Patent Application
20240336606
The present invention relates to the field of pharmaceuticals, and particularly to a substituted benzo- or pyrido-pyrimidinamine inhibitor, a method for preparing the same, and use thereof.
Lung cancer is one of the leading causes of cancer deaths worldwide. According to cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for 85% among all lung cancer patients. According to statistics, the global NSCLC market was approximately $20.9 billion in 2016, of which the US market occupied half, followed by Japan, Germany, and China. Based on current trends, the non-small cell lung cancer market will continuoulsy grow and is expected to reach $54 billion worldwide by 2023 (Nature, 2018; 553(7689):446-454).
At present, the major therapeutics for NSCLC include chemotherapies, targeted therapies, tumor immunotherapies, and the like. Among them, the chemotherapeutics mainly include gemcitabine, paclitaxel, platinum-based drugs, and the like, but such drugs generally possess poor selectivity and high toxicity, leading to relatively strong adverse effects. In recent years, the targeted therapies have gradually become a research hotspot due to their obvious advantages such as high selectivity, milder adverse effects, and the potential in precision medicine. Existing targeted therapies for NSCLC include EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, rociletinib, osimertinib, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib, etc.), and VEGFR inhibitors (sorafenib, regorafenib, cabozantinib, sunitinib, donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).
KRAS mutations occur in 20-40% of lung adenocarcinomas, with a higher prevalence in Western population (vs. Asian population; 26% vs 11%) and in smokers (vs non-smokers; 30% vs 10%). The most common mutations occur in codons 12 and 13, including G12C, G12V, and G12D. To date, no drug targeting KRAS mutation has been approved for marketing. KRAS protein transitions between inactivated and activated states within the cells. KRAS is in the inactivated state when it binds to guanosine diphosphate (GDP); it is in the activated state and can activate downstream signaling pathways when it binds to guanosine triphosphate (GTP). The transition between inactivated and activated states of KRAS is regulated by two types of factors. One type is guanine nucleotide exchange factor (GEF), including the SOS1 protein. Such proteins catalyze the binding of KRAS to GTP, thereby promoting the activation of KRAS. Another type is GTPase-activating protein (GAP), which promotes the hydrolysis of GTP binding to KRAS to GDP, thereby inhibiting KRAS activity.
To date, three major groups of RAS-specific GEFs have been identified, with SOS proteins being primarily found involved in tumors. SOS proteins are widely expressed in vivo and contain two isoforms SOS1 and SOS2. Published data indicate a critical role of SOS1 in mutant KRAS activation and oncogenic signaling in cancers. Depleting SOS1 levels decreased the proliferation rate and survival of tumor cells carrying a KRAS mutation whereas no effect was observed in KRAS wild type cell lines. Loss of SOS1 could not be rescued by introduction of SOS1 with mutations at the catalytic site, demonstrating the essentiality of SOS1's GEF activity in KRAS mutant cancer cells (see WO2019122129A1).
Since the binding of KRAS, whether mutant or wild-type, to GTP is dependent on SOS1, selective inhibition of SOS1, regardless of KRAS mutation, may prevent the interaction between SOS1 and KRAS, ultimately inhibiting KRAS activation.
Since the target protein SOS1 is pathologically associated with a variety of diseases, there is also a need for novel SOS1 inhibitors for clinical therapy. For highly selective and active SOS1 inhibitors with potentials to treat diseases such as cancers caused by KRAS mutations more effectively and to reduce off-target effects, there is a more urgent clinical need.
The present invention is intended to provide a compound with selective inhibition against SOS1 and/or better pharmacodynamic performance, and use thereof.
In a first aspect of the present invention, provided is a substituted benzo- or pyrido-pyrimidinamine compound having a structure of general formula (I), or a stereoisomer, a tautomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof:
wherein in the formula,
In another preferred embodiment, for the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof:
wherein in the formula,
In another preferred embodiment, for the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof:
wherein in the formula,
In another preferred embodiment, for the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof:
in the formula,
In another preferred embodiment, Y is selected from: O, NH, and NR7, Z is a bond, and W is C3-C20 cycloalkylene or 4- to 20-membered heterocyclylene; R1 is not hydrogen, deuterium, halogen, or cyano, and m1 is not 0.
In another preferred embodiment, each R2 is independently selected from the group consisting of: hydrogen, deuterium, halogen, cyano, —(CH2)m2R8, —(CH2)m′2(CH═CH)R8, —(CH2)m′2(C≡C)R8, —(CH2)m2O(CH2)p2R8, —(CH2)m′2SR8, —(CH2)m2COR8, —(CH2)m2C(O)OR8, —(CH2)m′2S(O)q2R8, —(CH2)m2NR8R9, —(CH2)m2C(O)NR8R9, —(CH2)m2NR8C(O)R9, —(CH2)m2NR8C(O)NR9R10, —(CH2)m′2S(O)q2NR8R9, —(CH2)m′2NR8S(O)q2R9, and —(CH2)m′2NR8S(O)q2NR9R10, wherein H in CH2 can be optionally substituted; R8, R9, and R10 are each independently selected from the group consisting of the following substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, C3-C20 cycloalkyl, and 4- to 20-membered heterocyclyl; or in —(CH2)m2NR8R9, —(CH2)m2C(O)NR8R9, or —(CH2)m′2S(O)q2NR8R9, R8 and R9, together with the N atom adjacent thereto, form a substituted or unsubstituted 4- to 8-membered heterocyclyl by cyclization; or in —(CH2)m2NR8C(O)R9, —(CH2)m2NR8C(O)NR9R10, —(CH2)m′2NR8S(O)q2R9, or —(CH2)m′2NR8S(O)q2NR9R10, R8 and R9, together with the N atom adjacent thereto, form a substituted or unsubstituted 4- to 8-membered heterocyclyl by cyclization, or R9 and R10, together with the atom adjacent thereto, form a substituted or unsubstituted 4- to 8-membered heterocyclyl by cyclization;
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of general formula (II):
wherein in the formula, R1, R2, R3, R4, X, Y, Z, W, and n are as defined above.
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of general formula (III):
wherein in the formula, R1, R2, R3, X, Y, Z, W, and n are as defined above.
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of general formula (IV):
wherein in the formula,
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of general formula (V):
wherein in the formula,
In another preferred embodiment, in formulas I-V, Z is selected from the group consisting of the following substituted or unsubstituted groups: a bond, C1-C6 alkylene, deuterated C1-C6 alkylene, and halogenated C1-C6 alkylene; wherein the substitution refers to substitution with one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, 4- to 6-membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, amido, sulfonamido, and ureido.
In another preferred embodiment, W is selected from the group consisting of: a bond, substituted or unsubstituted C3-C12 cycloalkylene, substituted or unsubstituted 4- to 12-membered heterocyclylene, OR11, NR11R12, SO2, NR12SO2, CO, and NR12CO;
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of formula (VI):
wherein in the formula,
In another preferred embodiment, in formula (VI), the moiety
selected from:
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of formula (VII):
wherein in the formula,
In another preferred embodiment, R1 is selected from the group consisting of: H, cyano, halogen, —(CH2)mR8, —(CH2)mO(CH2)pR8, —(CH2)mSR8, —(CH2)mS(O)qR8, and —(CH2)m(C≡C)R8; wherein H in CH2 can be optionally substituted; R8 is selected from the group consisting of the following substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, C1-C18 alkoxy, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C14 aryl, and 5- to 14-membered heteroaryl.
In another preferred embodiment, R1 is selected from the group consisting of: halogen, cyano, —(CH2)mR8, —(CH2)m(C≡CH), —(CH2)m(C≡C)R8, and —(CH2)mO(CH2)pR8, and preferably R8 is substituted or unsubstituted C1-C18 alkyl (preferably C1-C6 alkyl).
In another preferred embodiment, R1 is selected from the group consisting of: H, cyano, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkyl-O—, deuterated C1-C6 alkyl-O—, substituted or unsubstituted C3-C6 cycloalkyl-O—, substituted or unsubstituted 4- to 6-membered heterocyclyl-O—, C1-C6 alkoxy C1-C6 alkyl-O—, substituted or unsubstituted phenyl, substituted or unsubstituted 5- to 6-membered heteroaryl, substituted or unsubstituted phenyl-O—, substituted or unsubstituted 5- to 6-membered heteroaryl-O—, and substituted or unsubstituted C2-C6 alkynyl; wherein the substitution refers to substitution with one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, oxo C1-C6 alkyl, and C2-C6 ester group.
