Patent Application
20250215008
The present disclosure belongs to the field of medicine, and particularly relates to a small molecule compound related to kinase (such as but not limited to BRAF kinase) disorder, and a stereoisomer, a deuterated product or a pharmaceutical acceptable salt thereof and a use thereof in the preparation of a drug for treatment of a related disease.
Kinases are enzymes that catalyze the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is called phosphorylation, in which the substrate gains a phosphate group and the high-energy ATP molecule donates a phosphate group. Kinases are divided into the following broad categories based on the substrates on which they act: protein kinases, lipid kinases, and carbohydrate kinases. Kinases are found in a variety of species, from bacteria to molds, to worms, and to mammals. More than five hundred different kinases have been identified in humans.
MAP kinases (MAPKs) are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to participate in mitogenic stimulation of the MAPK pathway. Activation of this pathway at the receptor level initiates a signaling cascade whereby Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which activates MEK (MAPKK).
BRAF protein is a member of the RAF family of serine/threonine kinases that participates in cascades of the Ras Raf MEK extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK)/ERK signaling pathway that affect cell division and differentiation. Mutations in the BRAF gene can lead to uncontrolled growth and subsequent tumor formation. BRAF is mutated and/or overactivated in common human cancers, such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, and ovarian cancer and their metastatic cancers, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancers may still develop brain metastases during or subsequent to BRAF inhibitor therapy. An estimated 20% of subjects with cancer will develop brain metastases, with the majority of brain metastases occurring in those with melanoma, colorectal cancer, lung cancer, and renal cell carcinoma. Brain metastases remain a substantial contributor to overall cancer mortality in subjects with advanced cancers, and despite multimodality treatments and advances in systemic therapies, including combinations of surgery, radiotherapy, chemotherapy, immunotherapy, and/or targeted therapies, the prognosis remains poor.
Additionally, BRAF has been identified as a potential target for the treatment of primary brain tumors. The prevalence of BRAF V600E mutations in primary brain tumors has been reported. Schindler et al analyzed 1,320 central nervous system (CNS) tumors and Behling et al analyzed 969 CNS tumors in pediatric and adult populations. These studies combined with others have reported the presence of BRAF V600E mutations in various cancers, including papillary craniopharyngioma, pleomorphic xanthoastrocytoma (PXA), ganglioglioma, astroblastoma, etc.
The blood-brain barrier (BBB) is a highly selective physical transport and metabolic barrier that separates the CNS from the blood. The BBB prevents certain drugs from entering brain tissue and is a limiting factor in the delivery of many peripherally administered agents to the CNS. Many drugs commonly used to treat cancer cannot cross the blood-brain barrier. This means that these drugs cannot penetrate the brain and therefore cannot effectively kill cancer cells in the brain. Current treatments for subjects with brain tumors include surgical resection, radiotherapy, and/or chemotherapy with agents such as temozolomide and/or bevacizumab. However, surgical treatment of brain cancer is not always possible; for example, the tumor may not be accessible or the subject may not be able to withstand the trauma of neurosurgery. Additionally, radiotherapy and treatments with cytotoxic agents are known to have undesirable side effects. For example, there is growing evidence that the use of temozolomide itself can induce mutations and worsen prognosis in a significant proportion of subjects, and the bevacizumab label has a boxed warning for gastrointestinal perforation, surgical and wound healing complications, and bleeding. Kinase inhibitors are used to treat many peripheral cancers. However, many kinase inhibitors such as BRAF inhibitors (e.g., vemurafenib and dabrafenib), due to their structural properties, are substrates of active transporters such as P-glycoprotein (P gp) or breast cancer resistance protein (BCRP). For example, dabrafenib was reported to have an MDR1 efflux ratio of 11.4, a BCRP efflux ratio of 21.0, and a total brain-to-plasma ratio of 0.023; Vemurafenib was reported to have an MDR1 efflux ratio of 83, a BCRP efflux ratio of 495, and a total brain-to-plasma ratio of 0.004.
Given that both P gp and BCRP are expressed in the endothelial cells lining blood-brain capillaries, the activity of both P gp and BCRP in the BBB plays a critical role in preventing the distribution of most kinase inhibitors in the brain parenchyma. Therefore, kinase inhibitors are generally not suitable for the treatment of tumors or cancers in the brain (which is protected by the BBB). Therefore, treatments against tumors harboring BRAF mutations are still needed. Additionally, there remains an unmet need for the treatment of CNS tumors, including CNS tumors harboring BRAF mutations.
The present disclosure provides a small molecule compound with BRAF regulating activity, a stereoisomer, a deuterated product or a pharmaceutically acceptable salt thereof. The compound can better penetrate the blood-brain barrier, has a higher brain-blood ratio, and has good activity, few side effects, excellent pharmacokinetics and high bioavailability.
The present disclosure provides a compound of the following formula I, a stereoisomer, a deuterated product or a pharmaceutically acceptable salt thereof,
or Cy selected from
wherein, n=0 or 1;
Alternatively, R31 and R32, or R32 and R33 together with the atoms to which they are attached form a C3-6 carbocyclic ring or 5-membered or 6-membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, and O. The carbocyclic ring includes aryl and cycloalkyl. The heterocyclic ring includes heteroaryl and heterocycloalkyl, and is optionally substituted with 1-3 groups selected from halogen, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkyl, haloC1-4 alkyl, C1-4 alkoxy, OH, NH2 and CN. In some embodiments, the heterocyclic ring is optionally substituted with 1-3 groups selected from halogen, C1-4 alkyl, haloC1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy and CN. In some embodiments, R31 and R32, or R32 and R33 together with the atoms to which they are attached form C3-6 cycloalkyl, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, or form a 5-membered or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S, and O, such as azetinyl, oxetenly, azacyclopentyl, oxacyclopentyl, azacyclohexenyl, and oxacyclohexenyl, and the cycloalkyl and the heterocycloalkyl is optionally substituted with 1-3 groups selected from halogen, C1-4 alkyl, haloC1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy and CN;
Alternatively, R5 and R6 together with the atoms to which they are attached form 5-membered or 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from N, S, and O, and the heterocyclic ring includes heteroaryl and heterocycloalkyl. In some embodiments, a 5-membered heterocyclic ring is formed. In some embodiments, 5-membered cycloalkyl is formed, and is optionally substituted with 1 to 3 groups selected from halogen, OH, NH2, —NHC1-4 alkyl, —N(C1-4 alkyl)2, CN and C1-4 alkyl;
etc.,
etc., and
etc.
In some embodiments, when Cy is P3, the compound meets one of the following conditions:
A specific technical solution 1 of the present disclosure provides a compound represented by formula I, and a stereoisomer, a deuterated product or a pharmaceutically acceptable salt thereof,
A specific technical solution 2 of the present disclosure provides a compound represented by formula I, and a stereoisomer, a deuterated product or a pharmaceutically acceptable salt thereof,
In certain embodiments, in the compound of formula I, Cy is selected from P1, P2 or P3;
A specific technical solution 3 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 1 or 2,
A specific technical solution 4 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 1 or 2, wherein, when Cy is P3, the compound meets one of the following conditions:
A specific technical solution 5 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 3,
A specific technical solution 6 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 5, the compound has the structure of the following formula I-1,
A specific technical solution 7 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 5, the compound has the structure of the following formula I-2,
A specific technical solution 8 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 5, the compound has the structure of the following formula I-3,
A specific technical solution 9 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 1 or 2, the compound has the structure of the following formula I-4,
A specific technical solution 10 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 8, wherein
A specific technical solution 11 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 9, the compound has the structure of the following formula I-5,
A specific technical solution 12 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 8, solution 9 or solution 10, wherein
A specific technical solution 13 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 12, wherein
A specific technical solution 14 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 8, solution 9 or solution 10, wherein
A specific technical solution 15 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in the present disclosure, the compound has the structure of the following formula I-6,
The compound, or the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure, wherein,
A specific technical solution 16 of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in solution 11, solution 12 or solution 14 in the present disclosure, wherein,
The compound, or the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure, wherein,
Further, the compound, or the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure, wherein,
A specific technical solution of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in the present disclosure, the compound is selected from one of the structures in Table 1,
A specific technical solution of the present disclosure is the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in the present disclosure, the compound is selected from one of the structures in Table 2,
The present disclosure also provides a pharmaceutical composition or pharmaceutical preparation, which comprises the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in any one of the above solutions, and a pharmaceutically acceptable carrier and/or excipient. The pharmaceutical composition can be in a unit preparation form (the unit preparation is also referred to as “preparation specification”).
