube 3 ) -3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinoyl acid methyl ester (5.80g, 14.46mmol), pd 2 (dba) 3 (0.41g, 0.44mmol), n-butylbis (1-adamantyl) phosphine (0.48g, 1.32mmol), cesium carbonate (14.2g, 43.7mmol) and 1,4-dioxane (70 mL), evacuated and replaced with nitrogen 3 times, trimethylcyclotriboroxane (0.83mL, 29.2mmol,3.5M tetrahydrofuran solution) was added dropwise under nitrogen, and after completion of dropwise addition, the reaction was stirred at 80 ℃ overnight with keeping warm. Cooled to room temperature, the insoluble solid was filtered off, washed with ethyl acetate (20 mL), the filtrate was concentrated to dryness, water (150 mL) and ethyl acetate (150 mL) were added, stirred for 10 minutes, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 4.0g of a yellow solid in 72.5% yield. LC-MS (APCI) M/z =381.1 (M + 1) + .
Step 10 Synthesis of intermediate Compound F-2
To a 100mL single-neck flask equipped with magnetic stirring was added 2-methyl-6- (2- (methyl-d) in sequence 3 ) Methyl (4.0 g,10.5 mmol) of-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinoate and ethyl acetate (10 mL) were stirred to dissolve the clear solution, 5M HCl isopropanol solution (20 mL) was added dropwise, and the reaction was stirred under a nitrogen atmosphere for 3 hours. Precipitating a large amount of yellow solid, diluting with ethyl acetate (50 mL), filtering, and adding ethyl acetateThe ester was washed (5 mL) and dried in vacuo to give 2.69g of the yellow solid in 89.2% yield. LC-MS (APCI) M/z =251.1 (M + 1) + .
3 Intermediate F-3- (5-hydroxy-1-methyl-1H-pyrazol-4-yl) -6- (methyl-d) isonicotinic acid methyl ester hydrochloride Preparation of salt
Figure BDA0003651176390000661
The following synthetic route is adopted
Figure BDA0003651176390000662
Step 1 Compound 2,4, 6-Tris (methyl-d) 3 ) Synthesis of-1, 3,5,2,4, 6-trioxatriborane
Trimethyl borate (50 mL) and anhydrous THF (500 mL) were added to a 2L three-necked flask equipped with magnetic stirring, evacuated and nitrogen replaced 3 times, cooled to-78 deg.C, and deuterated methyl magnesium iodide (250mL, 1M in ether) was added slowly dropwise over 2 hours. After dropping, the reaction was stirred at constant temperature for 2 hours, 1M aqueous hydrochloric acid (125 mL) was added dropwise over 10 minutes, the mixture was warmed to room temperature, saturated brine (200 mL) was added, the insoluble solid was filtered off, washed with diethyl ether (20 mL), the organic phase was separated, the aqueous phase was extracted with diethyl ether (60 mLx 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to about 100mL, pyridine (50 mL) was added, and the mixture was stirred at room temperature under nitrogen overnight. A large amount of pale yellow solid precipitated, which was filtered and washed with diethyl ether (20 mL) to give 6.1g of solid, which was used directly in the next step.
Step 2 Compound 2- (methyl-d) 3 ) Synthesis of methyl (E) -6- (2-methyl-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate
To the reaction vessel is charged with 2,4, 6-tris (methyl-d) 3 ) A250 mL single neck flask of crude (6.1 g) 1,3,5,2,4, 6-trioxatriborane was charged with 1,4-dioxane (70 mL), stirred, and sequentially charged with 2-chloro-6- (2-methyl-3-oxoMethyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinate (2.90g, 7.23mmol), pd 2 (dba) 3 (0.22g, 0.22mmol), n-butylbis (1-adamantyl) phosphine (0.24g, 0.66mmol), and cesium carbonate (7.1g, 21.8mmol), and the reaction mixture was evacuated and replaced with nitrogen 3 times, heated to 80 ℃ under nitrogen atmosphere, and stirred overnight. Cooled to room temperature, the insoluble solid was filtered off, washed with ethyl acetate (20 mL), the filtrate was concentrated to dryness, water (60 mL) and ethyl acetate (60 mL) were added, stirred for 10 minutes, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mLx 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 1.5g of a yellow solid. LC-MS (APCI) M/z =381.1 (M + 1) + .
Step 3 Synthesis of intermediate Compound F-3
To a 100mL single-neck flask equipped with magnetic stirring was added 2- (methyl-d) in sequence 3 ) Methyl (1.5 g, 3.94mmol) of-6- (2-methyl-3-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydro-1H-pyrazol-4-yl) isonicotinoate and ethyl acetate (5 mL) were stirred to dissolve the clear solution, 5M HCl isopropanol solution (20 mL) was added dropwise, and the reaction was stirred under nitrogen for 3 hours. A large amount of yellow solid precipitated, which was diluted with ethyl acetate (50 mL), filtered, washed with ethyl acetate (5 mL) and dried in vacuo to give 1.04g of the yellow solid in 92.6% yield. LC-MS (APCI) M/z =251.1 (M + 1) + .
Preparation of intermediate G-1-amino-4-methylpentanoic acid ethyl ester hydrochloride
Figure BDA0003651176390000671
The following synthetic route is adopted
Figure BDA0003651176390000672
Step 1 Synthesis of Compound 5-methylpiperidin-2-one
Sequentially adding 5-Methylpyridin-2 (1H) -one (5.45g, 50mmol) and methanol (500 mL) were stirred to dissolve, pd/C (5.0 g,10%, wet) was added to each, vacuum was applied and hydrogen was replaced 3 times, and the reaction was stirred overnight under a hydrogen balloon pressure. Pd/C was filtered off, washed with methanol (50 mL), the filtrates were combined and concentrated under reduced pressure to dryness to give 28.25g of a pale yellow oil in 100% yield. LC-MS (APCI) M/z =114.1 (M + 1) +1 H NMR(500MHz,CDCl 3 )δ(ppm):6.29(br s,1H),3.31-3.26(m,1H),2.93-2.88(m,1H),2.43-2.29(m,2H),1.95-1.92(m,1H),1.88-1.83(m,1H),1.50-1.42(m,1H),1.00(d,J=6.5Hz,3H).
Step 2 Synthesis of Compound 5-amino-4-Methylpentanoic acid hydrochloride
5-methylpiperidin-2-one (28.25g, 0.25mol) and 6M aqueous hydrochloric acid (2.5L) were added in sequence to a 3L single-neck flask equipped with magnetic stirring, the temperature was raised to 90 ℃ and the reaction was carried out overnight with stirring under nitrogen. Cooled to room temperature, the aqueous hydrochloric acid solution was evaporated under reduced pressure, the toluene was taken up with water (100 ml x 3), and concentrated to dryness to give 41.75g of a white powder in 100% yield, which was used directly in the next step.
Step 3 Synthesis of intermediate Compound G-1
5-amino-4-methyl valeric acid hydrochloride (41.75g, 0.25mol) and absolute ethanol (300 mL) are added into a 1L single-neck bottle with magnetic stirring in sequence, stirred to be dissolved clearly, cooled in an ice-water bath, added with thionyl chloride (59.5 g,0.5 mol) slowly in a dropwise manner under nitrogen, removed from the ice bath after dropwise addition, and stirred at room temperature for reaction overnight. Concentrate to dryness under reduced pressure, add toluene (50 mL), concentrate to dryness to give 48.75g of a white solid, which is used directly in the next step.
Preparation of intermediate G-2-amino-4-methylpentanoic acid ethyl ester hydrochloride
Figure BDA0003651176390000681
The following synthetic route is adopted
Figure BDA0003651176390000682
Step 1 Synthesis of 4- (benzyloxy) butanal Compound
4- (benzyloxy) butan-1-ol (90g, 0.5 mol) and dichloromethane (900 mL) were added to a 2L single-neck flask equipped with magnetic stirring, stirred to dissolve, dess-martin reagent (254.5 g,0.6 mol) was slowly added with cooling in an ice-water bath, and after the addition, the ice bath was removed, and the reaction was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was quenched by addition of aqueous sodium sulfite (300 mL), the organic phase separated, aqueous dichloromethane extracted (200 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue passed through a silica gel column to give 70g of a colorless oil in 78.7% yield. 1 H NMR(400MHz,CDCl 3 )δ(ppm):9.79(s,1H),7.38-7.27(m,5H),4.50(s,2H),3.52(t,J=6.0Hz,2H),2.58-2.54(m,2H),1.99-1.93(m,2H).
Step 2 Compound 5- (benzyloxy) pentane-1, 1-d 3 Synthesis of (E) -2-alcohols
A2L three-necked flask equipped with magnetic stirring was charged with 4- (benzyloxy) butyraldehyde (70g, 0.39mol) and anhydrous THF (700 mL), stirred to dissolve, evacuated and nitrogen replaced three times, cooled to 0 deg.C, and CD was slowly added dropwise 3 MgI (470mL, 0.47mol,1M THF), was added dropwise, and the reaction was stirred at constant temperature for 2 hours. Adding saturated NH 4 The reaction was quenched with aqueous Cl (300 mL) and the organic phase separated, extracted with aqueous ethyl acetate (200 mL x 2), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue passed through a silica gel column to give 65g of colorless oil in 84.5% yield. 1 H NMR(400MHz,CDCl 3 )δ(ppm):7.39-7.29(m,5H),4.53(s,2H),3.84-3.80(m,1H),3.84-3.79(m,1H),3.52(t,J=6.0Hz,2H),1.77-1.70(m,2H),1.65-1.49(m,2H).
Step 3 Compound (4-bromopentane-5, 5-d) 3 ) Synthesis of benzyl ethers
To a 2L single-neck flask equipped with magnetic stirring was added 5- (benzyloxy) pentane-1, 1-d in sequence 3 -2-ol (65g, 0.33mol), carbon tetrabromide (142.3g, 0.43mol) and triphenylphosphine (129.8g, 0.5 mmol), evacuated and replaced with nitrogen 3 times, cooled in an ice-water bath, and added with anhydrous dichloromethane (700 mL) under stirring, after completion of addition, the ice bath was removed, and the reaction was stirred at room temperature under nitrogen atmosphere for 2 hours. Concentrating the solvent under reduced pressure to dryness, adding stoneOil ether (500 mL), stirring for 20 minutes, filtering off insoluble solids, petroleum ether washing (100 mL), filtrate concentration and silica gel column to obtain colorless oil 45g, yield 52.4%. 1 H NMR(300MHz,CDCl 3 )δ(ppm):7.37-7.27(m,5H),4.52(s,2H),4.20-4.13(m,1H),3.54-3.50(m,2H),1.95-1.80(m,4H).