In another preferred embodiment, in formula VII, R18 is selected from: OR11, NR11R12, and NR12SO2R2; wherein R11 is independently selected from: substituted C3-C12 cycloalkyl, substituted or unsubstituted 4- to 12-membered heterocyclyl, substituted or unsubstituted C3-C12 cycloalkylene C1-C6 alkylene, substituted or unsubstituted 4- to 12-membered heterocyclylene C1-C6 alkylene, substituted or unsubstituted C6-C14 aryl, and substituted or unsubstituted 5- to 14-membered heteroaryl; R12 is independently selected from the group consisting of: hydrogen, deuterium, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C3-C6 cycloalkyl;
In another preferred embodiment, R3 is selected from: substituted C6-C14 aryl and substituted 5- to 14-membered heteroaryl; the substitution refers to substitution with one or more groups selected from the group consisting of: R3a, hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, halogenated C1-C18 alkylhydroxy, C3-C20 cycloalkyl, C3-C20 cycloalkyl-O—, C1-C18 alkoxy, deuterated C1-C18 alkoxy, halogenated C1-C18 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 20-membered heterocyclyl, 4- to 20-membered heterocyclyl-O—, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, amido, sulfonamido, and ureido; wherein the C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, halogenated C1-C18 alkylhydroxy, C3-C20 cycloalkyl, C3-C20 cycloalkyl-O—, C1-C18 alkoxy, deuterated C1-C18 alkoxy, halogenated C1-C18 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 20-membered heterocyclyl, and 4- to 20-membered heterocyclyl-O— may be further substituted with one or more Ra, wherein Ra is selected from: C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O—, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl-O—, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, amido, sulfonamido, and ureido; provided that at least one R3a substituent is present;
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of formula (VIII):
wherein in the formula, R1, R2, R3, R6, and W are as defined above.
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of formula (IX-A) or (IX-B):
wherein in the formula, R2, R3, R8, R9, X, Y, Z, W, n, and q are as defined above.
In another preferred embodiment, the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof has a structure of formula (X):
In another preferred embodiment, R8 is selected from the group consisting of the following substituted or unsubstituted groups: C3-C6 cycloalkyl and 4- to 6-membered heterocyclyl; wherein the substitution refers to substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 6-membered heterocyclyl, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, amido, sulfonamido, and ureido.
In another preferred embodiment, Z and W are both bonds.
In another preferred embodiment, Y is O, and Z and W are bonds.
In another preferred embodiment, R3 is selected from the group consisting of the following substituted groups: phenyl, pyridyl, pyrimidinyl, and pyridazinyl; wherein the substitution refers to substitution with one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, amido, sulfonamido, and ureido; preferably, the substituent is selected from 1, 2, or 3 of halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C1-C6 alkoxy, halogen, hydroxy, cyano, ester group, amino, amido and sulfonamido.
In another preferred embodiment, R1 is methoxy.
In another preferred embodiment,
wherein * represents R or S configuration.
Preferably. R3 is selected from:
In another preferred embodiment, R3 is selected from:
In another preferred embodiment, R6 is selected from: hydrogen, deuterium, halogen, cyano, and C1-C6 alkyl.
In another preferred embodiment, R1, R2, R3, R4, R5, R6, X, Y, Z, W, and n are the specific groups corresponding to the specific compounds in the examples.
In another preferred embodiment, for the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof, the compound is selected from the group consisting of:
In another preferred embodiment, the compound is preferably a compound prepared in the examples.
In a second aspect of the present invention, provided is a method for preparing the substituted benzo- or pyrido-pyrimidinamine compound having the structure of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof, comprising:
In another preferred embodiment, the first base is potassium carbonate, cesium carbonate, or the like.
In another preferred embodiment, the second base is TEA, DIPEA, or the like.
In another preferred embodiment, the third base is TEA, DIPEA, or the like.
In a third aspect of the present invention, provided is a pharmaceutical composition comprising i) one or more compounds, or stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof according to the first aspect; and ii) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises one or more therapeutic agents selected from the group consisting of: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, and LZM009, or a biosimilar thereof), PD-L1 inhibitors (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, and MSB2311, or a biosimilar thereof), CD20 antibodies (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90 In-ibritumomab, and ibritumomab tiuxetan), CD47 antibodies (e.g., Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, or IMM01), ALK inhibitors (e.g., ceritinib, alectinib, brigatinib, lorlatinib, and ocatinib), PI3K inhibitors (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, and buparlisib), BTK inhibitors (e.g., ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, and vecabrutinib), EGFR inhibitors (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, and osimertinib), VEGFR inhibitors (e.g., sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, and donafenib), HDAC inhibitors (e.g., givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, and tacedinaline), CDK inhibitors (e.g., palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, and lerociclib), MEK inhibitors (e.g., selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, pimasertib (AS-703026), and PD184352 (CI-1040)), mTOR inhibitors (e.g., vistusertib), and SHP2 inhibitors (e.g., RMC-4630, JAB-3068, and TNO155), or a combination thereof.
In a fourth aspect of the present invention, provided is of the compound, or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to the first aspect, or the pharmaceutical composition according to the third aspect in preparing a pharmaceutical composition for preventing and/or treating a disease associated with the activity or expression level of SOS1.
In another preferred embodiment, the disease is cancer.
In another preferred embodiment, the cancer is selected from: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colon cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin carcinoma.
In a fifth aspect of the present invention, provided is a non-diagnostic and non-therapeutic method for inhibiting SOS1, comprising: administering to a patient in need an effective amount of the compound of general formula (I), or the stereoisomer, the tautomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate, the solvate, or the prodrug thereof according to the first aspect, or administering the pharmaceutical composition according to the third aspect.
It will be appreciated that within the scope of the present invention, the various technical features of the present invention described above and the technical features specifically described hereinafter (as in the examples) may be combined with each other to constitute a new or preferred technical scheme. Due to limited space, such schemes are not described herein.
The inventors, through extensive and intensive studies in a long period of time, have surprisingly found a novel class of compounds which selectively inhibit SOS1 and/or have improved pharmacodynamic performance. The present invention is implemented on this basis.
In the present invention, unless otherwise specified, the terms as used have the ordinary meaning known to those skilled in the art.
The term “alkyl” refers to a linear or branched or cyclic alkane group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms. Typical “alkyl” include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl,
pentyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term “C1-C18 alkyl” refers to a linear or branched or cyclic alkyl including 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl
n-butyl, t-butyl, isobutyl
n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, and isoheptyl. The “substituted alkyl” means that one or more positions in the alkyl are substituted with a substituent, especially 1 to 4 substituents, wherein the substitution may occur in any position. Typical substituents include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a monohalogen substituent or polyhalogen substituent such as trifluoromethyl or alkyl containing Cl3), nitrile group, nitro, oxygen (e.g., ═O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, ORa, SRa, S(═O)Rc, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORc, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRaC(═O)NRbRc, NRaS(═O)2NRbRc, NRaP(═O)2NRbRc, NRbC(═O)Ra, and NRbP(═O)2Re, wherein the Ra herein may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb, Rc, and Rd may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, or Rb and Rc, together with the N atom, may form a heterocycle; Rc may independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring. The aforementioned typical substituents such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring may be optionally substituted. The term “alkylene” refers to a group formed by further removal of one hydrogen atom from an “alkyl”, such as methylene, ethylene, propylene, isopropylene
butylene
pentylene
hexylene
and heptylene
The term “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group comprising 1 to 4 rings each containing 3 to 8 carbon atoms. The “substituted cycloalkyl” means that one or more positions in the cycloalkyl are substituted with a substituent, especially 1 to 4 substituents, wherein the substitution may occur in any position. Typical substituents include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a monohalogen substituent or polyhalogen substituent such as trifluoromethyl or alkyl containing Cl3), nitrile group, nitro, oxygen (e.g., ═O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, ORa, SRa, S(═O)Re, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORd, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRaC(═O)NRbRc, NRaS(═O)2NRbRc, NRaP(═O)2NRbRc, NRbC(═O)Ra, and NRbP(═O)2Re, wherein the Ra herein may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb, Rc, and Ra may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, or Rb and Rc, together with the N atom, may form a heterocycle; Re may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring. The aforementioned typical substituents may be optionally substituted. Typical substituents also include spiro, bridged or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spiroheterocycle (excluding heteroaromatic ring), bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycle (excluding heteroaromatic ring), fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, and fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocyclyl, and heterocycloaryl may be optionally substituted. Any two or more atoms on the ring may be further fused with other cycloalkyl, heterocyclyl, aryl, or heteroaryl.
The term “cycloalkylene” refers to a group formed by removal of two hydrogen atoms from cycloalkyl, such as:
The term “alkylene cycloalkylene” refers to a group formed by removal of two hydrogen atoms from the aforementioned cycloalkyl alkyl or alkyl cycloalkyl, wherein “C1-C18 alkylene C3-C20 cycloalkylene” or “C3-C20 cycloalkylene C1-C18 alkylene” has the same meaning preferably C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to:
The term “heterocyclyl” refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, for example, 3- to 7-membered monocyclic, 6- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems), wherein at least one heteroatom is present in a ring containing at least one carbon atom. Each heterocycle containing heteroatoms may carry 1, 2, 3, or 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the nitrogen or sulfur atom may be oxidized, and the nitrogen atom may be quaternized. The heterocyclyl may be attached to the residue of any heteroatom or carbon atom of the ring or cyclic molecule. Exemplary monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolidyl, hexahydroazepinyl, 4-piperidinonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-sulfoxyl, thiomorpholine-sulfonyl, 1,3-dioxanyl, and tetrahydro-1,1-dioxothienyl. A polycyclic heterocyclyl includes spiro, fused, and bridged heterocyclyls. The spiro, fused, and bridged heterocyclyls involved are optionally linked to other groups via single bonds, or are further fused with other cycloalkyl, heterocyclyl, aryl and heteroaryl via any two or more atoms of the ring. The heterocyclyl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate group, wherein any two or more atoms on the ring may be further fused with other cycloalkyl, heterocyclyl, aryl, or heteroaryl.