Further, the pharmaceutical composition or pharmaceutical preparation of the present disclosure comprises 1 mg-1500 mg of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in any one of the above solutions, and a pharmaceutically acceptable carrier and/or excipient.
The present disclosure further provides the use of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in any one of the above solutions in the preparation of a drug for the treatment/prevention of a BRAF-mediated disease.
Further, the BRAF-mediated disease is a tumor, and a further preferred tumor is a brain tumor.
The present disclosure also provides a method for treating diseases in a mammals, which method comprises administering to a subject a therapeutically effective amount of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof described in any one of the above solutions.
The disease is preferably a tumor.
Preferably, the therapeutically effective amount is 1 mg-1500 mg.
In some embodiments, the mammal mentioned in the present disclosure includes human.
The “effective amount” or “therapeutically effective amount” as described in the present application refers to administration of a sufficient amount of the compound disclosed in the present application that will alleviate to some extent one or more symptoms of the diseases or conditions being treated.
In some embodiments, the outcome is the reduction and/or remission of signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an “effective amount” in terms of the therapeutic use is an amount comprising the compound disclosed in the present application that is required to provide clinically significant reduction of the symptoms of the disease. Examples of the therapeutically effective amount include, but are not limited to 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10−1500 mg, 10−1000 mg, 10−900 mg, 10−800 mg, 10−700 mg, 10−600 mg, 10−500 mg, 10−450 mg, 10−400 mg, 10−300 mg, 10−250 mg, 10−200 mg, 10−150 mg, 10−125 mg, 10−100 mg, 10−90 mg, 10−80 mg, 10−70 mg, 10−60 mg, 10−50 mg, 10−40 mg, 10-30 mg, 10−20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg; 50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, and 100-200 mg;
In some embodiments, the pharmaceutical composition or pharmaceutical preparation of the present disclosure comprises the above therapeutically effective amount of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure.
The present disclosure relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure and a carrier and/or excipient.
The pharmaceutical composition can be in a unit preparation form (the amount of the active drug in the unit preparation is also referred to as the “preparation specification”). In some embodiments, the pharmaceutical composition comprises, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure.
A method for treating a disease in a mammal, the method comprises administering to a subject a therapeutically effective amount of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure, and a pharmaceutically acceptable carrier and/or excipient.
The therapeutically effective dose is preferably 1 mg-1500 mg.
The disease is preferably a tumor, especially a brain tumor.
A method for treating a disease in a mammal, the method comprises administering the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure, and the pharmaceutically acceptable carrier and/or excipient to a subject at a daily dose of 1 mg/day-1500 mg/day, the daily dose may be a single dose or divided doses.
In some embodiments, the daily dose includes, but is not limited to, 10−1500 mg/day, 20-1500 mg/day, 25-1500 mg/day, 50-1500 mg/day, 75-1500 mg/day, 100-1500 mg/day, 200-1500 mg/day, 10−1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day, 100-1000 mg/day, 200-1000 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, and 200-400 mg/day. In some embodiments, the daily dose includes, but is not limited to, 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, 1200 mg/day, 1400 mg/day, and 1500 mg/day.
The present disclosure relates to a kit, which can comprise a composition in the form of a single dose or multiple doses and comprises the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure. The amount of the compound, and the stereoisomer, the deuterated product or the pharmaceutically acceptable salt thereof of the present disclosure is the same as that described in the above-mentioned pharmaceutical composition.
In the present disclosure, the amount of the compound or the stereoisomer or pharmaceutically acceptable salt thereof according to the present disclosure is calculated in the form of a free base in each case.
The term “preparation specification” refers to the weight of the active drug contained in each vial, tablet or other unit preparation.
The preparation method of BRAF modulator is introduced in patent documents such as WO 2021116050 A1, and those skilled in the art would have been able to prepare the compounds of the present disclosure by means of combining the document and known organic synthesis techniques, wherein the starting materials used therein are commercially available chemicals and (or) compounds described in chemical documents. “Commercially available chemicals” are obtained from regular commercial sources, and suppliers include: Titan Technology Co., Ltd., Energy Chemical Co., Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., PharmaBlock Sciences (Nanjing), Inc., WuXi Apptec Co., Ltd., J & K Scientific Co., Ltd., etc.
Specific and similar reactants can be selectively identified by the indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, wherein the indexes are available in most public libraries and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, wherein many of standard chemical supply plants (such as those listed above) provide custom synthesis services.
Unless otherwise specified, the terms of the present disclosure have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen and halogen involved in the groups and compounds of the present disclosure all include isotopes thereof, and are optionally further replaced by one or more of the corresponding isotopes thereof, wherein the isotopes of carbon include 12C, 13C and 14C; the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen) and tritium (T, also known as superheavy hydrogen); the isotopes of oxygen include 16O, 17O and 18O; the isotopes of sulfur include 32S, 33S, 34S and 36S; the isotopes of nitrogen include 14N and 15N; the isotope of fluorine includes 19F; the isotopes of chlorine include 35Cl and 37Cl; and the isotopes of bromine include 79Br and 81Br.
The term “halogen” herein refers to F, Cl, Br, I, or isotopes thereof.
The term “halo” or “substituted with halogen” refers to being substituted with one or more groups selected from F, Cl, Br, I, or isotopes thereof, wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Generally, the circumstances of being substituted with 1-5 halogen, 1-3 halogen, 1-2 halogen, and 1 halogen are included.
The term “deuterium” refers to the isotope deuterium of hydrogen (H).
The term “deuterated” or “deuterated compound” refers to the case where a hydrogen atom on a group, such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl and alkynyl is substituted with at least one deuterium atom, wherein the upper limit of the number of deuterium substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of deuterium substituents is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.
Group “Cx-y” refers to a group comprising x to y carbon atoms, for example, “C1-6 alkyl” refers to alkyl comprising 1-6 carbon atoms.
The term “alkyl” refers to a monovalent straight or branched saturated aliphatic hydrocarbon group, usually an alkyl group with 1 to 20 carbon atoms, or an alkyl group with 1 to 8 carbon atoms, or an alkyl group with 1 to 6 carbon atoms, or an alkyl group with 1 to 4 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and alkyl may be further substituted with a substituent.
The term “alkylene” refers to a divalent straight or branched saturated alkyl group. Examples of alkylene include, but are not limited to methylene, ethylidene, etc.
The term “haloalkyl” refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms (e.g., fluorine, chlorine, bromine, iodine, or isotopes thereof), wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the alkyl group. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit. Generally, the alkyl group is substituted with 1-5 halogen, 1-3 halogen, 1-2 halogen or 1 halogen; and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Specific examples include, but are not limited to —CF3, —CH2Cl, —CH2CF3, —CCl2, CF3, etc.
The term “alkoxy” or “alkyloxy” refers to —O-alkyl, such as —O—C1-8 alkyl, —O—C1-6 alkyl, —O—C1-4 alkyl or —O—C1-2 alkyl. Non-limiting and specific examples of alkoxy or alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy, cyclobutoxy, etc. The alkoxy may be optionally substituted with a substituent.