Step 4 Compound 5- (benzyloxy) -2- (methyl-d 3 ) Synthesis of valeronitrile
To a 1L single-neck flask equipped with magnetic stirring was added (4-bromopentane-5, 5-d) 3 ) Benzyl ether (45g, 173mmol) and dry acetonitrile (450 mL) were stirred to dissolve, TMSCN (25.7g, 260mmol) and TBAF solid (67.9g, 260mmol) were added, vacuum was applied and nitrogen was replaced 3 times, the temperature was raised to 80 ℃ and the reaction was allowed to warm with stirring overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure, and a saturated brine (200 mL) and ethyl acetate (300 mL) were added, followed by stirring for 5 minutes to separate an organic phase, an aqueous phase was extracted with ethyl acetate (150 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a silica gel column to give 23g of a colorless oil with a yield of 64.4%. LC-MS (APCI) M/z =207.2 (M + 1) +
Step 5 Synthesis of intermediate Compound G-2
To two 250mL single-necked flasks equipped with magnetic stirring was added 5- (benzyloxy) -2- (methyl-d 3 ) Valeronitrile (5g, 24.2mmol) and ethanol (100 mL) were stirred well, and PtO was added 2 (1.5 g), evacuated and replaced with hydrogen 3 times, dioxane hydrochloride solution (12.1mL, 48.4mmol, 4M) was added via syringe, and the reaction was stirred at room temperature under hydrogen atmosphere overnight. The combined treatments were filtered off the catalyst, washed with ethanol (20 mL) and the filtrate was concentrated to dryness and used directly in the next step.
1 6 6 3 2 3 Example 1 (E) -1,2, 7-trimethyl-5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecanes Phen-3-one (compound T-1);
1 6 6 3 2 3 1 1 (R, E) -1,2, 7-trimethyl-5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 5-dihydro-1H, 5H- 11-oxa-4-aza-5 (2, 1) -benzo [ d ]]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-ones (Compound T-1-R);
1 6 6 3 2 3 1 1 (S, E) -1,2, 7-trimethyl-5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 5-dihydro-1H, 5H- 11-oxa-4-aza-5 (2, 1) -benzo [ d ]]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-ones Preparation of (Compound T-1-S)
Figure BDA0003651176390000701
The following synthetic route is adopted
Figure BDA0003651176390000711
Step 1 Synthesis of Compound 4- (3-fluoro-4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 1L single-neck flask equipped with magnetic stirring, 3-fluoro-4-nitrobenzaldehyde (33.8g, 0.2mol), piperazine-1-carboxylic acid tert-butyl ester (44.6 g, 0.24mol) and dichloromethane (500 mL) were added in this order, dissolved with stirring, 4A powder molecular sieve (20 g) was added, sodium tris (acetoxy) borohydride (84.8g, 0.4mmol) was added under ice-water bath, the ice bath was removed, and the reaction was stirred under nitrogen overnight. The reaction was quenched by the addition of water (300 mL), insoluble solid was filtered off, the filter cake was washed with dichloromethane (40 mL), the filtrates were separated, the aqueous phase was extracted with dichloromethane (200 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated and passed through a silica gel column to give 42.5g of a yellow solid in 62.7% yield. LC-MS (APCI) M/z =340.1 (M + 1) +1 H NMR(500MHz,CDCl 3 )δ(ppm):8.03-8.00(m,1H),7.35-7.32(m,1H),7.26-7.25(m,1H),3.56(s,2H),3.45(t,J=5.0Hz,4H),2.40(t,J=5.0Hz,4H),1.45(s,9H).
Step 2 Synthesis of Compound 4- (3- ((5-ethoxy-2-methyl-5-oxopentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 500mL single-neck flask equipped with a condenser and magnetic stirring were added tert-butyl 4- (3-fluoro-4-nitrobenzyl) piperazine-1-carboxylate (25g, 73.66mmol), intermediate G-1 (17.3g, 88.40mmol), and DMF (200 mL) in that order, potassium carbonate (25.4G, 184.15mmol) was slowly added with stirring, the temperature was raised to 60 ℃, and the reaction was allowed to proceed overnight with stirring under nitrogen with incubation. After cooling to room temperature, the reaction mixture was poured into dichloromethane (300 mL), the inorganic salts were filtered off, the dichloromethane was washed (50 mL), the filtrate was concentrated to dryness under reduced pressure, and the mixture was passed through a silica gel column to give 28.5g of a yellow oil with a yield of 80.8%. LC-MS (APCI) M/z =479.3 (M + 1) +1 H NMR(300MHz,CDCl 3 )δ(ppm):8.20(t,J=4.8Hz,1H),7.12(d,J=9.0Hz,1H),6.81(s,1H),6.63(dd,J=9.0Hz,J=1.5Hz,1H),4.14-4.12(m,2H),3.47-3.43(m,6H),3.30-3.22(m,1H),3.16-3.08(m,1H),2.44-2.35(m,6H),1.93-1.85(m,2H),1.60-1.56(m,1H),1.46(s,9H),1.28-1.25(m,3H),1.06(d,J=6.6Hz,3H).
Step 3 Synthesis of Compound 4- (3- ((5-hydroxy-2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
Under cooling in an ice-water bath, 4- (3- ((5-ethoxy-2-methyl-5-oxopentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (9.57g, 20mmol) and anhydrous THF (200 mL) were added sequentially to a 500mL single-neck flask equipped with magnetic stirring, stirred to dissolve, and LiAlH was slowly added 4 (0.76g, 20mmol), and after the addition, the reaction was stirred under a nitrogen atmosphere for 1 hour. Sodium sulfate decahydrate was added slowly until no air bubbles were produced, the insoluble solid was filtered off, washed with ethyl acetate (50 mL), the filtrate was concentrated and passed through a silica gel column to give 7.2g of a yellow oil in 82.5% yield. LC-MS (APCI) M/z =437.3 (M + 1) +
Step 4 Synthesis of Compound tert-butyl 4- (3- ((2-methyl-5- ((methylsulfonyl) oxy) pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylate
Under cooling in an ice-water bath, 4- (3- ((5-hydroxy-2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (7.2g, 16.5mmol), triethylamine (2.5g, 24.7mmol) and anhydrous DCM (200 mL) were added sequentially to a 500mL single-neck flask equipped with magnetic stirring, methanesulfonyl chloride (18.15 mmol) was slowly added dropwise, the ice bath was removed, and the reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was quenched by the addition of water (100 mL), the organic phase separated, the aqueous phase extracted with dichloromethane (80 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness for use in the next step.
Step 5 Synthesis of Compound 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 250mL single neck flask charged with tert-butyl- (3- ((2-methyl-5- ((methylsulfonyl) oxy) pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylate (ca. 16.5 mmol) was added DMF (80 mL), the solution was stirred, intermediate F-1 (4.67g, 16.5 mmol) and potassium carbonate (6.83g, 49.5 mmol) were added, the temperature was raised to 60 ℃ and the reaction was stirred under nitrogen overnight. After cooling to room temperature, ethyl acetate (200 mL) was added, the insoluble solid was filtered off, the filter cake (50 mL) was washed with ethyl acetate, the organic phases were combined and concentrated to dryness under reduced pressure, and the residue was passed through a silica gel column to give 7.8g of a pale yellow solid with a yield of 71.0%. LC-MS (APCI) M/z =666.7 (M + 1) +1 H NMR(300MHz,CDCl 3 )δ(ppm):8.23-8.18(m,1H),8.12(d,J=9.2Hz,1H),7.87(s,1H),7.86(br s,1H),7.48(s,1H),6.80(s,1H),7.63(d,J=8.8Hz,1H),4.15(t,J=6.4Hz,2H),3.94(s,3H),3.74(s,3H),3.45-3.41(m,7H),3.28-3.24(m,1H),3.19-3.14(m,1H),2.61(s,3H),2.41-2.36(m,4H),2.01-1.92(m,2H),1.90-1.85(m,2H),1.75-1.69(m,1H),1.45(s,9H),1.12(d,J=6.4Hz,3H).
Step 6 Synthesis of Compound 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 250mL single-neck flask equipped with magnetic stirring was added 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (4.0 g,6.0 mmol) and methanol (80 mL), the supernatant was stirred, pt/C (1.2 g, 10%) was added, vacuum was applied, and hydrogen replacedAnd the reaction is stirred for 2 hours at room temperature under hydrogen balloon atmosphere. The catalyst was filtered off, washed with dichloromethane (20 mL) and the filtrate was concentrated to dryness to give a brown solid 3.81g, 100% yield, which was used directly in the next step. LC-MS (APCI) M/z =636.7 (M + 1) +
Step 7 Synthesis of Compound tert-butyl 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) -1H-benzo [ d ] imidazol-6-yl) methyl) piperazine-1-carboxylate
In a 100mL single vial of 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester (3.81g, 6.0 mmol) was charged with glacial acetic acid (80 mL) in an ice-water bath, the solution was stirred, cyanogen bromide solid (0.82g, 7.8 mmol) was slowly added, the ice bath was removed after completion of the addition, and the reaction was stirred at room temperature under nitrogen overnight. Under the condition of ice water bath, adding ethyl acetate (150 mL) and water (50 mL) to quench the reaction, dropwise adding ammonia water, adjusting the pH value to 9, separating out an organic phase, extracting water phase ethyl acetate (60 mLx 2), combining the organic phases, drying by anhydrous sodium sulfate, filtering, concentrating to dryness, and passing the residue through a silica gel column to obtain an off-white solid of 3.0g with the yield of 75.7%. LC-MS (APCI) M/z =661.7 (M + 1) +
Step 8 Synthesis of Compound 2- (5- ((5- (2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d ] imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid
To a 100mL single-neck flask equipped with magnetic stirring was added 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) -1H-benzo [ d ] d]Imidazol-6-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 4.54mmol), THF (20 mL) and water (20 mL) were stirred to dissolve it, liOH-H was added 2 O (0.38g, 9.08mmol), was stirred under nitrogen at room temperature for 2 hours. The organic solvent was evaporated under reduced pressure, cooled in an ice-water bath, citric acid solid (0.58g, 3.03mmol) was slowly added to precipitate a large amount of white solid, filtered, the filter cake was washed with water (10 mL), dried to give 2.2g of white solid in 74.9% yield. LC-MS (APCI) M/z =647.7 (M + 1) +
Step 9 Compound (E) -4- ((1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 Synthesis of t-butyl (E) -yl) methyl) piperazine-1-carboxylate
To a 100mL single-neck flask equipped with magnetic stirring was added 2- (5- ((5- (2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d []Imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid (2.2 g,3.4 mmol) and dry dichloromethane (40 mL) were stirred to dissolve, DIPEA (0.88g, 6.8 mmol) and TBTU (1.64g, 5.1 mmol) were added, and after completion of addition, the reaction was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was diluted with dichloromethane (30 mL), water (50 mL) was added, the mixture was stirred for 5 minutes, the organic phase was separated, extracted with water-washed dichloromethane (30 mLx 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give 1.4g of a pale yellow solid with a yield of 65.5%. LC-MS (APCI) M/z =629.7 (M + 1) +1 H NMR(400MHz,CDCl 3 )δ(ppm):11.99(br s,1H),8.51(s,1H),8.18(s,1H),7.68(s,1H),7.34-7.32(m,1H),7.26-7.21(m,2H),4.52-4.47(m,1H),4.41-4.34(m,1H),3.94-3.89(m,1H),3.81(s,3H),3.80-3.73(m,1H),3.65(s,2H),3.54-3.41(m,4H),2.88-2.82(m,1H),2.67(s,3H),2.51-2.48(m,4H),2.32-2.26(m,1H),2.20-1.13(m,1H),2.07-1.97(m,2H),1.55(s,9H),0.93(d,J=6.8Hz,3H).