The term “heterocyclylene” refers to a group formed by removal of two hydrogen atoms from the aforementioned heterocyclyl, including but not limited to:
The term “heterocycloalkylene alkylene” refers to a group formed by removal of two hydrogen atoms from the cycloalkyl alkyl or alkyl cycloalkyl, wherein “4- to 20-membered heterocycloalkylene C1-C18 alkylene” or “C1-C18 alkylene 4- to 20-membered heterocycloalkylene” has the same meaning, preferably 4- to 12-membered heterocycloalkylene C1-6 alkylene, including but not limited to:
The term “aryl” refers to an aromatic cyclic hydrocarbon group having 1 to 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. When having two or more aromatic rings (bicyclic and the like), the aromatic rings of aryl may be linked by a single bond (such as biphenyl) or fused (such as naphthalene and anthracene). The “substituted aryl” means that one or more positions in the aryl are substituted with a substituent, especially 1 to 3 substituents, wherein the substitution may occur in any position. Typical substituents include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a monohalogen substituent or polyhalogen substituent such as trifluoromethyl or alkyl containing Cl3), nitrile group, nitro, oxygen (e.g., ═O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, ORa, SRa, S(═O)Rc, S(═O)2Re, P(═O)2Re, S(═O)2ORe, P(═O)2ORe, NRbRc, NRbS(═O)2Re, NRbP(═O)2Re, S(═O)2NRbRc, P(═O)2NRbRc, C(═O)ORa, C(═O)Ra, C(═O)NRbRc, OC(═O)Ra, OC(═O)NRbRc, NRbC(═O)ORe, NRaC(═O)NRbRc, NRaS(═O)2NRbRc, NRaP(═O)2NRbRc, NRbC(═O)Ra, and NRbP(═O)2Re, wherein the Ra herein may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, Rb, Rc, and Ra may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, or Rb and Rc, together with the N atom, may form a heterocycle; Re may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring. The aforementioned typical substituents may be optionally substituted. Typical substituents also include fused ring substituents, especially fused cycloalkyl, fused cycloalkenyl, fused heterocyclyl, and fused aryl, wherein the above cycloalkyl, cycloalkenyl, heterocyclyl, and heterocycloaryl may be optionally substituted.
The term “heteroaryl” refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and sulfur. The heteroaryl is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, and the like. The “heteroaryl” may be substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate group.
The term “C1-C18 alkoxy” refers to a linear or branched or cyclic alkoxy having 1 to 18 carbon atoms, including, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. C1-C8 alkoxy is preferred, and C1-C6 alkoxy is more preferred.
The term “C1-C18 alkyleneoxy” refers to a group formed by the removal of one hydrogen atom from “C1-C18 alkoxy”.
The term “halogen” or “halo” refers to chlorine, bromine, fluorine, or iodine.
The term “halogenated” means being substituted with a halogen.
The term “deuterated” means being substituted with deuterium.
The term “hydroxy” refers to a group with a structure of OH.
The term “nitro” refers to a group with a structure of NO2.
The term “cyano” refers to a group with a structure of CN.
The term “acyl” refers to a group with a structure of —COR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle. Preferably, the acyl is “C2-C6 acyl” (e.g., —COC1-C5 alkyl). Examples of acyl include, but are not limited to: —COCH3, —COCH2CH3, —COCH2CH2CH3, or —COCH2CH(CH3)2.
The term “ester group” refers to a group with a structure of —COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle. Preferably, the ester group is “C2-C6 ester group” (e.g., —COOC1-C5 alkyl). Examples of ester group include, but are not limited to: —COOCH3, —COOCH2CH3, —COOCH2CH2CH3, or —COOCH2CH(CH3)2.
The term “amino” refers to a group with a structure of —NRR′, wherein R and R′ may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R and R′ in the dialkylamine moiety may be identical or different. Preferably, the amine group is a C1-C6 amine group (i.e., an alkylamino containing 1-6 carbon atoms, such as C1-C6 alkyl-NH—). Examples of amine group include, but are not limited to: NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, anilino, diphenylamino, and the like.
The term “amido” refers to a group with a structure of —CONRR′, wherein R and R′ may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. Preferably, the amido is “C1-C6 amido” (e.g., —CONHC1-C5 alkyl or —CONH2). R and R′ in the dialkylamine moiety may be identical or different. Examples of amido include, but are not limited to: —CONH2, —CONHCH3, —CON(CH3)2, and the like.
The term “sulfonamido” refers to a group with a structure of —SO2NRR′ or RSO2NR′—, wherein R and R′ may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R and R′ in the dialkylamine moiety may be identical or different. Examples of sulfonamido include, but are not limited to: —SO2NH2, —SO2NHCH3, —SO2N(CH3)2, CH3SO2NH—, CH3SO2NCH3—, and the like. As used herein, “C1-C6 sulfonamido” refers to C1-C6 alkylsulfonamido, that is, the total number of carbon atoms in R and R′ is 1-6.
The term “ureido” refers to a group with a structure of —NRCONR′R″, wherein R, R′ and R″ may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R, R′, and R″ in the dialkylamine moiety may be identical or different. Examples of ureido include, but are not limited to: —NHCONH2, —NHCONHCH3, —NHCON(CH3)2, and the like. As used herein, “C1-C6 ureido” refers to C1-C6 alkylureido, that is, the total number of carbon atoms in R, R′, and R″ is 1-6.
The term “alkylaminoalkyl” refers to a group with a structure of —RNHR′, wherein R and R′ may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R and R′ may be identical or different. Examples of alkylaminoalkyl include, but are not limited to, —CH2NHCH3, —CH2CH2NHCH3, and the like.
The term “dialkylaminoalkyl” refers to a group with a structure of —RNR′R″, wherein R, R′ and R″ may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R, R′, and R″ in the dialkylamine moiety may be identical or different. Examples of dialkylaminoalkyl include, but are not limited to: —CH2N(CH3)2, —CH2CH2N(CH3)2, and the like.
The term “sulfonyl” refers to a group with a structure of —SO2R′, where R′ may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. Examples of sulfonyl include, but are not limited to: —SO2CH3, —SO2CH2CH3, —SO2-cyclopropyl, —SO2-cyclobutyl, —SO2-cyclopentyl, or —SO2-cyclohexyl.
The term “heterocyclylalkyl” refers to a group with a structure of —RR′, wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl; R′ represents heterocycle or substituted heterocycle. Examples of heterocyclylalkyl include, but are not limited to: azetidinyl-CH2—, oxetanyl-CH2—, azolidinyl-CH2—, oxolanyl-CH2—, azanyl-CH2—, or oxanyl-CH2—. According to the present invention, the term “substituted” means that one or more hydrogen atoms on a specific group are substituted with a specific substituent. Specific substituents are those described correspondingly in the preceding text or as present in the examples. Unless otherwise specified, a substituted group may have substituents selected from a specific group at any substitutable positions of the group. The substituents may be identical or different at the positions. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those stable or chemically available. The examples of such substituents include (but are not limited to): halogen, hydroxy, cyano, carboxyl (—COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl, C2-C10 ester group, amino, C1-C6 alkoxy, C1-C10 sulfonyl, C1-C6 ureido, and the like.
Unless otherwise stated, it is assumed that any heteroatom with insufficient valence has enough hydrogen atoms to supplement its valence state.
When the substituent is a non-terminal substituent, it is a “-ylene group” of the corresponding group. For example, the corresponding “-ylene group” of alkyl is alkylene, the corresponding “-ylene group” of cycloalkyl is cycloalkylene, the corresponding “-ylene group” of heterocyclyl is heterocyclylene, the corresponding “-ylene group” of alkoxy is alkyleneoxy, and so on.
As used herein, “compound of the present invention” refers to a compound of formula I, and also includes a stereoisomer or optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate of the compound of formula I.
The compound of formula I has the following structure:
wherein in the formula, R1, R2, R3, R4, R5, X, Y, Z, W, and n are as defined above.
Preferably, the compound of formula I has a structure of general formula (II):
wherein in the formula, R1, R2, R3, R4, X, Y, Z, W, and n are as defined above.
Preferably, the compound of formula I has a structure of general formula (III):
wherein in the formula, R1, R2, R3, X, Y, Z, W, and n are as defined above.
Preferably, the compound of formula I has a structure of general formula (IV):
wherein in the formula,
Preferably, the compound of formula I has a structure of general formula (V):
wherein in the formula,
Preferably, the compound of formula I has a structure of formula (VI):
wherein in the formula, R1, R2, R3, R6, R13, R14, ring C, t, and n are as defined above.