The term “haloalkoxy” refers to —O-haloalkyl, such as —O-halo C1-8 alkyl, —O-halo C1-6 alkyl, —O-halo C1-4 alkyl or —O-halo C1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen, 1-3 halogen, 1-2 halogen, and 1 halogen; and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Non-limiting examples of haloalkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.
The term “alkenyl” refers to a straight or branched hydrocarbon group comprising at least one carbon-carbon double bond (C═C) and generally comprises 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and still further such as 2 to 4 carbon atoms. Examples of alkenyl include, but are not limited to ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; and the alkenyl may further be optionally substituted with a substituent.
The term “alkenylene” refers to a straight or branched divalent unsaturated hydrocarbon group comprising at least one carbon-carbon double bond (C═C). Unless otherwise specified, the alkynylene contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Non-limiting examples of alkynylene include ethynylene, and the alkenylene may be optionally substituted with a substituent.
The term “alkynyl” refers to a straight or branched hydrocarbon group comprising at least one carbon-carbon triple bond (C═C) and generally comprises 2 to 18 carbon atoms, further comprises 2 to 8 carbon atoms, further comprises 2 to 6 carbon atoms, and still further comprises 2 to 4 carbon atoms. Examples of alkynyl include, but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, etc.; and the alkynyl may be optionally substituted with a substituent.
The term “alkynylene” refers to a straight or branched divalent unsaturated hydrocarbon group comprising a carbon-carbon triple bond (C═C) and generally comprises 2-6 carbon atoms, and further comprises 2-4 carbon atoms. Non-limiting examples of alkynylene include ethynylene, propynylene and butynylene; and the alkynylene may be optionally substituted with a substituent.
The term “cycloalkyl” refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group containing no ring heteroatoms. The cycloalkyl may be monocyclic, bicyclic or polycyclic, the bicyclic or polycyclic cycloalkyl may be in the form of a fused ring, a spiro ring, a bridged ring or a combination thereof, and may comprise one or more aromatic rings, but the ring system is non-aromatic as a whole, and the attachment site may be on an aromatic ring or a non-aromatic ring. Generally, the cycloalkyl contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and still further contains 3-6 carbon atoms; when the cycloalkyl is monocyclic cycloalkyl, the cycloalkyl contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when the cycloalkyl is bicyclic or polycyclic cycloalkyl, the cycloalkyl contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl,
etc., and the cycloalkyl may be optionally substituted with a substituent.
The term “cycloalkylene” refers to a divalent group of cycloalkyl.
The term “aryl” refers to an aromatic carbocycle that does not contain heteroatoms, including monocyclic aryl and fused aryl. Generally, the aryl contains 6 to 13 carbon atoms, and further contains 6 to 9 carbon atoms, and it is further phenyl. Non-limiting examples of aryl include phenyl, naphthyl, anthryl and phenanthryl, and the aryl may be optionally substituted with a substituent.
“Carbocycle” or “carbocyclyl” refers to a saturated, partially unsaturated, or aromatic carbocycle, and its meaning includes aryl and cycloalkyl. The carbocycle may be monocyclic, bicyclic or polycyclic, and the bicyclic or polycyclic carbocycle may be in the form of a bridged ring, a fused ring, a spiro ring and a combination thereof. Generally, the carbocycle contains 3-12 carbon atoms, or 3-10 carbon atoms, or 3-6 carbon atoms. Non-limiting examples of the monocyclic carbocycle include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, etc. A bicyclic bridged ring includes
etc., a bicyclic fused ring includes
etc., and a bicyclic spiro ring includes
etc. The carbocycle may be optionally substituted with a substituent.
“Heterocycloalkyl” refers to a saturated or partially unsaturated non-aromatic carbocycle containing 1, 2, 3, or 4 heteroatoms selected from N, S or O. The heterocycloalkyl may be monocyclic, bicyclic or polycyclic, the bicyclic or polycyclic heterocycloalkyl may be in the form of a bridged ring, a fused ring, a spiro ring or a combination thereof, and may comprise one or more aromatic rings or heteroaromatic rings, but the ring system is non-aromatic as a whole, and the attachment site may be on an aromatic ring or a non-aromatic ring. Generally, the heterocycloalkyl is a 3- to 20-membered ring. When the heterocycloalkyl is monocyclic heterocycloalkyl, the heterocycloalkyl is usually a 3- to 15-membered ring, or a 3- to 10-membered ring, or a 3- to 8-membered ring, or a 3- to 6-membered ring; when the heterocycloalkyl is bicyclic or polycyclic heterocycloalkyl, the heterocycloalkyl is usually a 5- to 12-membered ring, or a 5- to 11-membered ring, or a 6- to 9-membered ring. The heteroatoms N and S include their oxidation states. Non-limiting examples of heterocycloalkyl include azetidinyl, morpholinyl, piperazinyl, piperidyl, tetrahydropyranyl, oxetanyl, pyranyl, azacyclopentenyl, azacyclohexenyl, oxacyclopentenyl, oxacyclohexenyl, etc., and the heterocycloalkyl may be optionally substituted with a substituent.
“Heteroaromatic ring” or “heteroaryl”, unless otherwise specified, refers to an aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, which may be monocyclic, bicyclic or polycyclic, wherein the bicyclic or polycyclic heteroaromatic ring or heteroaryl may be in the form of a bridged ring, a fused ring, a spiro ring and a combination thereof. The bicyclic or polycyclic heteroaromatic ring or heteroaryl can be formed by fusion of heteroaryl to aryl, or of heteroaryl to heteroaryl, wherein the heteroaryl or aryl may be the attachment site. Non-limiting examples of heteroaromatic ring or heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, purinyl,
etc. The heteroaryl may be optionally substituted with a substituent.
The term “heterocycle” or “heterocyclyl” refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, and its meaning includes heteroaryl and heterocycloalkyl. The heterocycle may be in the form of a monocyclic heterocycle, a bicyclic bridged heterocycle, a bicyclic fused heterocycle, a bicyclic spiro heterocycle or a combination thereof. The heterocycle is usually a 3 to 12-membered heterocycle, or a 5- to 12-membered heterocycle, or a 5- to 7-membered heterocycle. Heterocyclyl can be connected to a heteroatom or a carbon atom. Non-limiting examples of heterocyclyl include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azacycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidyl, piperadinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzoimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptanyl,
etc., and the heterocycle may be optionally substituted with a substituent.
The term “heterocyclene” refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic, divalent heterocyclyl group. Non-limiting examples of heterocyclene include
etc.
The term “spiro ring” refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between rings, which may contain 0 or at least 1 double or triple bond, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states. Generally, a spiro ring is a 6- to 14-membered ring, or a 6- to 12-membered ring, or a 6- to 10-membered ring. Generally, a spiro ring is a spiro ring formed by a three-membered ring and a three-membered ring, a three-membered ring and a four-membered ring, a three-membered ring and a five-membered ring, a three-membered ring and a six-membered ring, a four-membered ring and a four-membered ring, a four-membered ring and a five-membered ring, a four-membered ring and a six-membered ring, a five-membered ring and a five-membered ring or a five-membered ring and a six-membered ring. Non-limiting examples of the spiro ring include:
and the spiro ring may be optionally substituted with a substituent.