Step 10 Compound (E) -1 1 ,2 6 7-trimethyl-5 6 - (piperazin-1-ylmethyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Synthesis of imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-one
To a 100mL single-necked flask equipped with magnetic stirring was added (E) -4- ((1) 1 ,2 6 7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 -yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (1.4g, 2.23mmol) and 5M isopropanol hydrochloride solution (20 mL), the reaction was stirred under nitrogen for 2 hours. Adding ethyl acetate (40 mL), precipitating a large amount of white solid, filtering, washing with ethyl acetate (10 mL), adding dichloromethane (20 mL) and water (5 mL) into a filter cake, dropwise adding ammonia water to adjust the pH value to 9, separating an organic phase, washing with water, extracting dichloromethane (10 mLx 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness to obtain 0.9g of brown solid, wherein the yield is 76.3%, and the brown solid is directly used in the next step. LC-MS (APCI) M/z =529.7 (M + 1) +
Step 11 Synthesis of Compound T-1
To a 50mL single-neck flask equipped with magnetic stirring was added (E) -1 1 ,2 6 7-trimethyl-5 6 - (piperazin-1-ylmethyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolo-cyclododecen-3-one (0.9g, 1.70mmol) and methanol (15 mL) were stirred to dissolve, deuterated formaldehyde (0.54g, 3.40mmol, 20% w/w aqueous solution) and glacial acetic acid (10mg, 0.17mmol) were added, the reaction was stirred under nitrogen for 20 minutes, deuterated sodium cyanoborohydride (0.17g, 2.55mmol) was added, and the reaction was stirred for 2 hours. The reaction was quenched by addition of brine (20 mL), extracted with ethyl acetate (30 mLx 3), the organic phases were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give an off-white solid (0.65 g, yield 70.1%). LC-MS (APCI) M/z =546.7 (M + 1) +1 H NMR(400MHz,CDCl 3 )δ(ppm):11.94(br s,1H),8.49(s,1H),8.16(s,1H),7.65(s,1H),7.31-7.27(m,2H),7.23-7.20(m,1H),4.51-4.45(m,1H),4.38-4.33(m,1H),3.92-3.87(m,1H),3.79(s,3H),3.76-3.71(m,1H),3.62(s,2H),2.87-2.81(m,1H),2.64-2.42(m,8H),2.65(s,3H),2.26-2.23(m,1H),2.15-2.06(m,1H),2.03-1.91(m,2H),1.54-1.46(m,2H),0.92(d,J=6.4Hz,3H).
Step 12 Synthesis of Compounds T-1-R and T-1-S
The racemic compound T-1 (0.65 g) was dissolved in methanol (80 mL) and subjected to chiral preparative resolution by SFC under the following resolution conditions:
the instrument comprises the following steps: waters SFC-150; chiral column: cellosolve OD 20 × 250mm,10um; mobile phase: CO2 2 /EtOH[0.5%NH 3 (7M in MeOH)]=70/30; flow rate: 100g/min, column temperature: 35 ℃; column pressure: 100bar; detection wavelength: 214nm; cycle time: 6min; sample introduction amount: 4mL.
Collecting corresponding fractions, and spin-drying to obtain isomer T-1-R of 300mg with corresponding retention time of 2.948min; and 300mg of the isomer T-1-S, corresponding to a retention time of 3.553min (where the chiral analysis conditions were HPLC, column: OD-3.6X 100mm 3um; mobile phase: etOH [1% NH3 (7M in MeOH) ]; flow rate: 3.0mL/min; column temperature: 40 ℃; pressure: 200 psi).
1 6 3 6 2 3 1 Example 2 (E) -1, 2-dimethyl-7- (methyl-d) -5- (piperazin-1-ylmethyl) -5, 5-dihydro-1H, 1 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene- 3-ketone (compound T-2);
1 6 3 6 2 3 1 (E) -1, 2-dimethyl-7- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro-1H, 1 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene- 3-ketone (compound T-3);
1 6 3 6 2 3 (R, E) -1, 2-dimethyl-7- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecanes Phen-3-one (compound T-3-R);
1 6 3 6 2 3 (S, E) -1, 2-dimethyl-7- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolo ringsTwelve aspects Preparation of Fenen-3-ones (Compound T-3-S)
Figure BDA0003651176390000761
The following synthetic route is adopted
Figure BDA0003651176390000771
Step 1 Compound 4- (3- ((5-hydroxy-2- (methyl-d) 3 ) Synthesis of pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 250mL single neck flask containing intermediate G-2 (about 48.4 mmol) was added DMF (100 mL), potassium carbonate (16.7G, 121mmol) and tert-butyl 4- (3-fluoro-4-nitrobenzyl) piperazine-1-carboxylate (15.3G, 45mmol) were added with stirring, the temperature was raised to 60 ℃ under nitrogen, and the reaction was allowed to warm with stirring overnight. After cooling to room temperature, the reaction mixture was poured into dichloromethane (200 mL), the inorganic salts were filtered off, the dichloromethane was washed (50 mL), the filtrate was concentrated to dryness under reduced pressure, and the mixture was passed through a silica gel column to give 16.5g of a yellow oil with a yield of 83.5%. LC-MS (APCI) M/z =440.5 (M + 1) + .
Step 2 Compound 4- (3- ((2- (methyl-d) 3 ) Synthesis of tert-butyl (5- ((methylsulfonyl) oxy) pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylate
4- (3- ((5-hydroxy-2- (methyl-d) was added to a 500mL single-neck flask equipped with magnetic stirring in sequence while cooling in an ice-water bath 3 ) Pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (7.3g, 16.5mmol), triethylamine (2.5g, 24.7mmol) and anhydrous DCM (200 mL) were added slowly dropwise to methanesulfonyl chloride (18.15 mmol) and the ice bath removed and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was quenched by the addition of water (100 mL), the organic phase separated, extracted with aqueous dichloromethane (80 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness for use in the next step.
Step 3 the compound 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-)Pyrazol-5-yl) oxy) -2- (methyl-d 3 ) Synthesis of pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To the flask was charged with 4- (3- ((2- (methyl-d) 3 ) In a 250mL single neck flask of-5- ((methylsulfonyl) oxy) pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (ca. 16.5 mmol) was added DMF (80 mL), the solution was stirred, intermediate F-1 (4.67g, 16.5 mmol) and potassium carbonate (6.83g, 49.5 mmol) were added, the temperature was raised to 60 deg.C, and the reaction was stirred overnight with nitrogen under incubation. After cooling to room temperature, ethyl acetate (200 mL) was added, the insoluble solid was filtered off, the filter cake (50 mL) was washed with ethyl acetate, the organic phases were combined and concentrated to dryness under reduced pressure, and the residue was passed through a silica gel column to give 8.2g of a pale yellow solid in 74.3% yield. LC-MS (APCI) M/z =669.4 (M + 1) +1 H NMR(300MHz,CDCl 3 )δ(ppm):8.23-8.18(m,1H),8.12(d,J=9.2Hz,1H),7.87(s,1H),7.86(br s,1H),7.48(s,1H),6.80(s,1H),7.63(d,J=8.8Hz,1H),4.15(t,J=6.4Hz,2H),3.94(s,3H),3.74(s,3H),3.45-3.41(m,7H),3.28-3.24(m,1H),3.19-3.14(m,1H),2.61(s,3H),2.41-2.36(m,4H),2.01-1.92(m,2H),1.90-1.85(m,2H),1.75-1.69(m,1H),1.45(s,9H).