Preferably, the compound of formula I has a structure of formula (VII):
wherein in the formula,
Preferably, the compound of formula I has a structure of formula (VIII):
wherein in the formula,
Preferably, the compound of formula I has a structure of formula (IX-A) or formula (IX-B):
wherein in the formula, R1, R2, R3, R8, R9, X, Y, Z, W, n, and q are as defined above.
Preferably, the compound of formula I has a structure of formula (X):
wherein in the formula, R1, R2, R3, X, Y, Z, W, n, and q are as defined above.
Preferably, in formulas I-VIII, R1 is selected from the group consisting of: hydrogen, deuterium, halogen, cyano, —(CH2)m1R8, —(CH2)m′1(CH═CH)R8, —(CH2)m′1(C≡C)R8, —(CH2)m1O(CH2)p1R8, —(CH2)m′1SR8, —(CH2)m1COR8, —(CH2)m1C(O)OR8, —(CH2)m′1S(O)q1R8, —(CH2)m1NR8R9, —(CH2)m1C(O)NR8R9, —(CH2)m1NR8C(O)R9, —(CH2)m1NR8C(O)NR9R10, —(CH2)m′1S(O)q1NR8R9, —(CH2)m′1NR8S(O)q1R9, and —(CH2)m′1NR8S(O)q1NR9R10, wherein H in CH2 can be optionally substituted; R8, R9, and R10 are each independently selected from the group consisting of the following substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, C3-C20 cycloalkyl, and 4- to 20-membered heterocyclyl; or in —(CH2)m1NR8R9, —(CH2)m1C(O)NR8R9, and —(CH2)m′1S(O)q1NR8R9, R8 and R9, together with the N atom adjacent thereto, form a substituted or unsubstituted 4- to 8-membered heterocyclyl by cyclization; or in —(CH2)m1NR8C(O)R9, —(CH2)m1NR8C(O)NR9R10, —(CH2)m′1NR8S(O)q1R9, and —(CH2)m′1NR8S(O)q1NR9R10, R8 and R9, together with the N atom adjacent thereto, form a 4- to 8-membered substituted or unsubstituted heterocyclyl by cyclization, or R9 and R10, together with the atom adjacent thereto, form a substituted or unsubstituted 4- to 8-membered heterocyclyl by cyclization;
Preferably, in formulas I-X, R3 is selected from the group consisting of the following substituted or unsubstituted groups: C3-C12 cycloalkyl, 4- to 12-membered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl; preferably, R3 is selected from the group consisting of the following substituted groups: phenyl, pyridyl, pyrimidinyl, and pyridazinyl; more preferably, R3 is selected from:
Preferably, in formula I, R4 and R5 are independently selected from the group consisting of the following substituted or unsubstituted groups: C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 6-membered heterocyclyl;
Preferably, R6 is selected from: hydrogen, deuterium, halogen, cyano, and C1-C6 alkyl.
Preferably, in the present invention, the substitution refers to substitution with one or more groups selected from the group consisting of: hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O—, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl-O—, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, amido, sulfonamido, and ureido; wherein the C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O—, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 6-membered heterocyclyl, or 4- to 6-membered heterocyclyl-O— may be further substituted with one or more Ra, wherein Ra is selected from: C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O—, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C6-C14 aryl, 5- to 14-membered heteroaryl, 4- to 6-membered heterocyclyl, 4- to 6-membered heterocyclyl-O—, halogen, oxo, nitro, hydroxy, cyano, ester group, amino, acyl, amido, sulfonyl, sulfonamido, and ureido.
The salts which the compound of the present invention may form are also within the scope of the present invention. Unless otherwise stated, the compound of the present invention is understood to include salts thereof. As used herein, the term “salt” refers to a salt in either an acid or a base form formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic moiety, the basis moiety includes, but is not limited to, pyridine or imidazole; when the compound of the present invention contains an acidic moiety, the acidic moiety includes, but is not limited to, carboxylic acid. The zwitterion (“inner salt”) that may be formed is encompassed within the scope of the term “salt”. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are useful, e.g., in isolation or purification steps of the preparation. The salt can be formed with the compound of the present invention, for example, by reacting compound I with an amount, e.g., an equivalent amount, of acid or base and then salting out from a medium, or by lyophilization in an aqueous solution.
The compound of the present invention contains a basic moiety, including but not limited to amine or a pyridine or imidazole ring, which may form salts with organic or inorganic acids. Typical acids which may form salts include acetate (e.g., formed with acetic acid or trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, laurylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, tosylate (e.g., p-toluenesulfonate), dodecanoate and the like.
Certain compounds of the present invention may contain an acidic moiety, including but not limited to carboxylic acid, which may form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts; alkali metal salts such as sodium, lithium, or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; salts formed with organic bases (such as organic amines) such as benzathine, dicyclohexylamine, hydrabamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine; salts with amino acids such as arginine and lysine. The basic nitrogen-containing groups may form quaternary ammonium salts with halides such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides, and iodides), and aralkyl halides (e.g., benzyl and phenyl bromides).
The prodrug and solvate of the compound of the present invention are also encompassed with the scope. As used herein, the term “prodrug” refers to a compound that undergoes a chemical conversion via a metabolic or chemical process to yield a compound, salt or solvate of the present invention when used in the treatment of a related disease. The compound of the present invention includes a solvate, such as a hydrate.
The compound, salt or solvate of the present invention may be present in a tautomeric form (e.g., amide and imine ether). All of these tautomers are part of the present invention.
Stereoisomers of all compounds (e.g., those asymmetric carbon atoms which may exist due to various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated within the scope of the present invention. The separate stereoisomer of the compound of the present invention may not be present simultaneously with the other isomers (e.g., as a pure or substantially pure optical isomer having specific activity), or may be present as a mixture, such as a racemate, or as a mixture with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S and R, and is defined by the International Union of Pure and Applied Chemistry (IUPAC) proposed in 1974. The racemic forms can be resolved by physical methods such as fractional crystallization, or separated and crystallized by derivation into diastereoisomers, or separated by chiral column chromatography. The individual optical isomer can be obtained from the racemate by any suitable methods, including but not limited to conventional methods, such as salt formation with optically active acids followed by crystallization.
The content, by weight, of the compound of the present invention, which is obtained by preparation, separation and then purification, is equal to or greater than 90%, e.g., is equal to or greater than 95%, or is equal to or greater than 99% (“very pure” compound), as listed in the text description. Herein, such “very pure” compounds of the present invention are also part of the present invention.
All configurational isomers of the compound of the present invention are encompassed with the scope, whether in admixture, pure or very pure form. The definition of the compound of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocycle and heterocycle.
Throughout the specification, the groups and substituents may be selected to provide stable moieties and compounds.
The definitions for specific functional groups and chemical terms are described in detail below. For purposes of the present invention, the chemical elements are in accordance with those defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. The definitions for specific functional groups are also described therein. In addition, the basic principles of organic chemistry, as well as specific functional groups and the reactivity thereof are also described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausaltito: 1999, which is incorporated by reference in its entirety.
Certain compounds of the present invention may be in the form of a specific geometric isomer or stereoisomer. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereoisomers, (D) isomer, (L) isomer, racemic mixtures, and other mixtures. Further, the asymmetric carbon atom may represent a substituent such as an alkyl. All isomers and mixtures thereof are encompassed by the present invention.
According to the present invention, the mixture of isomers may contain the isomers in a variety of ratios. For example, the mixture of only two isomers may have the isomers in the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of the isomers are encompassed within the scope of the present invention. Similar ratios, as well as more complex ratios of isomers of the mixtures, which are readily understood by those of ordinary skill in the art are also encompassed within the scope of the invention.
The present invention also includes isotopically-labeled compounds, equivalent to the original compounds disclosed herein. However, in fact, the substitution of one or more atoms with an atom with a different atomic weight or mass number usually occurs. Examples of isotopes that may be listed as the isotopes of the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl. The compounds, or enantiomers, diastereoisomers, isomers, pharmaceutically acceptable salts or solvates of the present invention containing the above isotopes or other isotopic atoms are encompassed within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, such as those labeled with radioisotopes of 3H and 14C, are also encompassed and useful in the drug and substrate tissue distribution assays. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) are relatively easy to prepare and detect. They are preferred among isotopes. In addition, substitution with heavier isotopes such as deuterium, i.e., 2H, has advantages in certain therapies due to the good metabolic stability of the isotopes, such as increased half-life in vivo or reduced dosage, and thus may be preferred in certain situations. Isotopically-labeled compounds can be prepared by general methods by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent using the protocols disclosed in the examples.
If the synthesis of a specific enantiomer of the compound of the present invention is to be designed, the enantiomer can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary reagent, wherein the resulting diastereoisomeric mixture is resolved and the chiral auxiliary reagent is removed to obtain a pure enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., an amino) or an acidic functional group (e.g., carboxyl), the molecule forms a diastereoisomeric salt with an appropriate optically active acid or base, and the resulting diastereomeric salt is resolved through a conventional means such as fractional crystallization or chromatography to obtain a pure enantiomer.