The term “fused ring” refers to a polycyclic group in which the rings share two adjacent ring atoms and one chemical bond, which may contain one or more double or triple bonds, and may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Generally, a fused ring is a 5- to 20-membered ring, or a 5- to 14-membered ring, or a 5- to 12-membered ring or a 5- to 10-membered ring. Generally, a fused ring is in the form of a three-membered ring fused a four-membered ring (indicating a fused ring formed by a three-membered ring and a four-membered ring, and either the three-membered ring or the four-membered ring may be possibly used as the basic ring according to the IUPC nomenclature; similarly hereinafter), a three-membered ring fused a five-membered ring, a three-membered ring fused a six-membered ring, a four-membered ring fused a four-membered ring, a four-membered ring fused a five-membered ring, a four-membered ring fused a six-membered ring, a five-membered ring fused a five-membered ring, a five-membered ring fused a six-membered ring, and a six-membered ring fused a six-membered ring. Non-limiting examples of the fused ring include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, and
the fused ring may be optionally substituted with a substituent.
The term “bridged ring” refers to a ring system in which two non-adjacent ring atoms are shared between two rings, which may contain one or more double or triple bonds. The bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Generally, the bridged ring has 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10 ring atoms. Non-limiting examples of the bridged ring include adamantane,
Unless otherwise specified, the term “substitution” or “substituent” refers to any substitution at a position allowed by chemical theory, and the number of substituents conforms to the rules of chemical bonding. Exemplary substituents include, but are not limited to: C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 heteroalkyl, C5-12 aryl, 5- to 12-membered heteroaryl, hydroxyl, C1-6 alkoxy, C5-12 aryloxy, thiol, C1-6 alkylthio, cyano, halogen, C1-6 alkylthiocarbonyl, C1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halo C1-6 alkyl, halo C1-6 alkoxy, amino, phosphonic acid, —CO2 (C1-6 alkyl), —OC(═O) (C1-6 alkyl), —OCO2 (C1-6 alkyl), —C(═O) NH2, —C(═O)N(C1-6 alkyl)2, —OC(═O)NH(C1-6 alkyl), —NHC(═O) (C1-6 alkyl), —N(C1-6 alkyl) C(═O) (C1-6 alkyl), —NHCO2 (C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —HC(═O)NH(C1-6 alkyl), —NHC(═O) NH2, —NHSO2 (C1-6 alkyl), —SO2N(C1-6 alkyl)2, —SO2NH(C1-6 alkyl), —SO2NH2, —SO2C1-6 alkyl, etc.
The term “optional” or “optionally” refers to that the events or circumstances subsequently described may but not necessarily occur, and the description includes the occasions where the events or circumstances occur or do not occur. For example, “alkyl optionally substituted with F” means that the alkyl may but not necessarily be substituted with F, and the description includes the case where the alkyl is substituted with F and the case where the alkyl is not substituted with F.
The term “pharmaceutically acceptable salt” refers to a salt of the compound of the present disclosure, which salt maintains the biological effectiveness and characteristics of a free acid or a free base and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or reacting the free base with a non-toxic inorganic acid or organic acid.
The term “pharmaceutical composition” represents a mixture of one or more compounds or stereoisomers, solvates, pharmaceutically acceptable salts or co-crystals thereof as described herein and other components including physiologically/pharmaceutically acceptable carriers and/or excipients.
The term “carrier” refers to: a system that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound and can change the way the drug enters the human body and the distribution of the drug in the body, control the release rate of the drug and delivery the drug to targeted organs. Non-limiting examples of the carrier include microcapsule, microsphere, nanoparticle, liposome, etc.
The term “excipient” refers to: a substance that is not a therapeutic agent per se, but used as a diluent, adjuvant, adhesive and/or vehicle for addition to a pharmaceutical composition, thereby improving the disposal or storage properties thereof, or allowing to or promoting the formation of a compound or a pharmaceutical composition into a unit dosage form for administration. As is known to those skilled in the art, pharmaceutically acceptable excipients can provide various functions and can be described as a wetting agent, a buffer, a suspending agent, a lubricant, an emulsifier, a disintegrating agent, an absorbent, a preservative, a surfactant, a colorant, a flavoring agent, and a sweetening agent. Examples of pharmaceutically acceptable excipients include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starch, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (such as croscarmellose sodium); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter or suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;
The term “stereoisomer” refers to an isomer produced as a result of different spatial arrangement of atoms in molecules, including cis-trans isomers, enantiomers and conformational isomers.
The compounds of the present disclosure also include tautomers thereof, for example, when the present disclosure describes the left side compound in which the pyrimidine ring is substituted with OH, the right side tautomer compound is also included.
The term “solvate” refers to a substance formed by the compound of the present disclosure or the salt thereof and a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, the solvate is a hydrate.
The term “co-crystal” refers to a crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between various components. The co-crystal is a multi-component crystal, which includes both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.
The technical solutions of the present disclosure will be described in detail below in conjunction with examples, but the protection scope of the present disclosure includes but is not limited thereto.
The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in the unit of 10−6 (ppm). NMR is determined with (Bruker Avance III 400 and Bruker Avance 300) NMR instrument, and the solvent for determination is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);
LCMS m/z=470.5 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.36 (s, 1H), 8.36 (s, 1H), 7.90-7.84 (m, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.53 (dd, 1H), 7.39 (d, 1H), 3.84 (s, 4H), 3.48 (s, 3H), 2.10 (t, 4H), 1.78-1.69 (m, 2H).
LCMS m/z=456.2 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.26 (s, 1H), 8.35 (s, 1H), 7.89-7.84 (m, 1H), 7.78 (d, 1H), 7.67 (dd, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 3.47 (s, 3H), 3.37-3.34 (m, 4H), 1.59-1.56 (m, 2H), 0.65-0.59 (m, 1H), 0.19-0.16 (m, 1H).
LCMS m/z=431.1 [M+H]+;
1H NMR (400 MHZ, CD3OD) δ8.26 (s, 1H), 7.77 (d, 1H), 7.67-7.54 (m, 3H), 7.48 (dd, 1H), 4.24-4.13 (m, 1H), 3.58 (s, 3H), 0.94-0.83 (m, 2H), 0.79-0.68 (m, 2H).
1H NMR (400 MHZ, DMSO-d6) δ 11.49 (s, 1H), 9.84 (s, 1H), 7.24-7.18 (m, 2H), 7.03 (dd, 1H).
LCMS m/z=183.1 [M+H]+;
LCMS m/z=193.1 [M+H]+;
LCMS m/z=330.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.64 (s, 1H), 7.98 (m, 1H), 7.83 (d, 1H), 7.75 (dd, 1H), 7.64-7.53 (m, 2H), 4.06 (s, 3H).
19F NMR (377 MHz, DMSO-d6)8-107.70 (s), —128.37 (s).
LCMS m/z=478.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.33 (s, 1H), 8.63 (s, 1H), 7.91-7.81 (m, 2H), 7.71 (dd, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 5.40 (m, 0.5H), 5.27 (m, 0.5H), 4.05 (s, 3H), 3.58-3.32 (m, 4H), 2.17 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.22 (s), —172.76 (s).
LCMS m/z=456.30 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.33 (s, 1H), 7.76 (d, 1H), 7.63 (dd, 2H), 7.48 (dd, 1H), 7.38 (d, 1H), 7.08 (s, 1H), 3.83 (s, 4H), 3.47 (s, 3H), 0.56 (s, 4H).
19F NMR (377 MHZ, DMSO-d6)8-134.36 (s).
LCMS m/z=488.20 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.42 (s, 1H), 8.34 (s, 1H), 7.77 (d, 2H), 7.66 (dd, 1H), 7.47 (dd, 1H), 7.38 (d, 1H), 5.01 (s, 0.5H), 4.87 (s, 0.5H), 3.81 (d, 4H), 3.47 (s, 3H), 2.56 (m, 2H), 2.37-2.18 (m, 2H).