Step 4 Compound 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2- (methyl-d) 3 ) Synthesis of pentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 250mL single-neck flask equipped with magnetic stirring was added 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2- (methyl-d) 3 ) Pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (4.0 g,6.0 mmol) and methanol (80 mL) were stirred to dissolve, pt/C (1.2g, 10%) was added, vacuum was applied and hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours under a hydrogen balloon atmosphere. The catalyst was filtered off, washed with dichloromethane (20 mL) and the filtrate was concentrated to dryness to give a brown solid 3.81g, 100% yield, which was used directly in the next step. LC-MS (APCI) M/z =640.0 (M + 1) +
Step 5 Compound 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2- (methyl-d) 3 ) Pentyl) -1H-benzo [ d]Imidazol-6-yl) methoxy)Synthesis of piperazine-1-carboxylic acid tert-butyl ester
In a 100mL single vial of 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2- (methyl-d 3) pentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester (3.81g, 6.0 mmol) was charged with glacial acetic acid (80 mL) in an ice-water bath, the solution was stirred, cyanogen bromide solid (0.82g, 7.8mmol) was slowly added, and after addition, the ice bath was removed and the reaction was stirred at room temperature under nitrogen overnight. Under the condition of ice water bath, adding ethyl acetate (150 mL) and water (50 mL) to quench reaction, dropwise adding ammonia water, adjusting the pH value to 9, separating an organic phase, extracting water phase ethyl acetate (60 mLx 2), combining the organic phases, drying by anhydrous sodium sulfate, filtering, concentrating to dryness, and passing the residue through a silica gel column to obtain an off-white solid of 3.3g with the yield of 82.8%. LC-MS (APCI) M/z =664.7 (M + 1) +
Step 6 Compound 2- (5- ((4- ((2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d)]Imidazol-1-yl) methyl) pentyl-5, 5-d 3 ) Synthesis of oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid
To a 100mL single-necked flask equipped with magnetic stirring was added 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2- (methyl-d 3 ) Pentyl) -1H-benzo [ d]Imidazol-6-yl) methoxy) piperazine-1-carboxylic acid tert-butyl ester (3.2g, 4.82mmol), THF (20 mL) and water (20 mL) were dissolved by stirring, and LiOH-H was added 2 O (0.38g, 9.08mmol), was stirred under nitrogen at room temperature for 2 hours. The organic solvent was evaporated under reduced pressure, cooled in an ice-water bath, citric acid solid (0.58g, 3.03mmol) was slowly added to precipitate a large amount of white solid, filtered, the filter cake was washed with water (10 mL), dried to give 2.3g of white solid, yield 73.4%. LC-MS (APCI) M/z =650.7 (M + 1) +
Step 7 Compound (E) -4- ((1) 1 ,2 6 -dimethyl-7- (methyl-d) 3 ) -3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 Synthesis of t-butyl (E) -yl) methyl) piperazine-1-carboxylate
Is equipped with magnetic stirringA stirred 100mL single neck bottle was charged with 2- (5- ((4- ((2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d [ -d)]Imidazol-1-yl) methyl) pentyl-5, 5-d 3) oxy) -1-methyl-1H-pyrazol-4-yl) -6-methylisonicotinic acid (2.2 g,3.4 mmol) and dry dichloromethane (40 mL) were stirred to dissolve the clear solution, DIPEA (0.88g, 6.8 mmol) and TBTU (1.64g, 5.1mmol) were added, and after completion, the reaction was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was diluted with dichloromethane (30 mL), water (50 mL) was added, the mixture was stirred for 5 minutes, the organic phase was separated, extracted with water-washed dichloromethane (30 mLx 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give 1.4g of a pale yellow solid with a yield of 65.5%. LC-MS (APCI) M/z =632.7 (M + 1) +
Step 8 Synthesis of Compound T-2
To a 100mL single-necked flask equipped with magnetic stirring was added (E) -4- ((1) 1 ,2 6 -dimethyl-7- (methyl-d) 3 ) -3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 -yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 2.22mmol) and 5M isopropanol hydrochloride solution (20 mL) were reacted with stirring under nitrogen for 2 hours. Adding ethyl acetate (40 mL), precipitating a large amount of white solid, filtering, washing with ethyl acetate (10 mL), adding dichloromethane (20 mL) and water (5 mL) into a filter cake, dropwise adding ammonia water to adjust the pH value to 9, separating out an organic phase, washing with water, extracting with dichloromethane (10 mLx 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness to obtain 0.9g of brown solid, wherein the yield is 76.3%, and the brown solid is directly used in the next step. LC-MS (APCI) M/z =532.7 (M + 1) +
Step 9 Synthesis of Compound T-3
To a 50mL single neck flask equipped with magnetic stirring was added compound T-2 (0.45g, 0.85mmol) and methanol (8 mL), stirred to dissolve, added formaldehyde (0.27g, 1.7mmol, 20% w/w solution) and glacial acetic acid (5 mg, 0.08mmol), stirred under nitrogen for 20 minutes, added sodium cyanoborohydride (80mg, 1.25mmol), and stirred for an additional 2 hours. Adding saturated saline (20 mL) to quench the reaction, extracting with ethyl acetate (30 mLx 3), combining the organic phases, saturatingAnd brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give an off-white solid (0.35 g) in 75.4% yield. LC-MS (APCI) M/z =546.7 (M + 1) + ,1H NMR(400MHz,CDCl 3 )δ(ppm):11.94(br s,1H),8.49(s,1H),8.16(s,1H),7.65(s,1H),7.31-7.27(m,2H),7.23-7.20(m,1H),4.51-4.45(m,1H),4.38-4.33(m,1H),3.92-3.87(m,1H),3.79(s,3H),3.76-3.71(m,1H),3.62(s,2H),2.87-2.81(m,1H),2.64-2.42(m,8H),2.65(s,3H),2.33(s,3H),2.26-2.23(m,1H),2.15-2.06(m,1H),2.03-1.91(m,2H),1.54-1.46(m,2H).
Step 10 Synthesis of Compounds T-3-R and T-3-S
Racemic compound T-3 (0.35 g) was dissolved in methanol (40 mL) and subjected to chiral preparative resolution by SFC under the following resolution conditions:
the instrument comprises the following steps: waters SFC-150; chiral column: cellosolve OD 20 × 250mm,10um; mobile phase: CO2/EtOH [0.5% ] -NH3 (7M in MeOH) ] =70/30; flow rate: 100g/min, column temperature: 35 ℃; column pressure: 100bar; detection wavelength: 214nm; cycle time: 6min; sample injection amount: 4mL.
Collecting corresponding fractions, and spin-drying to obtain isomer T-3-R of 150mg with corresponding retention time of 2.948min; and the isomer T-3-S was 150mg and the retention time was 3.553min (wherein the chiral analysis conditions were HPLC, column: OD-3.6X 100mm 3um; mobile phase: etOH [1% NH3 (7M in MeOH) ]; flow rate: 3.0mL/min; column temperature: 40 ℃ C.; pressure: 200 psi).
1 6 3 6 3 2 Example 3 (E) -1, 2-dimethyl-7- (methyl-d) -5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 3 1 1 5-dihydro-1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazoles Cyclododecen-3-one (compound T-4);
1 6 3 6 3 2 (R, E) - (E) -1, 2-dimethyl-7- (methyl-d) -5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 3 1 1 5-dihydro-1H, 5H-11-Oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazoles And cyclododecen-3-one (compound T-4-R);
1 6 3 6 3 2 (S, E) - (E) -1, 2-dimethyl-7- (methyl-d) -5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 3 1 1 5-dihydro-1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazoles Preparation of Cyclododecen-3-one (Compound T-4-S)
Figure BDA0003651176390000811
The following synthetic route is adopted
Figure BDA0003651176390000812
Step 1 Synthesis of Compound T-4
A50 mL single neck flask equipped with magnetic stirring was charged with Compound T-2 (0.45g, 0.85mmol) and methanol (8 mL), stirred to dissolve, deuterated formaldehyde (0.27g, 1.7mmol, w/w 20% aqueous solution) and glacial acetic acid (5mg, 0.08mmol) were added, the reaction was stirred under nitrogen for 20 minutes, deuterated sodium cyanoborohydride (80mg, 1.25mmol) was added, and the reaction was stirred for an additional 2 hours. The reaction was quenched by addition of saturated brine (20 mL), extracted with ethyl acetate (30 mLx 3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give an off-white solid (0.35 g) in 75.4% yield. LC-MS (APCI) M/z =546.7 (M + 1) +1 H NMR(400MHz,CDCl 3 )δ(ppm):11.94(br s,1H),8.49(s,1H),8.16(s,1H),7.65(s,1H),7.31-7.27(m,2H),7.23-7.20(m,1H),4.51-4.45(m,1H),4.38-4.33(m,1H),3.92-3.87(m,1H),3.79(s,3H),3.76-3.71(m,1H),3.62(s,2H),2.87-2.81(m,1H),2.64-2.42(m,8H),2.65(s,3H),2.26-2.23(m,1H),2.15-2.06(m,1H),2.03-1.91(m,2H),1.54-1.46(m,2H).
Step 2 Synthesis of Compounds T-4-R and T-4-S
The racemic compound T-4 (0.35 g) was dissolved in methanol (40 mL) and subjected to chiral preparative resolution by SFC under the following resolution conditions:
the instrument comprises the following steps: waters SFC-150; chiral column: cellosolve OD 20 × 250mm,10um; mobile phase: CO2/EtOH [0.5% ] -NH3 (7M in MeOH) ] =70/30; flow rate: 100g/min, column temperature: 35 ℃; column pressure: 100bar; detection wavelength: 214nm; cycle time: 6min; sample introduction amount: 4mL.
Collecting corresponding fractions, and spin-drying to obtain isomer T-4-R of 145mg with corresponding retention time of 2.948min; and the isomer T-4-S was 148mg with a retention time of 3.553min (where the chiral analysis conditions were HPLC, column: OD-3.6X 100mm 3um; mobile phase: etOH [1%NH3 (7M in MeOH) ]; flow rate: 3.0mL/min; column temperature: 40 ℃ C.; pressure: 200 psi).
6 1 3 6 2 3 1 Example 4 (E) -2, 7-dimethyl-1- (methyl-d) -5- (piperazin-1-ylmethyl) -5, 5-dihydro-1H, 1 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene- 3-Ketone (Compound T-5)
6 1 3 6 2 3 1 (E) -2, 7-dimethyl-1- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro-1H, 1 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene- 3-ketone (compound T-6);
6 1 3 6 2 3 (R, E) -2, 7-dimethyl-1- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecanes Phen-3-one (compound T-6-R);
6 1 3 6 2 3 (S, E) -2, 7-dimethyl-1- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecanes Preparation of Fenen-3-one (Compound T-6-S)
Figure BDA0003651176390000831
The following synthetic route is adopted
Figure BDA0003651176390000841
Step 1 Compound 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1- (methyl-d) 3 ) Synthesis of (E) -1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 100mL single vial charged with tert-butyl (3- ((2-methyl-5- ((methanesulfonyl) oxy) pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylate (about 9.38 mmol) was added DMF (30 mL), the solution was stirred, intermediate F-2 (2.69g, 9.38mmol) and potassium carbonate (3.88g, 28.0 mmol) were added, the temperature was raised to 60 deg.C, and the reaction was stirred overnight with incubation under nitrogen. Cooled to room temperature, ethyl acetate (100 mL) was added, the insoluble solid was filtered off, the filter cake was washed with ethyl acetate (50 mL), the organic phases were combined, concentrated to dryness under reduced pressure, and the residue was passed through a silica gel column to give 4.78g of a pale yellow solid in 76.2% yield. LC-MS (APCI) M/z =669.4 (M + 1) + .