As described herein, the compound of the present invention can be substituted with any number of substituents or functional groups to expand their inclusion range. In general, whether the term “substituted” appears before or after the term “optional”, a general formula including a substituent in the formula of the present invention means that the hydrogen radical is replaced with a substituent with the indicated structure. When a plurality of positions in a specific structure are substituted with a plurality of specific substituents, the substituents at each of the positions may be identical or different. As used herein, the term “substitution” includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic organic compounds. In the present invention, for example, the heteroatom nitrogen may have a hydrogen substituent or any permissible organic compound described above to supplement its valence. Furthermore, the present invention is not intended to limit the permissible substitution of organic compounds in any way. According to the present invention, the combination of substituents and variable groups in the form of stable compounds is excellent in the treatment of diseases, such as infectious diseases or proliferative diseases. As used herein for the purpose described above, the term “stable” means that a compound is stable enough to maintain the structural integrity of the compound when tested over a sufficient period of time, and preferably is effective over a sufficient period of time.
Metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that are convertible in vivo into the structures of the compounds and pharmaceutically acceptable salts thereof involved in the present application, are also encompassed by the claims of the present application.
The preparation methods for the compound having the structure of formula (I) of the present invention is more specifically described below, but these specific methods do not limit the present invention in any way. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described herein or known in the art, and such combinations can be easily determined by those skilled in the art to which the present invention pertains.
Typically, the compounds of the present invention are prepared by the following procedures, wherein the starting materials and reagents used are commercially available unless otherwise stated.
The pharmaceutical composition described herein is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immunological disease, and metabolic disease.
The compound of general formula (I) can be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode and dose of administration of the original drug can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered in combination with one or more other drugs, a pharmaceutical composition comprising one or more known drugs and the compound of formula I can be preferred. The drug combination also includes administering the compound of formula I and one or more other known drugs over an overlapping period of time. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or the known drugs can be lower than that of their administration alone.
The drugs or active ingredients that can be used in combination with the compound of general formula (I) include, but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or a biosimilar thereof), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311, or a biosimilar thereof), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90 In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, or IMM01), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, or ocatinib), PI3K inhibitors (such as idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib, etc.), BTK inhibitors (such as ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), CDK inhibitors (such as palbociclib, ribociclib, abemaciclib, milciclib, trilaciclib, lerociclib, etc.), MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), or a combination thereof.
Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): an injection, a tablet, a capsule, an aerosol, a suppository, a film, a dropping pill, a liniment for external use, or a controlled-released or sustained-release or nano formulation.
The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier, wherein the “safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition comprises 1-2000 mg of the compound of the present invention per dose, and more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, the “dose” is a capsule or a tablet.
The “pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. “Compatible” herein means that the components of the composition are capable of intermixing with the compound of the present invention and with each other, without significantly diminishing the pharmaceutical efficacy of the compound. Examples of the pharmaceutically acceptable carrier include cellulose and derivatives thereof (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oil (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
The mode of administration of the compound or the pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, pulvises and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffers.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may comprise opacifying agents, and the active compound or compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and wax-based substances. If necessary, the active compound can also be in microcapsule form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may comprise inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances. Besides such inert diluents, the composition may also comprise adjuvants, such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents. Suspensions, in addition to the active compound, may comprise suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate and agar, or mixtures of these substances.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for redissolving into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compound of the present invention include ointments, pulvises, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants that may be required if necessary.
The treatment method of the present invention can be used alone or in combination with other therapeutic means or drugs.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is administered to a mammal (such as a human) to be treated, wherein the administration dose is a pharmaceutically effective administration dose. For a human weighing 60 kg, the daily dose of administration is usually 1-2000 mg, preferably 50-1000 mg. In determining a specific dose, such factors as the route of administration, the health condition of the patient and the like will also be considered, which are well known to skilled physicians.
The present invention further provides a method for preparing the pharmaceutical composition, which comprises the step of mixing a pharmaceutically acceptable carrier with the compound of general formula (I), or the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof of the present invention to form the pharmaceutical composition.
The present invention further provides a treatment method, which comprises the step of administering to a subject in need of treatment the compound of general formula (I), or the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof of the present invention, or the pharmaceutical composition of the present invention to selectively inhibit SOS1.
The present invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are merely intended to illustrate the present invention rather than limit the scope of the present invention. Where specific conditions are not indicated in experimental method in the following examples, conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989) or conditions recommended by the manufacturer are followed. Unless otherwise indicated, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.
The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR is detected using a Bruker AVANCE-400 nuclear magnetic resonance instrument, and the measuring solvents include deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the like. The internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).
The liquid chromatography-mass spectrometry (LC-MS) is detected using a Waters SQD2 mass spectrometer. HPLC is determined using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100×3.0 mm column).
Qingdao GF254 silica gel plate is used for thin layer chromatography. The specification for TLC is 0.15-0.20 mm, and the specification for preparative thin-layer chromatography is 0.4-0.5 mm. Qingdao 200-300 mesh silica gel is generally used as the carrier in column chromatography.
Starting materials in the examples of the present invention are known and commercially available, or may be synthesized by using or according to the literature reported in the art.
Unless otherwise stated, all reactions in the present invention are carried out in a dry inert gas atmosphere (e.g., nitrogen or argon) with continuous magnetic stirring, and the reaction temperature is Celsius (° C.).
3-Bromo-5-iodobenzoic acid (4 g, 12.2 mmol) was added to tert-butanol (50 mL), and triethylamine (1.85 g, 18.3 mmol) and triphenylphosphoryl azide (3.7 g, 13.5 mmol) were added. The mixture was refluxed overnight, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (3.4 g, yield: 71%).
LC-MS: m/z 398 (M+H)+.
tert-Butyl (3-bromo-5-iodophenyl)carbamate (3.97 g, 10 mmol) was added to dimethyl sulfoxide (30 mL), and ethyl 2-bromo-2,2-difluoroacetate (5.1 g, 25 mmol) and copper powder (1.6 g, 25 mmol) were added. The mixture was then heated to 70° C. and stirred overnight, poured into water (100 mL), and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (3.4 g, yield: 79%).
LC-MS: m/z 394 (M+H)+.
Ethyl 2-(3-bromo-5-((tert-butoxycarbonyl)amino)phenyl)-2,2-difluoroacetate (3 g, 7.6 mmol) was added to tetrahydrofuran (30 mL), and methylmagnesium bromide (10.2 mL, 30.5 mmol) was added at 0° C. After being reacted at room temperature for 1 h, the mixture was poured into ice (50 g), and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (2.8 g).
LC-MS: m/z 380 (M+H)+.
tert-Butyl (3-bromo-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate (3 g, 7.9 mmol) was added to tetrahydrofuran (30 mL), and n-butyllithium (2.5 M, 12.6 mL, 31.6 mmol) was added at −60° C. After the addition was complete, the mixture was stirred for 0.5 h with the temperature maintained, and then N-methoxy-N-methylacetamide (3.3 g, 31.6 mmol) was added. The mixture was slowly heated to room temperature, stirred overnight, poured into ice (50 g), and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (1.1 g).
LC-MS: m/z 344 (M+H)+.
tert-Butyl (3-acetyl-5-(1,1-difluoro-2-hydroxy-2-methylpropyl)phenyl)carbamate (1 g, 2.9 mmol) was added to tetrahydrofuran (20 mL), and then (R)-2-methylpropane-2-sulfinamide (0.53 g, 4.4 mmol) and tetraethyl titanate (2.6 g, 12 mmol) were added. Then, the reaction solution was stirred under reflux overnight, cooled, concentrated, and separated by silica gel column chromatography to give the target product (0.68 g, yield: 52%).
LC-MS: m/z 447 (M+H)+.
(R,Z)-tert-Butyl(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(1,1-difluoro-2-hydroxy-2-methylprop yl)phenyl)carbamate (0.68 g, 1.5 mmol) was added to tetrahydrofuran/water (8 mL/0.16 mL), and sodium borohydride (116 mg, 3.0 mmol) was added at 0° C. The reaction solution was stirred at room temperature for 0.5 h, and then a saturated ammonium chloride solution (20 mL) was added. The mixture was extracted 2 times with ethyl acetate (60 mL), and the organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to give the target product (600 mg, yield: 88%).
LC-MS: m/z 449 (M+H)+.
tert-Butyl (3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-5-((R)-1-((R)-1,1-dimethylethylsulfinylamino)ethyl) phenyl)carbamate (600 mg, 1.34 mmol) was added to methanol (3 mL), and a solution of 4 N hydrogen chloride in dioxane (6 mL) was added. Then the reaction solution was stirred at room temperature for 16 h, and concentrated, and the crude product was separated by preparative liquid chromatography to give the target product (188 mg, yield: 50%).
LC-MS: m/z 245 (M+H)+. 1H NMR (400 MHZ,DMSO) δ 8.37 (brs, 3H), 6.82-6.66 (m, 3H), 5.74-4.94 (m, 2H), 4.30-4.16 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.17 (s, 6H).