LCMS m/z=486.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H), 8.63 (s, 1H), 7.93-7.85 (t, 1H), 7.84 (d, 1H), 7.72 (dd, 1H), 7.54 (dd, 1H), 7.41 (d, 1H), 4.04 (s, 3H), 3.84 (s, 4H), 2.10 (t, 4H), 1.81-1.66 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.26 (s).
LCMS m/z=472.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.48 (s, 1H), 8.63 (s, 1H), 7.93-7.86 (t, 1H), 7.84 (d, 1H), 7.72 (dd, 1H), 7.60 (dd, 1H), 7.43 (d, 1H), 4.05 (s, 3H), 3.98 (s, 4H), 0.62 (s, 4H).
19F NMR (377 MHz, DMSO-d6)8-127.15 (s).
LCMS m/z=128.2 [M+H]+;
LCMS m/z=245.2 [M+H]+;
LCMS m/z=382.0 [M+H]+;
LCMS m/z=538.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.36 (s, 1H), 8.39 (s, 1H), 7.89-7.82 (dd, 2H), 7.75-7.72 (dd, 1H), 7.55-7.52 (dd, 1H), 7.44-7.43 (d, 1H), 4.98-4.91 (q, 2H), 3.83 (s, 4H), 2.11-2.07 (t, 4H), 1.77-1.70 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.30 (s), —67.08 (s).
LCMS m/z=100.2 [M+H]+;
1H NMR (400 MHZ, CDCl3) δ8.23 (s, 1H), 6.32 (s, 1H), 6.01-5.67 (m, 1H), 3.71-3.60 (m, 2H).
LCMS m/z=227.2 [M+H]+;
LCMS m/z=364.2 [M+H]+;
LCMS m/z=520.0 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.37 (s, 1H), 8.34 (s, 1H), 7.87-7.80 (m, 2H), 7.74-7.71 (dd, 1H), 7.54-7.50 (dd, 1H), 7.41-7.40 (d, 1H), 6.51-6.22 (m, 1H), 4.51-4.43 (m, 2H), 3.82 (s, 4H), 2.11-2.07 (t, 4H), 1.78-1.70 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.22 (s), —120.46 (s).
LCMS m/z=86.20 [M+H]+;
LCMS m/z=203.10 [M+H]+;
LCMS m/z=340.10 [M+H]+;
LCMS m/z=496.20 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.37 (s, 1H), 8.27 (s, 1H), 7.91-7.85 (m, 1H), 7.76 (d, 1H), 7.67 (dd, 1H), 7.53 (dd, 1H), 7.37 (d, 1H), 3.84 (s, 4H), 3.28-3.14 (m, 1H), 2.13-2.06 (m, 4H), 1.79-1.70 (m, 2H), 1.06-0.90 (m, 4H).
LCMS m/z=470.50 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.23 (s, 1H), 8.35 (s, 1H), 7.92-7.84 (m, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.54 (dd, 1H), 7.36 (d, 1H), 3.56-3.50 (m, 2H), 3.47 (s, 3H), 1.94-1.84 (m, 2H), 1.80-1.72 (m, 2H), 1.08-0.98 (m, 2H), 0.57-0.51 (m, 2H).
LCMS m/z=492.4 [M+H]+;
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.83 (dd, 1H), 7.63-7.58 (m, 3H), 7.47 (t, 1H), 6.86 (s, 1H), 4.20-4.14 (m, 4H), 3.63 (s, 3H), 1.52 (t, 2H).
LCMS m/z=462.1 [M+H]+;
1H NMR (400 MHZ, CD3OD) δ8.22 (s, 1H), 7.75-7.70 (m, 1H), 7.57 (dd, 2H), 7.47 (dd, 1H), 7.33-7.25 (m, 1H), 4.59 (d, 1H), 4.47 (d, 1H), 3.88 (t, 2H), 3.64 (dd, 2H), 3.57 (s, 3H), 2.88-2.76 (m, 1H).
19F NMR (377 MHz, DMSO-d6)8-146.12 (s), —220.65 (s).
LCMS m/z=480.4 [M+H]+;
1H NMR (400 MHZ, CD3OD) δ8.25 (s, 1H), 7.77-7.72 (m, 1H), 7.59 (dd, 2H), 7.46 (dd, 1H), 7.30 (t, 1H), 6.11 (td, 1H), 3.91 (t, 2H), 3.82-3.75 (m, 2H), 3.59 (s, 3H), 2.98-2.84 (m, 1H).
19F NMR (377 MHz, DMSO-d6)8-121.73 (s), —145.77 (s).
LCMS m/z=498.5 [M+H]+;
1H NMR (400 MHZ, CD3OD) δ8.23 (s, 1H), 7.75-7.70 (m, 1H), 7.57 (dd, 2H), 7.45 (dd, 1H), 7.34-7.26 (m, 1H), 3.96 (t, 2H), 3.89-3.82 (m, 2H), 3.57 (s, 3H), 3.33-3.24 (m, 1H).
19F NMR (377 MHz, DMSO-d6)8-70.81 (s), —145.19 (s).
LCMS m/z=456.5 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.39 (s, 1H), 8.36 (s, 1H), 7.86 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.63 (dd, 1H), 7.38 (d, 1H), 3.48 (s, 3H), 3.39 (t, 1H), 3.18 (m, 1H), 2.93 (m, 1H), 2.05 (m, 1H), 1.98 (m, 1H), 1.61 (m, 1H), 0.78 (m, 1H), 0.52 (m, 1H).
19F NMR (377 MHz, DMSO-d6)8-128.22 (s).
LCMS m/z=472.5 [M+H]+;
1H NMR (400 MHZ, CDCl3) δ8.31 (s, 1H), 7.84 (d, 1H), 7.62 (dd, 1H), 7.57 (d, 1H), 7.54 (dd, 1H), 7.45 (t, 1H), 6.95 (s, 1H), 4.78 (s, 4H), 4.18 (s, 4H), 3.63 (s, 3H).
LCMS m/z=484.60 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.36 (s, 1H), 8.36 (s, 1H), 7.88 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.56 (dd, 1H), 7.39 (d, 1H), 3.72 (s, 4H), 3.48 (s, 3H), 1.71 (m, 4H), 1.50 (m, 4H).
19F NMR (377 MHz, DMSO-d6)8-127.31 (s).
LCMS m/z=114.2 [M+H]+.
LCMS m/z=193.1 [M+H]+.
LCMS m/z=486.1 [M+H]+.
1H NMR (400 MHZ, CDCl3) δ8.00 (s, 1H), 7.73 (d, 1H), 7.68 (s, 1H), 7.61 (d, 1H), 7.58 (dd, 1H), 7.52 (dd, 1H), 7.41-7.34 (m, 1H), 4.57-4.45 (m, 2H), 3.93-3.87 (m, 1H), 3.56 (s, 3H), 3.56-3.51 (m, 2H), 3.40 (d, 1H), 2.73-2.63 (m, 2H), 2.49-2.40 (m, 1H), 2.07-1.98 (m, 1H).
Compound 21 (200 mg) can be obtained by using 21B (3 g) as raw material through the same synthesis method as compound 20.
LCMS m/z=486.1 [M+H]+.
1H NMR (400 MHZ, CDCl3) δ8.01 (s, 1H), 7.75 (s, 1H), 7.73 (d, 1H), 7.61 (d, 1H), 7.57 (dd, 1H), 7.51 (dd, 1H), 7.40-7.34 (m, 1H), 4.56-4.45 (m, 2H), 3.92-3.86 (m, 1H), 3.56 (s, 3H), 3.55-3.51 (m, 2H), 3.40 (d, 1H), 2.71-2.63 (m, 2H), 2.47-2.40 (m, 1H), 2.06-1.98 (m, 1H).