Step 2 Compound 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1- (methyl-d) 3 ) Synthesis of (E) -1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 100mL single-necked flask equipped with magnetic stirring was added 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6-methyl)Pyridin-2-yl) -1- (methyl-d 3 ) -1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (4.0g, 6.0 mmol) and methanol (80 mL) were stirred to dissolve, pt/C (1.2g, 10%) was added, vacuum was applied and hydrogen was replaced three times, and the reaction was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered off, washed with dichloromethane (20 mL) and the filtrate was concentrated to dryness to give a brown solid 3.81g, 100% yield, which was used directly in the next step. LC-MS (APCI) M/z =639.5 (M + 1) +
Step 3 Compound 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1- (methyl-d) 3 ) -1H-pyrazol-5-yl) oxy) -2-methylpentyl) -1H-benzo [ d]Synthesis of imidazol-6-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester
Under ice-water bath, the flask was charged with 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1- (methyl-d) 3 ) -1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester (3.81g, 6.0 mmol) was added to a 100mL single-necked flask with glacial acetic acid (40 mL), the solution was stirred, cyanogen bromide solid (0.82g, 7.8mmol) was slowly added, the ice bath was removed after the addition was complete, and the reaction was stirred at room temperature under nitrogen overnight. Under the condition of ice water bath, adding ethyl acetate (150 mL) and water (50 mL) to quench the reaction, dropwise adding ammonia water, adjusting the pH value to 9, separating an organic phase, extracting water phase ethyl acetate (60 mLx 2), combining the organic phases, drying by anhydrous sodium sulfate, filtering, concentrating to dryness, and passing the residue through a silica gel column to obtain an off-white solid 3.5g with the yield of 87.9%. LC-MS (APCI) M/z =664.7 (M + 1) +
Step 4 the compound 2- (5- ((5- (2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d)]Imidazol-1-yl) -4-methylpentyl) oxy) -1- (methyl-d 3 ) Synthesis of (E) -1H-pyrazol-4-yl-6-methylisonicotinic acid
To a 100mL single-necked flask equipped with magnetic stirring was added 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6-methylpyridin-2-yl) -1- (methyl-d) 3 ) -1H-pyrazol-5-yl) oxy) -2-methylpentyl) -1H-benzo [ d]Imidazol-6-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (3.2g, 4.82mmol), THF (20 mL), and water (20 mL) were stirred to dissolve it, liOH-H was added 2 O (0.38g, 9.08mmol), N, room temperatureThe reaction was stirred for 2 hours. The organic solvent was evaporated under reduced pressure, cooled in an ice-water bath, citric acid solid (0.58g, 3.03mmol) was slowly added to precipitate a large amount of white solid, filtered, the filter cake was washed with water (10 mL), dried to give 2.2g of white solid in 70.2% yield. LC-MS (APCI) M/z =650.7 (M + 1) +
Step 5 Compound (E) -4- ((2) 6 7-dimethyl-1 1 - (methyl-d) 3 ) -3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 Synthesis of t-butyl (E) -yl) methyl) piperazine-1-carboxylate
To a 100mL single-neck flask equipped with magnetic stirring was added 2- (5- ((5- (2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d []Imidazol-1-yl) -4-methylpentyl) oxy) -1- (methyl-d 3 ) -1H-pyrazol-4-yl) -6-methylisonicotinic acid (2.2g, 3.4mmol) and anhydrous dichloromethane (40 mL) were stirred to dissolve, DIPEA (0.88g, 6.8mmol) and TBTU (1.64g, 5.1mmol) were added, and after completion of the addition, the reaction was stirred at room temperature under nitrogen for 2 hours. The reaction was diluted with dichloromethane (30 mL), water (50 mL) was added, the mixture was stirred for 5 minutes, the organic phase was separated, extracted with dichloromethane (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give 1.5g of a pale yellow solid in 69.8% yield. LC-MS (APCI) M/z =632.7 (M + 1) +
Step 6 Synthesis of Compound T-5
To a 100mL single-neck flask equipped with magnetic stirring was added (E) -4- ((2) 6 7-dimethyl-1 1 - (methyl-d) 3 ) -3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 -yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 2.22mmol) and 5M isopropanol hydrochloride solution (20 mL) were reacted with stirring under nitrogen for 2 hours. Adding ethyl acetate (40 mL), precipitating a large amount of white solid, filtering, washing with ethyl acetate (10 mL), adding dichloromethane (20 mL) and water (5 mL) into a filter cake, dropwise adding ammonia water to adjust the pH value to 9, separating an organic phase, washing with water, and extracting with dichloromethane(10 ml x 3), combine the organic phases, dry over anhydrous sodium sulphate, filter and concentrate the filtrate to dryness to give 0.91g of brown solid in 77.1% yield, which is used directly in the next step. LC-MS (APCI) M/z =532.7 (M + 1) +
Step 7 Synthesis of Compound T-6
To a 50mL single neck flask equipped with magnetic stirring was added compound T-5 (0.45g, 0.85mmol) and methanol (8 mL), stirred to dissolve, added formaldehyde (0.27g, 1.7mmol, 20% w/w solution) and glacial acetic acid (5 mg, 0.08mmol), stirred under nitrogen for 20 minutes, added sodium cyanoborohydride (80mg, 1.25mmol), and stirred for an additional 2 hours. The reaction was quenched by addition of brine (20 mL), extracted with ethyl acetate (30 mLx 3), the organic phases were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give an off-white solid (0.36 g, 77.6% yield). LC-MS (APCI) M/z =546.7 (M + 1) +1 H NMR(400MHz,CDCl 3 )δ(ppm):11.94(br s,1H),8.49(s,1H),8.16(s,1H),7.65(s,1H),7.31-7.27(m,2H),7.23-7.20(m,1H),4.51-4.45(m,1H),4.38-4.33(m,1H),3.92-3.87(m,1H),3.76-3.71(m,1H),3.62(s,2H),2.87-2.81(m,1H),2.64-2.42(m,8H),2.65(s,3H),2.33(s,3H),2.26-2.23(m,1H),2.15-2.06(m,1H),2.03-1.91(m,2H),1.54-1.46(m,2H),0.92(d,J=6.4Hz,3H).
Step 8 Synthesis of Compounds T-6-R and T-6-S
The racemic compound T-6 (0.35 g) was dissolved in methanol (40 mL) and subjected to chiral preparative resolution by SFC under the following resolution conditions:
the instrument comprises the following steps: waters SFC-150; chiral column: cellosolve OD 20 × 250mm,10um; mobile phase: CO2 2 /EtOH[0.5%NH3(7M in MeOH)]=70/30; flow rate: 100g/min, column temperature: 35 ℃; column pressure: 100bar; detection wavelength: 214nm; cycle time: 6min; sample injection amount: 4mL.
Collecting corresponding fractions, and spin-drying to obtain isomer T-6-R of 150mg with corresponding retention time of 2.948min; and the isomer T-6-S was 150mg and the retention time was 3.553min (wherein the chiral analysis conditions were HPLC, column: OD-3.6X 100mm 3um; mobile phase: etOH [1% NH3 (7M in MeOH) ]; flow rate: 3.0mL/min; column temperature: 40 ℃ C.; pressure: 200 psi).
6 1 3 6 3 2 Example 5 (E) -2, 7-dimethyl-1- (methyl-d) -5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 3 1 1 5-dihydro-1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazoles Cyclododecen-3-one (compound T-7);
6 1 3 6 3 2 3 (R, E) -2, 7-dimethyl-1- (methyl-d) -5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 5-di 1 1 Hydrogen-1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolo-cyclododecane Diphen-3-one (compound T-7-R);
6 1 3 6 3 2 3 (S, E) -2, 7-dimethyl-1- (methyl-d) -5- ((4- (methyl-d) piperazin-1-yl) methyl) -5, 5-di 1 1 Hydrogen-1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolo-cyclododecane Preparation of Bifen-3-one (Compound T-7-S)
Figure BDA0003651176390000871
The following synthetic route is adopted
Figure BDA0003651176390000881
Step 1 Synthesis of Compound T-7
To a 50mL single neck flask equipped with magnetic stirring was added compound T-5 (0.45g, 0.85mmol) and methanol (8 mL), dissolved by stirring, deuterated formaldehyde (0.27g, 1.7mmol, w/w 20% heavy water) and glacial acetic acid (5mg, 0.08mmol), nitrogen, addedThe reaction was stirred under an atmosphere for 20 minutes, sodium deuterocyanoborohydride (80mg, 1.25mmol) was added, and the reaction was stirred for an additional 2 hours. The reaction was quenched by addition of saturated brine (20 mL), extracted with ethyl acetate (30 mLx 3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give an off-white solid (0.35 g) in 75.4% yield. LC-MS (APCI) M/z =546.7 (M + 1) +1 H NMR(400MHz,CDCl 3 )δ(ppm):11.94(br s,1H),8.49(s,1H),8.16(s,1H),7.65(s,1H),7.31-7.27(m,2H),7.23-7.20(m,1H),4.51-4.45(m,1H),4.38-4.33(m,1H),3.92-3.87(m,1H),3.76-3.71(m,1H),3.62(s,2H),2.87-2.81(m,1H),2.64-2.42(m,8H),2.65(s,3H),2.26-2.23(m,1H),2.15-2.06(m,1H),2.03-1.91(m,2H),1.54-1.46(m,2H),0.92(d,J=6.4Hz,3H).
Step 2 Synthesis of Compound T-7-R and Compound T-7-S
The racemic compound T-7 (0.35 g) was dissolved in methanol (40 mL) and subjected to chiral preparative resolution by SFC under the following resolution conditions:
the instrument comprises: waters SFC-150; chiral column: cellosolve OD 20 × 250mm,10um; mobile phase: CO2/EtOH [0.5% ] -NH3 (7M in MeOH) ] =70/30; flow rate: 100g/min, column temperature: 35 ℃; column pressure: 100bar; detection wavelength: 214nm; cycle time: 6min; sample introduction amount: 4mL.
Collecting corresponding fractions, and spin-drying to obtain isomer T-7-R of 145mg with corresponding retention time of 2.948min; and the isomer T-7-S was 148mg, corresponding to a retention time of 3.553min (where the chiral analysis conditions were HPLC, column: OD-3.6X 100mm 3um; mobile phase: etOH [1% NH3 (7M in MeOH) ]; flow rate: 3.0mL/min; column temperature: 40 ℃; pressure: 200 psi).
1 6 3 6 2 3 1 Example 6 (E) -1, 7-dimethyl-2- (methyl-d) -5- (piperazin-1-ylmethyl) -5, 5-dihydro-1H, 1 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene- 3-ketone (Compound T-8);
1 6 3 6 2 3 1 (E) -1, 7-dimethyl-2- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro-1H, 1 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene- 3-ketone (compound T-9);
1 6 3 6 2 3 (R, E) -1, 7-dimethyl-2- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecanes Phen-3-one (compound T-9-R);
1 6 3 6 2 3 (S, E) -1, 7-dimethyl-2- (methyl-d) -5- ((4-methylpiperazin-1-yl) methyl) -5, 5-dihydro- 1 1 1H, 5H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecanes Preparation of Fenen-3-one (Compound T-9-S)
Figure BDA0003651176390000891
The following synthetic route is adopted
Figure BDA0003651176390000901
Step 1 Compound 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6- (methyl-d) 3 ) Synthesis of pyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 50mL single-necked flask charged with tert-butyl 4- (3- ((2-methyl-5- ((methylsulfonyl) oxy) pentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylate (about 3.49 mmol) was added DMF (10 mL) and the solution was stirredThen, intermediate F-3 (1.0 g, 3.49mmol) and potassium carbonate (1.44g, 10.46mmol) were added thereto, and the mixture was heated to 60 ℃ and stirred under nitrogen for reaction overnight. Cooled to room temperature, ethyl acetate (100 mL) was added, the insoluble solid was filtered off, the filter cake was washed with ethyl acetate (50 mL), the organic phases were combined, concentrated to dryness under reduced pressure, and the residue was passed through a silica gel column to give a pale yellow solid 1.77g, yield 75.8%. LC-MS (APCI) M/z =669.4 (M + 1) + .