2-Chloro-4-iodopyridine (4.0 g, 16.7 mmol), ethyl 2-bromo-2,2-difluoroacetate (8.5 g, 41.8 mmol) and active copper powder (2.7 g, 41.8 mmol) were added to dimethyl sulfoxide (30 mL). The mixture was stirred at 55° C. for 16 h in nitrogen atmosphere, cooled to room temperature, diluted with water/ethyl acetate (150 mL/100 mL), stirred, and filtered to remove insoluble solids. The filtrate was separated. The aqueous phase was extracted with ethyl acetate (100 mL). The ethyl acetate layers were combined, washed three times with saturated brine (50 mL), dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (3.5 g, yield: 86%).
LC-MS: m/z 236 (M+H)+.
Ethyl 2-(2-chloropyridin-4-yl)-2,2-difluoroacetate (3.06 g, 13.0 mmol) was added to anhydrous toluene (30 mL). The system was purged 3 times with nitrogen, and methylmagnesium bromide (3 M, 10 mL, 30.0 mmol) was added dropwise in an ice bath. The reaction solution was then stirred at room temperature for 1 h. A saturated ammonium chloride solution (100 mL) was added. The mixture was extracted 2 times with ethyl acetate (50 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to give the target product (1.8 g, purity: about 80%, yield: 58%).
LC-MS: m/z 222 (M+H)+.
1-(2-Chloropyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol (1.68 g, 7.6 mmol) was added to N,N-dimethylformamide (15 mL), and then tributyl(1-ethoxyvinyl)stannane (3.29 g, 9.1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (266 mg, 0.38 mmol) were added. The system was purged with nitrogen. The reaction solution was stirred at 120° C. overnight, then cooled to room temperature, poured into water/ethyl acetate (50 mL/50 mL), and filtered under reduced pressure through celite to remove flocculent black solids. The filtrate was separated, and the aqueous phase was extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed three times with saturated brine (30 mL), dried, and concentrated to give the target product, which was used directly in the next step without purification.
LC-MS: m/z 258 (M+H)+.
1-(2-(1-Ethoxyvinyl)pyridin-4-yl)-1,1-difluoro-2-methylpropan-2-ol (crude) obtained in the last step was dissolved in tetrahydrofuran (30 mL), and then a 2 M aqueous hydrochloric acid solution (15 mL) was added. The reaction solution was then stirred at room temperature for 1 h, adjusted to pH=8 with saturated sodium bicarbonate, and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried and concentrated. The residue was separated by silica gel column chromatography to give the target product (1.29 g, yield over two steps: 70%).
LC-MS: m/z 230 (M+H)+.
1-(4-(1,1-Difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethanone (1.07 g, 4.69 mmol) was added to tetrahydrofuran (20 mL), and then (R)-2-methylpropane-2-sulfinamide (850 mg, 7.03 mmol) and tetraethyl titanate (4.3 g, 18.76 mmol) were added. Then, the reaction solution was stirred under reflux for 1.5 h, cooled, concentrated, and separated by silica gel column chromatography to give the target product (455 mg, yield: 29%).
LC-MS: m/z 333 (M+H)+.
(R,E)-N-(1-(4-(1,1-Difluoro-2-hydroxy-2-methyl-2-methylpropyl)pyridin-2-yl)ethylidene)-2-m ethylpropane-2-sulfinamide (455 mg, 1.37 mmol) was dissolved in tetrahydrofuran/water (7 mL/0.14 mL), and sodium borohydride (78 mg, 2.06 mmol) was added in batches at −50° C. The reaction solution was slowly heated to room temperature. Half-saturated brine (30 mL) was added. The mixture was extracted 3 times with ethyl acetate (20 mL). The organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography to give the target product (290 mg, yield: 56%).
LC-MS: m/z 335 (M+H)+.
(R)—N—((R)-1-(4-(1,1-Difluoro-2-hydroxy-2-methylpropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (290 mg, 0.87 mmol) was dissolved in methanol (2 mL), and a solution of hydrogen chloride/dioxane (4 M, 4 mL) was added. The reaction solution was stirred at room temperature for 16 h, and concentrated to dryness, and the crude product was separated by preparative liquid chromatography to give the target product (179 mg, yield: 77%).
LC-MS: 231 m/z (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.73 (d, J=4.8 Hz, 1H), 8.60 (brs, 3H), 7.65 (s, 1H), 7.49 (d, J=5.2 Hz, 1H), 5.52 (s, 1H), 4.60 (q, J=6.4 Hz, 1H), 1.52 (d, J=7.2 Hz, 3H), 1.19 (s, 6H).
The Following Compounds were Synthesized in the Same Manner as Intermediate-2 with Different Starting Materials:
LC-MS: 231 m/z (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.61 (s, 3H), 8.04-8.00 (m, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 5.28 (s, 1H), 4.54 (m, 1H), 1.56 (d, J=6.8 Hz, 3H), 1.24 (s, 6H).
LC-MS: 231 m/z (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.86 (brs, 3H), 8.70 (d, J=5.2 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J=5.2 Hz, 1H), 4.54-4.50 (m, 1H), 1.53 (d, J=6.8 Hz, 3H), 1.23 (s, 6H).
LC-MS: 231 m/z
3-Bromo-4-fluoroaniline (5 g, 26.5 mmol) was added to acetonitrile/water (50 mL/8 mL), and concentrated hydrochloric acid (11 mL) and sodium nitrite (2 g, 29.1 mmol) were added at 0° C. The mixture was reacted for 0.5 h, and then a solution of potassium iodide (6.6 g, 39.8 mmol)/water (15 mL) was added. The mixture was stirred at room temperature for 3 h, poured into water (100 mL), and extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (15.8 g, yield: 100%).
2-Bromo-1-fluoro-4-iodobenzene (15.8 g, 52.7 mmol) was added to dimethyl sulfoxide (110 mL), and ethyl 2-bromo-2,2-difluoroacetate (26.8 g, 131.6 mmol) and copper powder (8.4 g, 131.6 mmol) were added. The mixture was then heated to 70° C. and stirred overnight, poured into water (300 mL), and extracted twice with ethyl acetate (800 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (9.8 g, yield: 63%).
1H NMR (400 MHZ, CDCl3) δ 7.83 (dd, J=6.4 Hz, 2.0 Hz; 1H), 7.61-7.51 (m, 1H), 7.20 (t, J=8.4 Hz; 1H), 4.32 (q, J=7.2 Hz; 2H), 1.32 (t, J=6.8 Hz; 3H).
Ethyl 2-(3-bromo-4-fluorophenyl)-2,2-difluoroacetate (9.8 g, 33 mmol) was added to tetrahydrofuran (150 mL), and methylmagnesium bromide (33 mL, 99 mmol) was added at 0° C. After being reacted at room temperature for 1 h, the mixture was poured into ice (100 g), and extracted twice with ethyl acetate (400 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (9 g, yield: 97%).
1H NMR (400 MHZ, CDCl3) δ 7.74 (dd, J=6.4 Hz, 2.0 Hz; 1H), 7.54-7.43 (m, 1H), 7.16 (t, J=8.4 Hz; 1H), 1.32-1.29 (m, 6H). Step 4: Preparation of 1-(3-(1-ethoxyvinyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol
1-(3-Bromo-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (9.3 g, 32.9 mmol) was added to N,N-dimethylformamide (100 mL), and tributyl(1-ethoxyvinyl)stannane (14.2 g, 39.4 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.2 g, 1.65 mmol) were added. After the addition was complete, the mixture was heated to 120° C. and stirred for 16 h in nitrogen atmosphere. After the reaction was complete, the mixture was cooled, poured into water (300 mL), and extracted twice with ethyl acetate (600 mL). The organic phases were combined, dried, and concentrated to dryness by rotary evaporation to give the target product, which was used directly in the next step.
1-(3-(1-Ethoxyvinyl)-4-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (crude) was added to tetrahydrofuran (60 mL), and then an aqueous hydrochloric acid solution (20 mL, 4 mol/L) was added. The mixture was stirred at room temperature for 1 h, then adjusted to pH=7.0-8.0 with a saturated aqueous sodium bicarbonate solution, and extracted twice with ethyl acetate (600 mL). The organic phases were combined, dried, concentrated to dryness by rotary evaporation, and separated by silica gel column chromatography to give the target product (6.6 g, yield over two steps: 81%).
LC-MS: m/z 247 (M+H)+.
1-(5-(1,1-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethanone (6.6 g, 26.8 mmol) was added to tetrahydrofuran (70 mL), and then (R)-2-methylpropane-2-sulfinamide (4.9 g, 40.2 mmol) and tetraethyl titanate (23.9 g, 107 mmol) were added. Then, the reaction solution was stirred at 60° C. overnight, cooled, concentrated, and separated by silica gel column chromatography to give the target product (6.4 g, yield: 68%).
LC-MS: m/z 350 (M+H)+.