LCMS m/z=200.10 [M+H]+;
LCMS m/z=186.10 [M+H]+;
LCMS m/z=323.30 [M+H]+;
LCMS m/z=479.10 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H), 9.27 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.87 (t, 1H), 7.62 (d, 1H), 7.59 (d, 1H), 7.58-7.53 (m, 2H), 3.83 (s, 4H), 2.08 (t, 4H), 1.75-1.66 (m, 2H).
LC-MS(ESI): m/z=177.1 [M+H]+.
LC-MS(ESI): m/z=314.1 [M+H]+.
1H NMR ((400 MHZ, DMSO-d6) δ 10.41 (s, 1H), 8.38 (d, 1H), 8.30 (d, 1H), 8.00 (dd, 1H), 7.86 (t, 1H), 7.78 (d, 1H), 7.53 (dd, 1H), 3.82 (s, 4H), 2.12 (s, 3H), 2.09 (t, 4H), 1.77-1.69 (m, 2H).
LC-MS(ESI): m/z=470.1 [M+H]+.
LCMS m/z=462.1 [M+H]+;
1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.80 (d, 1H), 7.65-7.61 (m, 2H), 7.58 (dd, 1H), 7.44 (t, 1H), 4.24 (t, 2H), 4.15 (s, 3H), 3.73 (t, 2H), 2.47-2.40 (m, 2H).
LCMS m/z=486.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.41 (s, 1H), 8.70 (s, 1H), 7.99 (d, 1H), 7.89 (dd, 2H), 7.77 (dd, 1H), 7.56 (dd, 1H), 3.87 (s, 3H), 3.83 (s, 4H), 2.09 (t, 4H), 1.78-1.65 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.24 (s).
LCMS m/z=199.10 [M+H]+;
LCMS m/z=209.10 [M+H]+;
LCMS m/z=346.10 [M+H]+;
LCMS m/z=502.10 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.37 (s, 1H), 8.33 (s, 1H), 7.88 (t, 1H), 7.80 (d, 1H), 7.76-7.68 (m, 1H), 7.56-7.51 (m, 1H), 7.39 (d, 1H), 4.79-4.62 (m, 2H), 4.36-4.25 (m, 2H), 3.83 (s, 4H), 2.09 (t, 4H), 1.78-1.69 (m, 2H).
LCMS m/z=464.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.63 (s, 1H), 7.96-7.78 (m, 2H), 7.73 (dd, 1H), 7.56 (dd, 1H), 7.44 (d, 1H), 5.47-5.28 (m, 1H), 4.25-4.16 (m, 2H), 4.05 (s, 3H), 4.04-3.95 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-126.63 (s), —177.31 (s).
LCMS m/z=482.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.64 (s, 1H), 7.91 (dd, 1H), 7.84 (d, 1H), 7.73 (dd, 1H), 7.58 (dd, 1H), 7.45 (d, 1H), 4.41 (t, 4H), 4.05 (s, 3H).
19F NMR (377 MHZ, DMSO-d6)8-90.00 (s), —126.12. (s).
LCMS m/z=502.10 [M+H]+;
LCMS m/z=504.10 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.49 (s, 1H), 8.63 (s, 1H), 7.89 (t, 1H), 7.83 (d, 1H), 7.75-7.68 (m, 1H), 7.57-7.53 (m, 1H), 7.42 (d, 1H), 5.04-4.84 (m, 1H), 4.18 (d, 1H), 4.04 (s, 3H), 3.94 (d, 1H), 3.86-3.79 (m, 2H), 2.19-2.10 (m, 1H), 2.02-1.78 (m, 2H), 1.70-1.62 (m, 1H).
LCMS m/z=217.1 [M+H]+;
LCMS m/z=354.1 [M+H]+;
LCMS m/z=510.2 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H), 8.36 (s, 1H), 7.93-7.84 (m, 1H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.54 (dd, 1H), 7.35 (d, 1H), 3.84 (s, 4H), 2.10 (t, 4H), 1.75 (dd, 2H), 1.45 (s, 3H), 1.06 (t, 2H), 0.94 (t, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.33 (s).
LCMS m/z=504.8 [M+H]+;
1H NMR (400 MHZ, CDCl3) δ8.09 (s, 1H), 7.79 (d, 1H), 7.64-7.56 (m, 3H), 3.99 (s, 4H), 3.60 (s, 3H), 2.20 (t, 4H), 1.89-1.81 (m, 2H).
LCMS m/z=520.9 [M+H]+;
1H NMR (400 MHZ, CDCl3) δ8.33 (s, 1H), 7.84 (d, 1H), 7.66-7.59 (m, 3H), 4.17 (s, 3H), 3.99 (s, 4H), 2.20 (t, 4H), 1.89-1.81 (m, 2H).
LCMS m/z=209.1 [M+H]+;
LCMS m/z=219.1 [M+H]+;
LCMS m/z=356.2 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.39 (s, 1H), 8.00-7.94 (m, 1H), 7.82-7.80 (d, 1H), 7.76-7.73 (dd, 1H), 7.61-7.55 (m, 2H), 5.55-4.47 (p, 1H), 4.97-4.93 (t, 2H), 4.89-4.85 (t, 2H).
LCMS m/z=512.6 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.37 (s, 1H), 8.38 (s, 1H), 7.89-7.80 (m, 2H), 7.72-7.69 (dd, 1H), 7.55-7.52 (dd, 1H), 7.37-7.36 (d, 1H), 5.53-5.45 (p, 1H), 4.96-4.92 (t, 2H), 4.88-4.84 (t, 2H), 3.83 (s, 4H), 2.12-2.08 (t, 4H), 1.78-1.70 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.30 (s).
LCMS m/z=213.1 [M+H]+;
LCMS m/z=223.2 [M+H]+;
LCMS m/z=360.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.44 (s, 1H), 8.01-7.95 (m, 1H), 7.81-7.73 (m, 2H), 7.62-7.56 (m, 2H), 5.17-5.04 (m, 1H), 4.91-4.86 (dd, 0.5H), 4.79-4.75 (m, 1H), 4.67-4.63 (dd, 0.5H), 1.48-1.45 (dd, 3H).
LCMS m/z=516.2 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.37 (s, 1H), 8.42 (s, 1H), 7.90-7.85 (dd, 1H), 7.82-7.79 (d, 1H), 7.73-7.70 (dd, 1H), 7.56-7.52 (dd, 1H), 7.38-7.37 (d, 1H), 5.13-5.04 (m, 1H), 4.90-4.85 (dd, 0.5H), 4.78-4.73 (m, 1H), 4.65-4.62 (dd, 0.5H), 3.84 (s, 4H), 2.11-2.07 (t, 4H), 1.77-1.70 (m, 2H), 1.45-1.44 (m, 3H).
19F NMR (377 MHz, DMSO-d6)8-72.80 (s), —127.34 (s).
LCMS m/z=213.1 [M+H]+;
LCMS m/z=223.2 [M+H]+;
LCMS m/z=360.1 [M+H]+;
LCMS m/z=516.6 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.37 (s, 1H), 8.42 (s, 1H), 7.90-7.79 (m, 2H), 7.73-7.70 (dd, 1H), 7.56-7.52 (dd, 1H), 7.38-7.37 (d, 1H), 5.13-5.04 (m, 1H), 4.89-4.85 (dd, 0.5H), 4.78-4.73 (m, 1H), 4.65-4.62 (dd, 0.5H), 3.83 (s, 4H), 2.11-2.07 (t, 4H), 1.77-1.70 (m, 2H), 1.46-1.44 (d, 3H).
19F NMR (377 MHz, DMSO-d6)8-74.66 (s), —129.42 (s).