Step 2 Compound 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6- (methyl-d) 3 ) Synthesis of pyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester
To a 100mL single-necked flask equipped with magnetic stirring was added 4- (3- ((5- ((4- (4- (methoxycarbonyl) -6- (methyl-d) 3 ) Pyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) -4-nitrobenzyl) piperazine-1-carboxylic acid tert-butyl ester (1.7g, 2.54mmol) and methanol (30 mL) were stirred to dissolve the clear solution, pt/C (0.51g, 10%) was added, vacuum was applied and hydrogen replaced three times, and the reaction was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered off, washed with dichloromethane (20 mL) and the filtrate was concentrated to dryness to give 1.7g of a brown solid in 100% yield which was used directly in the next step. LC-MS (APCI) M/z =639.5 (M + 1) +
Step 3 Compound 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6- (methyl-d) 3 ) Pyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) -1H-benzo [ d]Synthesis of imidazol-6-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester
Under ice-water bath, the solution was charged with 4- (4-amino-3- ((5- ((4- (4- (methoxycarbonyl) -6- (methyl-d) 3 ) Pyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) amino) benzyl) piperazine-1-carboxylic acid tert-butyl ester (1.7g, 2.54mmol) was added to a 100mL single vial with glacial acetic acid (20 mL), the solution was stirred, cyanogen bromide solid (0.32g, 3.05mmol) was slowly added, after the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature under nitrogen overnight. Adding ethyl acetate (60 mL) and water (20 mL) in an ice-water bath to quench the reaction, dropwise adding ammonia water, adjusting the pH value to 9, separating out an organic phase, extracting water phase ethyl acetate (40 mLx 2), combining the organic phases, drying by anhydrous sodium sulfate, filtering, concentrating to dryness,the residue was passed through a silica gel column to give 1.34g of an off-white solid in a yield of 79.6%. LC-MS (APCI) M/z =664.7 (M + 1) +
Step 4 the compound 2- (5- ((5- (2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d)]Imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6- (methyl-d 3 ) Synthesis of isonicotinoyl acid
To a 100mL single-neck flask equipped with magnetic stirring was added 4- ((2-amino-1- (5- ((4- (4- (methoxycarbonyl) -6- (methyl-d) 3 ) Pyridin-2-yl) -1-methyl-1H-pyrazol-5-yl) oxy) -2-methylpentyl) -1H-benzo [ d]Imidazol-6-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (1.3g, 1.96mmol), THF (15 mL) and water (15 mL) were stirred to dissolve it clearly, liOH-H was added 2 O (0.16g, 3.92mmol), the reaction was stirred at room temperature under nitrogen for 2 hours. The organic solvent was evaporated under reduced pressure, cooled in an ice-water bath, citric acid solid (0.25g, 1.31mmol) was slowly added to precipitate a large amount of white solid, filtered, the filter cake was washed with water (10 mL), dried to give 0.83g of white solid, yield 65.5%. LC-MS (APCI) M/z =650.7 (M + 1) +
Step 5 Compound (E) -4- ((1) 1 7-dimethyl-2 6 - (methyl-d) 3 ) -3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 Synthesis of t-butyl (E) -yl) methyl) piperazine-1-carboxylate
To a 100mL single-neck flask equipped with magnetic stirring was added 2- (5- ((5- (2-amino-6- ((4- (tert-butoxycarbonyl) piperazin-1-yl) methyl) -1H-benzo [ d ] c]Imidazol-1-yl) -4-methylpentyl) oxy) -1-methyl-1H-pyrazol-4-yl) -6- (methyl-d 3 ) Isonicotinoyl acid (0.8g, 1.23mmol) and dry dichloromethane (15 mL) were stirred to dissolve the supernatant, DIPEA (0.32g, 2.46mmol) and TBTU (0.59g, 1.84mmol) were added, and the reaction was stirred at room temperature under nitrogen for 2 hours after the addition. The reaction mixture was diluted with dichloromethane (30 mL), water (50 mL) was added, the mixture was stirred for 5 minutes, the organic phase was separated, extracted with dichloromethane (30 mLx 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give a pale yellow solid 0.53g, yield 68.2%. LC-MS (APCI) M/z =632.7 (M + 1) +
Step 6 Synthesis of Compound T-8
To a 100mL single-necked flask equipped with magnetic stirring was added (E) -4- ((1) 1 7-dimethyl-2 6 - (methyl-d) 3 ) -3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecene-5 6 T-butyl (o) -methyl) piperazine-1-carboxylate (0.53g, 0.84mmol) and ethyl acetate (2 mL) were added 5M isopropanol hydrochloride solution (10 mL) and the reaction was stirred under nitrogen for 2 hours. Ethyl acetate (40 mL) was added to precipitate a large amount of white solid, which was filtered, washed with ethyl acetate (10 mL), the filter cake was added with dichloromethane (20 mL) and water (5 mL), ammonia water was added dropwise to adjust the pH to 9, the organic phase was separated, washed with water, extracted with dichloromethane (10 mLx 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 0.31g of a brown solid, a yield of 69.4%, and used directly in the next step. LC-MS (APCI) M/z =532.7 (M + 1) +
Step 7 Synthesis of Compound T-9
A50 mL single neck flask equipped with magnetic stirring was charged with compound T-8 (0.3g, 0.56mmol) and methanol (8 mL), stirred to dissolve, charged with formaldehyde (0.18g, 1.18mmol, w/w 20% solution) and glacial acetic acid (3mg, 0.05mmol), stirred under nitrogen for 20 minutes, charged with sodium cyanoborohydride (53mg, 0.84mmol), and stirred for an additional 2 hours. The reaction was quenched by addition of brine (20 mL), extracted with ethyl acetate (30 mLx 3), the organic phases were combined, washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was passed through a silica gel column to give an off-white solid (0.22 g, yield 72.0%).
Step 8 Synthesis of Compounds T-9-R and T-9-S
The racemic compound T-9 (0.22 g) was dissolved in methanol (30 mL) and subjected to chiral preparative resolution by SFC under the following resolution conditions:
the instrument comprises the following steps: waters SFC-150; chiral column: cellosolve OD 20 × 250mm,10um; mobile phase: CO2 2 /EtOH[0.5%NH3(7M in MeOH)]=70/30; flow rate: 100g/min, column temperature: 35 ℃; column pressure: 100bar; detection wavelength: 214nm; cycle time:6min; sample introduction amount: 4mL.
Collecting corresponding fractions, and spin-drying to obtain isomer T-9-R of 150mg with corresponding retention time of 2.948min; and the isomer T-9-S was 150mg, corresponding to a retention time of 3.553min (where the chiral analysis conditions were HPLC, column: OD-3.6X 100mm 3um; mobile phase: etOH [1% ]NH) 3 (7M in MeOH)](ii) a Flow rate: 3.0mL/min; column temperature: 40 ℃; pressure: 200 psi).
And (4) testing the biological activity.
(1) Wild type EGFR and mutant EGFR kinase activity inhibition assay
The inhibitory activity of the test drugs on EGFR WT, EGFR del19, EGFR L858R, EGFR del 19T 790M, EGFR L858R T790M, EGFR del 19T 790M and EGFR L858R T790M C797S (SignalChem, E-10-132 GG) kinases is determined by using an HTRF KinEASE-TK kit (Cisbio, 62TK0 PEC).
The highest concentration of the drug to be tested is 1 mu M,3 times of gradient dilution, 12 concentrations, and DMSO is prepared into 100 multiplied gradient solution. After 40 Xdilution with 1 Xkinase buffer, 4. Mu.L of each concentration of drug solution and 4. Mu.L of substrate and ATP were added to each well in 384 well plates (Perkin Elmer, 6008280), mixed with 2. Mu.L of EGFR WT, 2. Mu.L of EGFR del 19T 790M, 2. Mu.L of EGFR L858R T790M, 2. Mu.L of EGFR del 19T 790M C797S or 2. Mu.L of EGFR L858R 790M C797S, respectively, double wells, 1 DMSO as positive control, no kinase well as negative control, and incubated at 25 ℃ for 20-60min. The final detection concentration and action time of the kinase, the substrate and the ATP are determined after respective kinase optimization, and the HTRF KinEASE-TK kit is referred to in the steps. Then adding 10 mu L TKAb-Cryptate and Sa-XL665 detection system, mixing uniformly, and continuing to incubate for 60min at 25 ℃. Reading on a BioTek plate reader (Synergy Neo 2), and calculating the inhibition rate of the compound on the enzyme at different concentrations. Data were analyzed using GraphPad Prism7.0 software, and dose-response curves were derived by fitting the data using non-linear curve regression, and IC was calculated therefrom 50 The value is obtained.
The compounds of the present invention were tested in the above kinase inhibition experiments and found to have potent activity against EGFR del19, EGFR L858R, EGFR del 19T 790M, EGFR L858R T790M, EGFR del 19T 790M C797S, EGFR L858R T790M C797S kinase while retaining activity against EGFR WT.
(2) Testing of growth inhibitory Activity of wild-type EGFR and mutant EGFR cells
Detection of example Compound Pair Ba/F 3 Parental, ba/F 3 EGFR WT、Ba/F 3 EGFR del19、Ba/F 3 EGFR L858R、Ba/F 3 EGFR del19 T790M、Ba/F 3 EGFR L858R T790M、Ba/F 3 EGFR del19 T790M C797S、Ba/F 3 EGFR L858R T790M C797S, A431 (human skin squamous cell carcinoma cell EGFR WT), HCC827 (human non-small cell lung carcinoma NSCLC, EGFR del 19), NCI-H1975 (human lung adenocarcinoma cell line EGFR L858R T790M) and NCI-H1975L 858R T790M C797S (human lung adenocarcinoma cell line EGFR L858R T790M C797S) totalize the inhibitory effects of 12 cell activities.
Consumable and reagent: fetal bovine serum FBS (GIBCO, catalog number 10099141), cellTiter-
Figure BDA0003651176390000941
Luminecent Cell visual Assay (Promega, catalog No. G7572), 96-well transparent flat-bottom black-wall plate (r) ((r))
Figure BDA0003651176390000942
Directory number 3603).