(R,Z)-N-(1-(5-(1,1-Difluoro-2-hydroxy-2-methyl-2-methylpropyl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (6.3 g, 18.1 mmol) was added to tetrahydrofuran/water (80 mL/1.6 mL), and sodium borohydride (1.4 g, 36.2 mmol) was added at 0° C. The reaction solution was stirred at room temperature for 0.5 h, and then a saturated ammonium chloride solution (100 mL) was added. The mixture was extracted 2 times with ethyl acetate (300 mL), and the organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to give the target product (4.1 g, yield: 64%).
LC-MS: m/z 352 (M+H)+.
(R)—N—((R)-1-(5-(1,1-Difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)-2-methylprop ane-2-sulfinamide (4 g, 11.4 mmol) was added to methanol (20 mL), and a solution of 4 N hydrogen chloride in dioxane (20 mL) was added. The reaction solution was then stirred at room temperature for 16 h, and concentrated, and the residue was separated by preparative liquid chromatography to give the target product (2.32 g, yield: 82%).
LC-MS: m/z 248 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.70 (brs, 3H), 7.79 (dd, J=7.2 Hz, 2.4 Hz; 1H), 7.56-7.49 (m, 1H), 7.37 (t, J=9.6 Hz; 1H), 5.33 (s, 1H), 4.63 (q, J=6.4 Hz; 1H), 1.53 (d, J=6.8 Hz, 3H), 1.18 (s, 6H).
The following compounds were synthesized in the same manner as intermediate-6 with different starting materials:
LC-MS: m/z 248 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.72 (s, 3H), 7.62 (d, J=9.7 Hz, 1H), 7.49 (s, 1H), 7.27 (d, J=9.4 Hz, 1H), 4.52-4.47 (m, 1H), 1.53 (d, J=6.8 Hz, 3H), 1.18 (s, 6H).
LC-MS: m/z 248 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.57 (brs, 3H), 7.72 (s, 1H), 7.62-7.60 (m, 1H), 7.35 (dd, J=10.8 Hz, 8.8 Hz, 1H), 5.38 (s, 1H), 4.50-4.44 (m, 1H), 1.51 (d, J=6.8 Hz, 3H), 1.21 (s, 6H).
LC-MS: m/z 260 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.67 (s, 3H), 7.36 (s, 1H), 7.18 (s, 1H), 6.98 (s, 1H), 5.31 (brs, 1H), 4.44-4.40 (m, 1H), 3.81 (s, 3H), 1.53 (d, J=6.8 Hz, 3H), 1.18 (s, 6H).
LC-MS: m/z 264 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.74 (brs, 3H), 7.90 (dd, J=8.8 Hz, 3.2 Hz, 1H), 7.65-7.54 (m, 2H), 5.45 (s, 1H), 4.63 (q, J=8.8 Hz, 1H), 1.54 (d, J=8.8 Hz, 3H), 1.27 (s, 6H).
LC-MS: m/z 244 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.49 (brs, 3H), 7.69 (d, J=7.2 Hz, 1H), 7.41-7.34 (m, 2H), 4.71-4.65 (m, 1H), 3.57 (s, 1H), 2.46 (s, 3H), 1.48 (d, J=6.8 Hz, 3H), 1.22 (s, 6H).
LC-MS: m/z 255 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.97 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 5.40 (s, 1H), 4.14 (q, J=6.6 Hz, 1H), 1.28 (d, J=6.6 Hz, 3H), 1.17 (s, 6H).
To a solution of 2,6-dibromopyridin-4-amine (19.0 g, 75.4 mmol, 1.00 eq) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25.4 g, 151 mmol, 2.00 eq) in dioxane (150 mL) and H2O (30 mL) were added K2CO3 (31.3 g, 226 mmol, 3.00 eq) and Pd(PPh3)2Cl2 (3.71 g, 5.28 mmol, 0.07 eq) in nitrogen atmosphere. The reaction solution was reacted at 80° C. for 16 h. The resulting reaction solution was quenched with water (500 mL) and then extracted with EtOAc (500 mL×2). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (8.00 g, 37.6 mmol, yield: 49.8%).
LC-MS: m/z 213 (M+H)+.
To a solution of 2-bromo-6-(prop-1-en-2-yl)pyridin-4-amine (8.00 g, 37.6 mmol, 1.00 eq) in DCM (80 mL) were added (Boc)2O (32.8 g, 150 mmol, 34.5 mL, 4.00 eq) and DMAP (1.38 g, 11.3 mmol, 0.30 eq). The reaction solution was reacted at 25° C. for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the target product (8.00 g, 19.4 mmol, yield: 51.6%).
LC-MS: m/z 413 (M+H)+.
To diethyl zinc (1.00 M, 38.7 mL, 4.00 eq) in DCM (20 mL) was added TFA (4.41 g, 38.7 mmol, 2.87 mL, 4.00 eq) at 0° C. in nitrogen atmosphere. The reaction solution was reacted at 0° C. for 15 min. A solution of CH2I2 (10.4 g, 38.7 mmol, 3.12 mL, 4.00 eq) in DCM (20 mL) was then added dropwise at 0° C. The reaction solution was reacted at 0° C. for 20 min. A solution of tert-butyl (2-bromo-6-(prop-1-en-2-yl)pyridin-4-yl)(tert-butoxycarbonyl)carbamate (4.00 g, 9.68 mmol, 1.00 eq) in DCM (20 mL) was then added at 0° C. The reaction solution was reacted at 20° C. for 5 h. The resulting reaction solution was quenched with water (200 mL) and then extracted with DCM (100 mL×2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (1.08 g, 2.64 mmol, yield: 17.0%, purity: 80.0%).
LC-MS: m/z 327 (M+H)+.
To a solution of tert-butyl (2-bromo-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (1.05 g, 3.21 mmol, 1.00 eq) in dioxane (5 mL) were added tributyl(1-ethoxyvinyl)tin (1.43 g, 3.96 mmol, 1.34 mL, 1.24 eq), TEA (649 mg, 6.42 mmol, 893 μL, 2.00 eq) and Pd(PPh3)2Cl2 (113 mg, 160 μmol, 0.05 eq) in nitrogen atmosphere. The reaction solution was reacted at 60° C. for 16 h. The resulting reaction solution was quenched with 1 N HCl (50 mL) and then extracted with EtOAc (200 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (560 mg, 1.93 mmol, yield: 60.1%).
LC-MS: m/z 291 (M+H)+.
To tert-butyl (2-acetyl-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (0.56 g, 1.93 mmol, 1.00 eq) and tert-butylsulfinamide (351 mg, 2.90 mmol, 1.50 eq) in THF (5 mL) was added Ti(OEt)4 (1.10 g, 4.82 mmol, 999 μL, 2.50 eq). The reaction solution was reacted at 80° C. for 16 h and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the target product (440 mg, 1.01 mmol, yield: 52.1%, purity: 90.0%).
LC-MS: m/z 394 (M+H)+.
To a solution of tert-butyl (E)-(2-(1-((tert-butylsulfinyl)imino)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (440 mg, 1.12 mmol, 1.00 eq) in THF (5 mL) and H2O (0.1 mL) was added NaBH4 (46.5 mg, 1.23 mmol, 1.10 eq) at 0° C. The reaction solution was reacted at 25° C. for 1 h. The resulting reaction solution was quenched with water (20 mL) and then extracted with EtOAc (100 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (300 mg, 758 μmol, yield: 67.8%).
LC-MS: m/z 396 (M+H)+.
To a solution of tert-butyl (2-(1-((tert-butylsulfinyl)amino)ethyl)-6-(1-methylcyclopropyl)pyridin-4-yl)carbamate (300 mg, 758 μmol, 1.00 eq) in dioxane (1 mL) was added HCl/dioxane (1 mL) at 0° C. The reaction solution was reacted at 25° C. for 16 h and then filtered. The filter cake was dried in vacuo to give the target product as a white solid (165 mg, 647 μmol, yield: 85.4%, purity: 89.3%).
LC-MS: m/z 192 (M+H)+. 1H NMR (400 MHZ, CD3OD) δ 6.91 (d, J=2.3 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H), 4.78-4.65 (m, 1H), 4.78-4.65 (m, 1H), 1.75-1.71 (m, 1H), 1.75-1.71 (m, 1H), 1.73 (d, J=7.0 Hz, 4H), 1.54-1.50 (m, 1H), 1.51 (s, 3H), 1.15-1.10 (m, 2H), 1.01-0.95 (m, 2H).
A mixture of 2-chloro-4-nitropyridine (16.0 g, 101 mmol, 1.00 eq), 1-fluorocyclopropane-1-carboxylic acid (13.7 g, 131 mmol, 1.30 eq) and AgNO3 (3.43 g, 20.2 mmol, 0.200 eq) in ACN (50.0 mL) and H2O (65.0 mL) was heated to 80° C., followed by addition of a solution of (NH4)2S2O8 (46.0 g, 202 mmol, 43.9 mL, 2.00 eq) in H2O (65.0 mL). The reaction solution was reacted at 80° C. for 48 h. The resulting reaction solution was quenched with a 2 M NaOH solution (500 mL) and then extracted with EtOAc (500 mL). The combined organic phase was dried over anhydrous MgSO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (2.50 g, 11.5 mmol, yield: 11.4%).