Compound 17 (300 mg) was subjected to chiral SFC resolution to obtain P1 (retention time: 0.588 min, set as compound 36) and P2 (retention time: 0.694 min, set as compound 37). Resolution method: instrument name: Waters 150 Prep-SFC F; chromatographic column: Chiralcel AD-Column; mobile phase: A for CO2 and B for 0.1% NH3·H2O in MEOH and ACN; gradient: isocratic elution, mobile phase B: 35%; flow rate: 120 mL/min. Sample preparation: the compound was dissolved in acetonitrile at a concentration of 10 mg/mL; injection: 2.0 mL/injection; treatment: after the separation, the obtained product was concentrated by a rotary evaporator at 35° C., and then the solvent was dried by a lyophilizer at −80° C. to obtain compound 36 (86 mg, 29%) and compound 37 (74 mg, 25%).
LCMS m/z=456.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.40 (s, 1H), 8.35 (s, 1H), 7.84 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.62 (dd, 1H), 7.37 (d, 1H), 3.47 (s, 3H), 3.40-3.34 (m, 1H), 3.17 (dd, 1H), 2.93 (dd, 1H), 2.10-2.01 (m, 1H), 1.96 (dd, 1H), 1.60 (dt, 1H), 0.81-0.75 (m, 1H), 0.50 (dd, 1H).
19F NMR (377 MHZ, DMSO-d6)8-128.22 (s).
LCMS m/z=456.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.42 (s, 1H), 8.36 (s, 1H), 7.85 (t, 1H), 7.78 (d, 1H), 7.68 (dd, 1H), 7.62 (dd, 1H), 7.38 (d, 1H), 3.47 (s, 3H), 3.37 (s, 1H), 3.17 (s, 1H), 2.93 (dd, 1H), 2.09-2.00 (m, 1H), 1.98 (d, 1H), 1.60 (s, 1H), 0.78 (s, 1H), 0.50 (d, 1H).
19F NMR (377 MHz, DMSO-d6)8-128.22 (s).
LCMS m/z=239.1 [M+H]+;
LCMS m/z=249.1 [M+H]+;
LCMS m/z=386.2 [M+H]+;
LCMS m/z=542.4 [M+H]+;
LCMS m/z=513.1 [M+H]+;
LCMS m/z=495.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.36 (s, 1H), 8.40 (s, 1H), 7.90-7.82 (m, 2H), 7.75-7.73 (dd, 1H), 7.56-7.52 (dd, 1H), 7.44-7.43 (d, J=2.9 Hz, 1H), 5.08 (s, 2H), 3.84 (s, 4H), 2.11-2.08 (t, 4H), 1.78-1.70 (m, 2H).
19F NMR (377 MHz, DMSO-d6)8-127.33 (s).
LCMS m/z=520.50 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.34 (s, 1H), 7.80 (d, 1H), 7.75 (dd, 1H), 7.59 (d, 1H), 7.53 (dd, 1H), 4.72 (dt, 2H), 4.32 (dt, 2H), 3.85 (s, 4H), 2.10 (t, 4H), 1.79-1.68 (m, 2H).
19F NMR (376 MHz, DMSO-d6)8-121.46 (s), —150.87 (s), —222.31 (s).
LCMS m/z=538.5 [M+H]+;
19F NMR (376 MHZ, DMSO-d6)8-120.44 (s), —171.59 (s), —216.41 (s).
Compound 41: (P2: 140 mg, 13%), 1H NMR (400 MHZ, DMSO-d6) δ 10.45 (s, 1H), 8.34 (s, 1H), 7.88-7.80 (m, 2H), 7.73-7.70 (dd, 1H), 7.54-7.51 (dd, 1H), 7.43-7.42 (d, 1H), 6.51-6.22 (m, 1H), 5.03-4.99 (dt, 1H), 4.51-4.43 (td, 2H), 4.17-4.15 (d, 1H), 3.93-3.78 (m, 3H), 2.18-2.10 (m, 1H), 2.00-1.79 (m, 2H), 1.69-1.62 (m, 1H).
19F NMR (376 MHZ, DMSO-d6)8-120.44 (s), —127.17 (s), —171.59 (s).
LCMS m/z=257.1 [M+H]+;
LCMS m/z=213.2 [M+H]+;
LCMS m/z=556.0 [M+H]+.
1H NMR (400 MHZ, DMSO-d6) δ 10.57 (s, 1H), 8.34 (s, 1H), 7.92-7.87 (m, 1H), 7.83-7.80 (d, 1H), 7.73-7.70 (dd, 1H), 7.55-7.52 (dd, 1H), 7.44 (d, 1H), 6.51-6.22 (m, 1H), 4.52-4.43 (m, 2H), 4.08-4.06 (d, 2H), 3.91-3.88 (d, 2H), 2.47-2.42 (m, 2H), 2.04-2.00 (m, 2H).
19F NMR (376 MHZ, DMSO-d6)8-98.98 (s), —120.45 (s), —126.75 (s).
LCMS m/z=538.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.35 (s, 1H), 7.81 (d, 1H), 7.77 (dd, 1H), 7.59 (d, 1H), 7.52 (dd, 1H), 6.52-6.23 (m, 1H), 4.49 (td, 2H), 3.83 (s, 4H), 2.08-2.11 (m, 4H), 1.77-1.70 (m, 2H).
LCMS m/z=234.3 [M+H]+;
LCMS m/z=216.2 [M+H]+;
LCMS m/z=214.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 9.01 (s, 1H), 7.86-7.84 (d, 1H), 7.74-7.73 (d, 1H), 7.35 (s, 1H), 7.32-7.29 (dd, 1H), 3.94 (s, 3H), 2.58 (s, 3H).
LCMS m/z=200.1 [M+H]+;
LCMS m/z=337.0 [M+H]+;
LCMS m/z=493.5 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.44 (s, 1H), 9.19 (s, 1H), 8.00-7.98 (d, 1H), 7.93-7.88 (t, 1H), 7.81 (s, 1H), 7.59-7.55 (m, 2H), 7.52-7.51 (d, 1H), 3.84 (s, 4H), 2.36 (s, 3H), 2.10-2.06 (t, 4H), 1.73-1.65 (m, 2H).
19F NMR (376 MHZ, DMSO-d6)8-127.37 (s).
LCMS m/z=210.2 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 11.25 (s, 3H), 4.74-4.72 (m, 1H), 4.62-4.60 (m, 1H), 4.36-4.34 (m, 1H), 4.29-4.27 (m, 1H).
LCMS m/z=215.1 [M+H]+;
LCMS m/z=225.1 [M+H]+;
LCMS m/z=362.4 [M+H]+;
LCMS m/z=518.2 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H), 8.58 (s, 1H), 7.91-7.83 (m, 2H), 7.74-7.71 (dd, 1H), 7.56-7.53 (dd, 1H), 7.42-7.41 (d, 1H), 4.83-4.69 (m, 2H), 4.59-4.49 (m, 2H), 3.84 (s, 4H), 2.12-2.08 (t, 4H), 1.78-1.70 (m, 2H).
19F NMR (376 MHz, DMSO-d6)8-127.24 (s), —220.60 (s).
LCMS m/z=338.3 [M+H]+;
LCMS m/z=401.0 [M+H]+;
LCMS m/z=497.8 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 9.28 (s, 1H), 8.10-8.09 (d, 1H), 8.02-7.99 (d, 1H), 7.78-7.77 (d, 1H), 7.62-7.58 (m, 2H), 7.50-7.46 (m, 1H), 3.79 (s, 4H), 2.10-2.06 (t, 4H), 1.75-1.67 (m, 2H).
LCMS m/z=488.30 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 10.47 (s, 1H), 8.33 (s, 1H), 7.88 (t, 1H), 7.80 (d, 1H), 7.76-7.68 (m, 1H), 7.61-7.56 (m, 1H), 7.41 (d, 1H), 4.79-4.62 (m, 2H), 4.36-4.25 (m, 2H), 3.97 (s, 4H), 0.61 (s, 4H).