The experimental method comprises the following steps:
cell culture and inoculation:
1. cells in the logarithmic growth phase were harvested and counted using a platelet counter. Detecting the cell viability by using a trypan blue exclusion method to ensure that the cell viability is over 90 percent;
2. adjusting the cell concentration to 500-5000 cells per well; add 100 μ Ι _ of cell suspension to 96-well plates, respectively;
3. the cells in a 96 well plate were incubated at 37 ℃ and 5% CO 2 Culturing overnight under the condition of 95% humidity;
4. laying another 96-well plate, setting cells with the same concentration in 3-4 multiple wells, taking culture medium in 3-4 multiple wells as blank control, measuring T0 plate, and reading plate when adding medicine the next day. The values measured for the cellular and acellular pores are LumT0 and LumB0, respectively.
Drug dilution and dosing:
1. preparing 3 times of drug solution, wherein the highest concentration is 10 mu M,9 concentrations are 3 mu M,1 mu M, 0.3 mu M, 0.1 mu M and other gradients downwards in sequence, 50 mu L of drug solution is added into each hole of a 96-hole plate for inoculating cells, and three multiple holes are arranged for each drug concentration; 0.5% DMSO as vehicle control. Wells without cells are blank.
2. If the activity is higher, the maximum concentration is adjusted downward to 3. Mu.M or 1. Mu.M or 0.3. Mu.M or 0.1. Mu.M, and 9 concentrations are withdrawn downward to allow the IC of the drug to be tested 50 Within a reasonable range of the selected concentration interval.
3. The cells in the dosed 96-well plate were placed at 37 ℃ and 5% CO 2 And further cultured under 95% humidity conditions for 72 hours, after which CTG analysis was performed. The values measured for the cellular and acellular pores are LumT and LumB, respectively.
Reading the plate at the end:
1. melting the CTG reagent to room temperature for 30 minutes;
2. an equal volume (40 μ L) of CTG reagent was added to each well;
3. vibrating on an orbital shaker for 10 minutes to lyse the cells;
4. the plate was left at room temperature for 30 minutes to stabilize the luminescence signal;
5. and reading the cold light value.
Data processing
Data were analyzed using GraphPad Prism7.0 software, fitted to data using nonlinear S-curve regression to derive dose-response curves, and IC was calculated therefrom 50 The value is obtained.
Cell growth inhibition (%) =1- (Lum test drug-Lum vehicle control)/(Lum cell control-Lum vehicle control) × 100%.
Data were analyzed using GraphPad Prism7.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom 50 The value is obtained. The experimental results show that: non-deuterated Compound (E) -1 1 ,2 6 7-trimethyl-5 6 - ((4-methylpiperazin-1-yl) methyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-one (defined as compound
Figure BDA0003651176390000951
) In contrast, the racemic compound of the present invention pairs Ba/F associated with side effects of the drug 3 EGFR WT and A431 wild type cells showed lower inhibitory activity, but for Ba/F 3 EGFR del19、Ba/F 3 EGFR L858R、Ba/F 3 EGFR del19 T790M、Ba/F 3 EGFR L858R T790M、Ba/F 3 EGFR del 19T 790M C797S and Ba/F 3 Cells of EGFR L858R T790M C797S, HCC827, NCI-H1975 and NCI-H1975L 858R T790M C797S mutants show higher inhibitory activity;
non-deuterated Compound (R, E) -1 1 ,2 6 7-trimethyl-5 6 - ((4-methylpiperazin-1-yl) methyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-one (i.e., BI-4020, defined as a compound
Figure BDA0003651176390000952
) In contrast, the R configuration compound of the invention has Ba/F related to side effect of medicine 3 EGFR WT and A431 wild type cells showed lower inhibitory activity, but for Ba/F 3 EGFR del19、Ba/F 3 EGFR L858R、Ba/F 3 EGFR del19 T790M、Ba/F 3 EGFR L858R T790M、Ba/F 3 EGFR del 19T 790M C797S and Ba/F 3 Cells of EGFR L858R T790M C797S, HCC827, NCI-H1975, and NCI-H1975L 858R T790M C797S mutants exhibit higher inhibitory activity;
non-deuterated Compound (S, E) -1 1 ,2 6 7-trimethyl-5 6 - ((4-methylpiperazin-1-yl) methyl) -5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5 (2, 1) -benzo [ d]Imidazo-2 (2, 4) -pyrido-1 (4, 5) -pyrazolocyclododecen-3-one (defined as compound
Figure BDA0003651176390000953
) In contrast, the S-configuration compounds of the invention show lower inhibitory activity against wild-type Ba/F3 EGFR WT and A431 cells associated with side effects of the drug, while showing higher inhibitory activity against wild-type Ba/F3 EGFR del19, ba/F3 EGFR L858R, ba/F3 EGFR del 19T 790M, ba/F3 EGFR L858R T790M, ba/F3 EGFR del 19T 790M C797S and Ba/F3 EGFR L858R T790M C797S, HCC827, NCI-H1975 and NCI-H1975L 858R T790M C797S mutants.
Thus, the compounds of the invention exhibit higher activity and selectivity for EGFR del19/L858R variants with or without T790M and/or C797S mutations compared to non-deuterated compounds, and more importantly, the compounds of the invention significantly inhibit C797S mutated EGFR while still retaining activity for wild-type EGFR, with excellent selectivity (e.g., by IC of Ba/F3 EGFR WT cells) 50 IC divided by Ba/F3 EGFR L858R T790M C797S 50 Obtained), for example, of the compounds of the invention T-3-R and T-4-R vs Ba/F 3 EGFR L858R T790M C797S has the same relative Ba/F 3 Selectivity of EGFR WT higher than 1000. The results for representative example compounds are summarized in tables 1 and 2 below.
Table 1:
Figure BDA0003651176390000961
table 2:
Figure BDA0003651176390000962
Figure BDA0003651176390000971
(3) Evaluation of Metabolic stability
Metabolic stability, which is generally used to describe the rate and extent to which a compound is metabolized, is one of the major factors affecting pharmacokinetic properties. Many compounds are substrates for CYP450 enzymes and other drug metabolizing enzymes, while liver microsomes are CYP450 rich systems, and the purpose of this experiment was to study the in vitro metabolic stability by incubating the compounds of the invention with human and SD rat liver microsomes separately and measuring the remaining proportion of compound using LC-MS/MS.
(1) Preparation of the solution
Phosphate Buffered Saline (PBS): taking prepared KH 2 PO 4 (0.5M) 150mL of solution and K 2 HPO 4 700mL of the (0.5M) solution was mixed, and then K was added 2 HPO 4 (0.5M) solution the pH of the mixture was adjusted to 7.4 and the mixture was stored at 4 ℃ as 5-fold concentration PBS for further use. Before use, the mixture was diluted 5-fold with ultrapure water, and 3.3mM magnesium chloride was added to obtain phosphate buffered saline PBS (100 mM).
NADPH regenerating system solution: an NADPH solution containing 6.5mM NADP,16.5mM G-6-P,3U/mL G-6-P D was prepared in 5mL of PBS.
Internal standard stop solution: and preparing 50ng/mL propranolol hydrochloride and 200ng/mL tolbutamide as internal standard working solution by using acetonitrile.
Human liver microsome solution: 0.31mL of human liver microsomes (25 mg/mL) was added to 0.961mL of PBS (pH 7.4) and mixed to obtain a human liver microsome dilution with a protein concentration of 0.625 mg/mL.
SD rat liver microsome solution: 0.31mL of rat liver microsome (25 mg/mL) was added to 0.961mL of PBS (pH 7.4) and mixed to obtain a diluted SD rat liver microsome with a protein concentration of 0.625 mg/mL.
Sample working solution: compound of the invention and non-deuterated compound powders, positive control dextromethorphan powder and omeprazole powder were formulated in DMSO to 10mM as sample stocks. Then diluted with 70% acetonitrile-water to obtain 0.25mM sample working solution.
(2) Sample incubation
398. Mu.L of human liver microsome diluent was added to a 96-well incubation plate (N = 2), and 2. Mu.L of 0.25mM test compound and dextromethorphan were added, respectively, and mixed well.
398. Mu.L of the diluted solution of SD rat liver microsomes was added to a 96-well incubation plate (N = 2), and 2. Mu.L of 0.25mM test compound and omeprazole were added, respectively, and mixed well.
Add 300. Mu.L of pre-cooled stop solution to each well in a 96-well deep-well plate and place on ice as a stop plate.
The 96-well incubation plate and the NADPH regeneration system are placed in a 37 ℃ water bath box, shaken at 100 rpm and pre-incubated for 5min. 80. Mu.L of the incubation solution was taken out of each well of the incubation plate, added to the stop plate, mixed well, and supplemented with 20. Mu.L of NADPH regenerating system solution as a 0min sample. Then 80. Mu.L of NADPH regenerating system solution was added to each well of the incubation plate, the reaction was started, and the timer was started. The reaction concentration of the test compound was 1. Mu.M, and the protein concentration was 0.5mg/mL.
When the reaction was carried out for 10 min, 30 min and 90min, 100. Mu.L of each reaction solution was added to the stop plate and vortexed for 3min to terminate the reaction.
The plates were centrifuged at 5000rpm at 4 ℃ for 15min. And (3) taking 200 mu L of supernatant into a 96-well plate which is added with 200 mu L of ultrapure water in advance, mixing uniformly, carrying out sample analysis by adopting LC-MS/MS, and injecting 10uL of sample.
(3) Sample analysis method
In the experiment, an LC-MS/MS system is adopted to detect the peak areas of the compound to be detected, dextromethorphan, omeprazole and the internal standard, and the peak area ratio of the compound to the internal standard is calculated.
(4) Data processing
The peak areas of the sample and the internal standard are obtained by a mass spectrometer and analysis software, and a substrate elimination rate constant K can be obtained by using a Graphpad prism7.0 software single exponential degradation model to plot the residual amount (R%) of the compound and time
Ct/C0=exp(-K*t)
And calculating the half-life T according to the following formula 1/2 And intrinsic clearance CL int Wherein V/M is equal to 1/C (protein).
Figure BDA0003651176390000981
t 1/2 (min);CL int (μL/min/mg)。
The experimental results are as follows: the compounds of the invention and non-deuterated compounds thereof were tested simultaneously and compared to assess their metabolic stability in liver microsomes in human and SD rats. With non-deuteriumCompared with the substituted compound, the compound of the invention has longer half-life T 1/2 And lower clearance CL int The metabolic stability can be obviously improved. The results for representative example compounds are summarized in table 3.
Table 3:
Figure BDA0003651176390000982
Figure BDA0003651176390000991
(4) Pharmacokinetic experiment of rat
6 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups of 3 animals each, and a single dose of the compound (10 mg/kg per oral dose) was administered intravenously or orally to compare the pharmacokinetic differences.
Rats were fed standard chow and given water. Fasting was initiated 16 hours prior to the test. The drug was dissolved with PEG400 and dimethylsulfoxide. Blood was collected from the orbit at 0.083, 0.25, 0.5, 1,2, 4,6, 8, 12 and 24 hours post-dose.
The rats were briefly anesthetized after ether inhalation and 300. Mu.L of blood was collected from the orbit into a test tube. In the test tube there was 30. Mu.L of 1% heparin salt solution. Before use, the tubes were dried overnight at 60 ℃. After completion of blood collection at the last time point, the rats were sacrificed after ether anesthesia.
Immediately after blood collection, the tubes were gently inverted at least 5 times to ensure mixing and then placed on ice. The blood samples were centrifuged at 5000rpm for 5 minutes at 4 ℃ to separate the plasma from the erythrocytes. Aspirate 100 μ L of plasma with a pipette into a clean plastic centrifuge tube, indicating the name of the compound and the time point. Plasma was stored at-80 ℃ before analysis. The concentration of the compound of the present invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on blood drug concentration at different time points for each animal.
Experiments show that the compound has better pharmacokinetic property in animals, thereby having better pharmacodynamics and treatment effect.
The foregoing is a more detailed description of the invention in connection with specific preferred embodiments and it is not intended that the invention be limited to these specific details. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.
In summary, the present invention relates to the following technical solutions:
1. a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:
Figure BDA0003651176390001001
wherein,
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Each independently selected from hydrogen, deuterium or halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that the above-mentioned compounds contain at least one deuterium atom.
2. The compound according to claim 1, which is a compound of formula (IA):
Figure BDA0003651176390001011
wherein Y is 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 1;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
3. The compound according to claim 1, which is a compound of formula (IB):
Figure BDA0003651176390001021
wherein, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 1;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
4. The compound according to any one of claims 1 to 3, wherein X 1 Is a CD 3
5. Root of herbaceous plantThe compound according to any one of claims 1 to 4, wherein X 2 Is a CD 3
6. The compound according to any one of claims 1 to 5, wherein X 3 Is a CD 3
7. The compound according to any one of claims 1 to 6, wherein X 4 Is a CD 3
8. The compound according to claim 1, which is a compound of formula (II):
Figure BDA0003651176390001031
wherein,
R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
9. The compound according to claim 8 which is a compound of formula (IIA):
Figure BDA0003651176390001032
Figure BDA0003651176390001041
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 8;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
10. The compound according to claim 8, which is a compound of formula (IIB):
Figure BDA0003651176390001042
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 8;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
11. The compound of any one of claims 8-10, wherein X 1 Is a CD 3
12. The compound of any one of claims 8-11, wherein X 2 Is a CD 3
13. The compound of any one of claims 8-12, wherein X 3 Is a CD 3
14. The compound according to any one of claims 8 to 13, wherein X 4 Is a CD 3
15. The compound of any one of claims 8-14, wherein R 10 And R 11 Is deuterium.
16. The compound according to any one of claims 8-15, wherein R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium.
17. The compound according to claim 1, which is a compound of formula (III):
Figure BDA0003651176390001051
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
18. The compound according to claim 17, which is a compound of formula (IIIA):
Figure BDA0003651176390001052
wherein, X 1 、X 2 、X 3 And X 4 As defined in claim 17;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
19. The compound according to claim 17, which is a compound of formula (IIIB):
Figure BDA0003651176390001061
wherein, X 1 、X 2 、X 3 And X 4 As defined in claim 17;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
20. The compound of any one of claims 17-19, wherein X 1 Is a CD 3
21. The compound of any one of claims 17-20, wherein X 2 Is a CD 3
22. The compound of any of claims 17-21, wherein X 3 Is a CD 3
23. The compound of any of claims 17-22, wherein X 4 Is a CD 3
24. The compound according to claim 1, which is a compound of formula (IV):
Figure BDA0003651176390001071
wherein,
R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
Or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
25. The compound according to claim 24, which is a compound of formula (IVA):
Figure BDA0003651176390001072
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 24;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
26. The compound according to claim 24, which is a compound of formula (IVB):
Figure BDA0003651176390001081
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 24;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
27. The compound of any of claims 24-26, wherein X 1 Is a CD 3
28. The compound of any of claims 24-27, wherein X 2 Is a CD 3
29. The compound of any of claims 24-28, wherein X 3 Is a CD 3
30. The compound of any one of claims 24-29, wherein X 4 Is a CD 3
31. The compound of any one of claims 24-30, wherein R 10 And R 11 Is deuterium.
32. The compound of any one of claims 24-31, wherein R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 And R 19 Is deuterium.
33. The compound according to claim 1, which is a compound of formula (V):
Figure BDA0003651176390001091
wherein,
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
Or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
34. The compound according to claim 33, which is a compound of formula (VA):
Figure BDA0003651176390001092
wherein, X 1 、X 2 、X 3 And X 4 As defined in claim 33;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
35. The compound according to claim 33, which is a compound of formula (VB):
Figure BDA0003651176390001101
wherein X 1 、X 2 、X 3 And X 4 As defined in claim 33;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
36. The compound of any of claims 33-35, wherein X 1 Is a CD 3
37. The compound of any of claims 33-36, wherein X 2 Is a CD 3
38. The compound of any of claims 33-37, wherein X 3 Is a CD 3
39. The compound of any of claims 33-38, wherein X 4 Is a CD 3
40. The compound according to claim 1, selected from the compounds of the formula:
Figure BDA0003651176390001102
Figure BDA0003651176390001111
Figure BDA0003651176390001121
Figure BDA0003651176390001131
Figure BDA0003651176390001141
Figure BDA0003651176390001151
Figure BDA0003651176390001161
Figure BDA0003651176390001171
Figure BDA0003651176390001181
Figure BDA0003651176390001191
Figure BDA0003651176390001201
Figure BDA0003651176390001211
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
41. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1-40, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
42. Use of a compound of any one of claims 1-40, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition of claim 41, in the manufacture of a medicament for the treatment and/or prevention of a disease associated with or mediated by mutant EGFR;
43. the use according to claim 42, wherein the mutant EGFR is selected from EGFR del19, EGFR L858R, EGFR del 19T 790M, EGFR L858R T790M, EGFR del 19T 790M C797X (X = S, G, N), EGFR L858R T790M C797X (X = S, G, N), EGFR del 19T 790M L792X (X = F, H, Y), or EGFR L858R T790M L792X (X = F, H, Y).
44. The use according to claim 42, wherein the mutant EGFR is selected from EGFR del19, EGFR L858R, EGFR del 19T 790M, EGFR L858R T790M, EGFR del 19T 790M C797S or EGFR L858R T790M C797S.
45. The use of claim 42, wherein the disease associated with or mediated by mutant EGFR is cancer.
46. The use according to claim 45, wherein the cancer is lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer, mesothelioma, and metastases thereof.
47. The use according to claim 46, wherein the metastasis is brain metastasis.
48. The use according to claim 46, wherein the lung cancer is locally advanced or metastatic NSCLC, NSCLC adenocarcinoma, NSCLC with squamous histology, and NSCLC with non-squamous histology.
49. The use of claim 48, wherein the lung cancer is NSCLC adenocarcinoma.

Claims (10)

1. A compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:
Figure FDA0003651176380000011
wherein,
Y 1 、Y 2 、Y 3 、Y 4 、Y 5 and Y 6 Each independently selected from hydrogen, deuterium or halogen;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that the above-mentioned compounds contain at least one deuterium atom.
2. The compound of claim 1, which is a compound of formula (IA):
Figure FDA0003651176380000021
wherein, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 1;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
3. The compound of claim 1 which is a compound of formula (IB):
Figure FDA0003651176380000022
wherein, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 1;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
4. A compound according to any one of claims 1-3, wherein X 1 Is a CD 3
5. The compound of any one of claims 1-4, wherein X 2 Is a CD 3
6. The compound of any one of claims 1-5, wherein X 3 Is a CD 3
7. The compound of any one of claims 1-6, wherein X 4 Is a CD 3
8. The compound of claim 1, which is a compound of formula (II):
Figure FDA0003651176380000031
wherein,
R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen or deuterium;
X 1 、X 2 and X 3 Each independently selected from CH 3 、CD 3 、CHD 2 Or CH 2 D;
X 4 Selected from H, CH 3 、CD 3 、CHD 2 Or CH 2 D;
With the proviso that said compound contains at least one deuterium atom;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
9. The compound of claim 8, which is a compound of formula (IIA):
Figure FDA0003651176380000041
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 8;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
10. The compound of claim 8, which is a compound of formula (IIB):
Figure FDA0003651176380000042
wherein R is 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、X 1 、X 2 、X 3 And X 4 As defined in claim 8;
or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046221A1 (en) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Egfr inhibitors and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20240104016A (en) * 2022-12-26 2024-07-04 보로노이 주식회사 Heteroaryl derivative compounds, and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159742A (en) * 2011-12-16 2013-06-19 北京韩美药品有限公司 5-Chloropyrimidine compound and application of 5-Chloropyrimidine compound serving as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
CN104379575A (en) * 2012-06-06 2015-02-25 Irm责任有限公司 Compounds and compositions for modulating egfr activity
WO2020260252A1 (en) * 2019-06-24 2020-12-30 Boehringer Ingelheim International Gmbh New macrocyclic compounds and derivatives as egfr inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230159559A1 (en) * 2019-12-16 2023-05-25 Beijing Tide Pharmaceutical Co., Ltd. Compound for inhibiting and inducing degradation of egfr kinase
CN113527335A (en) * 2020-04-15 2021-10-22 南京圣和药业股份有限公司 Macrocyclic compound as EGFR inhibitor and application thereof
CN114163454A (en) * 2020-09-11 2022-03-11 上海翰森生物医药科技有限公司 Pyridine-containing polycyclic derivative inhibitor, and preparation method and application thereof
WO2022117051A1 (en) * 2020-12-03 2022-06-09 北京鞍石生物科技有限责任公司 Macrocyclic compound, preparation method therefor and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159742A (en) * 2011-12-16 2013-06-19 北京韩美药品有限公司 5-Chloropyrimidine compound and application of 5-Chloropyrimidine compound serving as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor
CN104379575A (en) * 2012-06-06 2015-02-25 Irm责任有限公司 Compounds and compositions for modulating egfr activity
WO2020260252A1 (en) * 2019-06-24 2020-12-30 Boehringer Ingelheim International Gmbh New macrocyclic compounds and derivatives as egfr inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046221A1 (en) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Egfr inhibitors and uses thereof

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