LCMS m/z=506.90 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.34 (s, 1H), 7.93 (t, 1H), 7.86-7.76 (m, 3H), 7.74-7.69 (m, 1H), 7.48 (d, 1H), 6.54-6.18 (m, 1H), 4.53-4.43 (m, 1H), 3.55 (s, 2H), 3.25 (s, 2H), 0.64 (s, 4H).
LCMS m/z=465.3 [M+H]+.
1H NMR (400 MHZ, DMSO-d6) δ 9.27 (s, 1H), 8.09 (d, 1H), 8.01 (d, 1H), 7.74 (t, 1H), 7.63 (d, 1H), 7.60-7.52 (m, 3H), 3.89 (s, 4H), 0.57 (s, 4H).
LCMS m/z=506.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.33 (s, 1H), 7.79 (d, 1H), 7.74 (dd, 1H), 7.57 (d, 1H), 7.51 (dd, 1H), 4.71 (dt, 2H), 4.32 (dt, 2H), 3.93 (s, 4H), 0.59 (s, 4H).
LCMS m/z=512.1 [M+H]+;
1H NMR (400 MHZ, DMSO-d6) δ 8.34 (s, 1H), 7.80 (d, 1H), 7.74 (dd, 1H), 7.58 (d, 1H), 7.52 (dd, 1H), 5.40 (s, 1H), 5.26 (s, 1H), 4.72 (dt, 2H), 4.32 (dt, 2H), 3.57-3.31 (m, 4H), 2.23-1.99 (m, 2H).
LCMS m/z=524.2 [M+1]+.
1H NMR (400 MHZ, DMSO-d6) δ 8.35 (s, 1H), 7.81 (d, 1H), 7.77 (dd, 1H), 7.62 (d, 1H), 7.57 (dd, 1H), 6.37 (tt, 1H), 4.49 (td, 2H), 3.99 (s, 4H), 0.61 (s, 4H).
LCMS m/z=530.1 [M+1]+.
1H NMR (400 MHZ, DMSO-d6) δ 8.35 (s, 1H), 7.81 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.52 (dd, 1H), 6.37 (tt, 1H), 5.33 (d, 1H), 4.49 (td, 2H), 3.58-3.34 (m, 4H), 2.21-2.01 (m, 2H).
BRAFV600E (ABCAM, ab204154) and MEK1K97R (USBio, M2865-06J) proteins were diluted at an appropriate dilution factor using 1× Assay buffer (PH=7.4 Tris-HCl buffer, supplemented with 10 mM MgCl2) such that the final concentration of BRAFV600E was 10 ng/μL and the final concentration of substrate MEK1K97R was 1 μM. 1 μL of BRAFV600E, 1 μL of compound serial dilution (final concentration starting from 2 μM, 5-fold dilution, 8 concentrations), and 6 μL of Assay buffer were pipetted to a 384-well reaction plate with a capacity of 20 μL. The plate was pre-incubated in a constant temperature incubator at 37° C. for 30 min. 1 μL of 200 μM ATP and 1 μM MEK1K97R were added to the reaction wells corresponding to the compound incubation, mixed evenly by vortexing, and pre-incubation was performed in a constant temperature incubator at 37° C. for 60 min for enzymatic reaction. After the reaction was completed, 5 μL of the above reaction product was pipetted to another 384-well plate, and 5 μL of formulated ADP-Glo· Reagent (Promega, V9101) was added and mixed evenly by pipetting, and then the plate was placed at room temperature for 40 min. 10 μL Kinase Detection Reagent was added to the 384-well plate and incubated at room temperature for 40 min. Finally, a microplate reader (BMG LRBTECH) was used and Luminescence module was selected to detect the LUM fluorescence value of each well (the gain value was fixed at 3600), and the formula
was used to calculate the inhibition rate of the compound on BRAFV600E. The Graphpad software log (inhibitor) vs. response—Variable slope (four parameters) equation was used to perform fitting analysis and calculate the IC50 value of the sample.
The compounds of the present disclosure, such as the compounds in the examples, have very good enzymatic activities, with IC50≤100 nM. The inhibitory activities of some compounds on BRAFV600E are shown in Table 1.
Conclusion: the compounds of the present disclosure, such as the compounds in the examples, show high inhibitory activities on BRAFV600E.
A375 cells (ATCC, CRL-1619) were cultured in DMEM complete medium (+10% FBS) in a CO2 incubator at 37° C. for 48 h. The cells were trypsinized and counted, and then the density was adjusted to 1.67×104 cells/mL. 90 μL (1500 cells) of cells were inoculated into each well of a 96-well transparent bottom plate, and the plate was transferred to a CO2 incubator and the cells were cultured overnight at 37° C. After the cells were incubated overnight, 10 μL of the diluted compound (final concentration starting from 10 μM, 3-fold dilution, 11 concentrations) was added to each well using a multi-channel pipette. The positive control was a serum-free medium containing DMSO. After mixing evenly, the cells were placed in a CO2 incubator at 37° C. for 72 h. After the incubation, the CellCounting-Lite®2.0 kit detection solution (Vazyme, DD1101-03) was taken out and returned to room temperature. 100 μL of CellCounting-Lite2.0 detection solution was added to each well, the plate was sealed with a sealing film, and the plate was placed on a shaker for shaking for 15 min (the whole process should be kept away from light). The Luminescence module of the microplate reader (BMG LRBTECH) was used to detect the fluorescence signal value LUM of each well. The formula
The compounds of the present disclosure, such as the compounds in the examples, have very good cell activities, with IC50≤100 nM. The inhibitory activities of some compounds on A357 cells are shown in Table 2.
Conclusion: the compounds of the present disclosure, such as the compounds in the examples, show high inhibitory activities at the cellular level.
Before and after administration, 0.06 mL of blood was taken from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube for centrifugation at 5000 rpm at 4° C. for 10 min, followed by plasma collection. The blood collection time points for the intravenous administration group and intragastric administration group were 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h and 24 h. Before analysis and detection, all samples were stored at −80° C., and a quantitative analysis of samples was performed using LC-MS/MS.
Conclusion: The compounds of the present disclosure, such as compounds in the examples, have good pharmacokinetic characteristics in mice and have better brain-penetrating properties than the control compounds.
(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; MC: Methylcellulose solution) Before and after the administration, 1 ml of blood was taken from the jugular veins or limb veins, and placed in an EDTAK2 centrifuge tube. Centrifugation was performed at 5000 rpm at 4° C. for 10 min, and plasma was collected. The blood collection time points for the intravenous group and intragastric group were both 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h, and 72 h. Before analysis and detection, all samples were stored at −80° C. The samples were analyzed quantitatively by LC-MS/MS.
Conclusion: The compounds of the present disclosure, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.
Before and after the administration, 0.1 ml of blood was taken from the orbit of the animals under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4° C. for 10 min to collect plasma. Blood sampling time points for the intravenous administration group: 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h; blood sampling time points for the intragastric administration group: 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h. Before analysis and detection, all samples were stored at −80° C.
Conclusion: The compounds of the present disclosure, such as the compounds in the examples, have good bioavailability and pharmacokinetic characteristics in rats.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202210848185.6 | Jul 2022 | CN | national |
| 202211051796.4 | Aug 2022 | CN | national |
| 202211292824.1 | Oct 2022 | CN | national |
| 202211432056.5 | Nov 2022 | CN | national |
| 202310003195.4 | Jan 2023 | CN | national |
| 202310329117.3 | Mar 2023 | CN | national |
| 202310502696.7 | May 2023 | CN | national |
This application is a National Stage of International Application No. PCT/CN2023/108142, filed Jul. 19, 2023, which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2023/108142 | 7/19/2023 | WO |