1H NMR (400 MHZ, CDCl3) δ 8.55-8.62 (m, 1H) 7.45 (d, J=5.25 Hz, 1H) 1.48-1.55 (m, 2H) 0.87-0.95 (m, 2H).
A solution of 2-chloro-6-(1-fluorocyclopropyl)-4-nitropyridine (2.37 g, 11.0 mmol, 1.00 eq), tributyl(1-ethoxyvinyl)tin (7.00 g, 19.4 mmol, 6.54 mL, 1.75 eq), and Pd(PPh3)2Cl2 (778 mg, 1.11 mmol, 0.100 eq) in dioxane (25.0 mL) was reacted at 110° C. for 16 h in nitrogen atmosphere. The resulting reaction solution was quenched with H2O (60 mL) and then extracted with EtOAc (60 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (1.66 g, 6.58 mmol, yield: 59.4%).
1H NMR (400 MHZ, CDCl3) δ 8.77 (dd, J=5.13, 1.25 Hz, 1H) 7.49 (d, J=5.13 Hz, 1H) 4.51-4.69 (m, 2H) 3.94 (q, J=7.00 Hz, 2H) 1.30-1.38 (m, 5H) 0.77-0.85 (m, 2H).
To a solution of 2-(1-ethoxyvinyl)-6-(1-fluorocyclopropyl)-4-nitropyridine (1.63 g, 6.46 mmol, 1.00 eq) in THF (5.00 mL) was added an aqueous HCl solution (2.00 M, 4.85 mL, 1.50 eq). The reaction solution was reacted at 25° C. for 1 h. The resulting reaction solution was quenched with H2O (30 mL) and then extracted with EtOAc (50 mL). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (1.44 g, 6.26 mmol, yield: 96.8%, purity: 97.4%).
1H NMR (400 MHZ, CDCl3) δ (dd, J=5.14, 1.38 Hz, 1H) 7.69 (d, J=5.27 Hz, 1H) 2.74 (s, 3H) 1.45-1.55 (m, 2H) 0.77-0.86 (m, 2H).
To 1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethan-1-one (1.24 g, 5.53 mmol, 1.00 eq) and tert-butylsulfinamide (1.01 g, 8.30 mmol, 1.50 eq) in THF (15.0 mL) was added Ti(OEt)4 (5.05 g, 22.1 mmol, 4.59 mL, 4.00 eq). The reaction solution was reacted at 80° C. for 16 h. The resulting reaction solution was quenched with H2O (200 mL) and then extracted with EtOAc (300 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product (750 mg, 2.44 mmol, yield: 44.1%).
1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J=5.02, 1.00 Hz, 1H) 7.57-7.70 (m, 1H) 2.65-2.87 (m, 3H) 1.40-1.55 (m, 2H) 1.31 (d, J=12.30 Hz, 9H) 0.84 (dd, J=9.03, 2.51 Hz, 2H).
To a solution of (E)-N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethylene)-2-methylpropane-2-sulfonimide (730 mg, 2.23 mmol, 1.00 eq) in THF (8.00 mL) and H2O (0.100 mL) was added NaBH4 (126 mg, 3.34 mmol, 1.50 eq). The reaction solution was reacted at 0° C. for 0.5 h. At 0° C., the resulting reaction solution was quenched with water (20 mL) and then extracted with EtOAc (20 mL). The combined organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the target product as a yellow solid (0.300 g, 911 μmol, yield: 40.8%).
1H NMR (400 MHZ, CDCl3) δ 8.80 (br s, 1H) 7.40 (br s, 1H) 5.35 (br d, J=6.50 Hz, 1H) 4.90 (br d, J=9.01 Hz, 1H) 1.62 (br s, 5H) 1.26 (br s, 9H) 0.82-0.99 (m, 2H).
To a solution of N-(1-(6-(1-fluorocyclopropyl)-4-nitropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (200 mg, 607 μmol, 1.00 eq) and Boc2O (159 mg, 729 μmol, 167 μL, 1.20 eq) in MeOH (2.00 mL) was added Pd/C (607 μmol, 2.00 mL, purity: 10.0%, 1.00 eq) in nitrogen atmosphere. The reaction solution was reacted at 25° C. for 2 h in hydrogen atmosphere and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography to give the target product (140 mg, 468 μmol, yield: 77.0%).
LC-MS: m/z 300 (M+H)+.
To a solution of N-(1-(4-amino-6-(1-fluorocyclopropyl)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 401 μmol, 1.00 eq) in dioxane (1.00 mL) was added HCl/dioxane (1.80 mL). The reaction solution was reacted at 25° C. for 0.5 h, and then concentrated under reduced pressure to give the target product (52.0 mg, 259 μmol, yield: 64.6%, purity: 97.1%).
LC-MS: m/z 196 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 9.02-9.39 (m, 3H) 8.23 (d, J=6.85 Hz, 1H) 6.99 (d, J=6.85 Hz, 1H) 5.20 (br d, J=5.50 Hz, 1H) 1.68 (br d, J=6.85 Hz, 3H) 1.56-1.66 (m, 2H) 1.27-1.39 (m, 1H) 0.95 (br s, 1H).
To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (2.00 g, 8.55 mmol, 1.00 eq) in DMF (20.0 mL) was added NIS (2.12 g, 9.40 mmol, 1.10 eq). The resulting mixture was reacted at 80° C. for 2 h, then quenched with water (100 mL) and filtered. The filter cake was collected and dried to give the target product (2.20 g, yield: 67.2%), which was used directly in the next step without purification.
LC-MS: m/z 360 (M+H)+.
A solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5.20 g, 14.5 mmol, 1.00 eq) in Ac2O (50 mL) was reacted at 138° C. for 12 h, and then concentrated under reduced pressure. The residue was reacted with a mixed solvent of EtOH (50 mL) and NH3·H2O (50 mL) at 80° C. for 5 h, and then filtered. The filter cake was collected and dried to give the target product (4.00 g, yield: 69.6%), which was used directly in the next step without purification.
LC-MS: m/z 383 (M+H)+.
To a solution of 7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-ol (1.60 g, 4.18 mmol, 1.00 eq) in DMF (16 mL) were added PyBOP (4.35 g, 8.36 mmol, 2.00 eq) and TEA (2.11 g, 20.9 mmol, 2.91 mL, 5.00 eq). The reaction solution was reacted at room temperature for 0.5 h, followed by addition of (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol hydrochloride (1.54 g, 5.43 mmol, 1.30 eq). The resulting mixture was reacted at 25° C. for 16 h, followed by addition of EtOAc (50 mL) and H2O (50 mL). The organic phase was separated, then dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography to give the target product (1.10 g, yield: 43.2%).
LC-MS: m/z 612 (M+H)+. 1H NMR (400 MHz, DMSO) δ8.93 (s, 1H) 8.78 (br d, J-7.21 Hz, 1H) 7.59 (br t, J=6.54 Hz, 1H) 7.29-7.36 (m, 1H) 7.19-7.26 (m, 1H) 5.76 (t, J=7.09 Hz, 1H) 5.33 (s, 1H) 2.36 (s, 3H) 1.58 (d, J=7.09 Hz, 3H) 1.22 (br d, J=10.27 Hz, 6H).
In nitrogen atmosphere, a mixture of (R)-1-(3-(1-((7-bromo-8-fluoro-6-iodo-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (1 g, 1.63 mmol, 1 eq), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (461 mg, 1.96 mmol, 1.2 eq), Pd(dppf)Cl2 (120 mg, 163 μmol, 0.1 eq) and K3PO4 (1.04 g, 4.90 mmol, 3 eq) in dioxane (5 mL), MeCN (5 mL) and H2O (5 mL) was reacted at 90° C. for 6 h. EtOAc (20 mL) and H2O (20 mL) were then added. The organic phase was separated, then dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography to give the target product (750 mg, yield: 77.4%).
LC-MS: m/z 593 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.71 (br d, J=7.28 Hz, 1H) 8.34 (s, 1H) 8.00 (d, J=2.51 Hz, 1H) 7.57-7.65 (m, 2H) 7.29-7.36 (m, 1H) 7.18-7.26 (m, 1H) 6.53 (d, J=9.29 Hz, 1H) 5.81 (br t, J=7.15 Hz, 1H) 5.34 (s, 1H) 3.54 (s, 3H) 2.40 (s, 3H) 1.58 (d, J=7.03 Hz, 3H) 1.23 (br d, J=10.04 Hz, 6H).
N-Methyl-L-prolinol (500.0 mg, 4.34 mmol) was dissolved in toluene (5 mL), and thionyl chloride (2.0 mL) was added. The resulting reaction solution was stirred at 100° C. for 2.0 h, and then concentrated under reduced pressure. The crude product obtained was used directly in the next step without further purification.
6-Hydroxy-7-methoxy-2-methylquinazolin-4(3H)-one (120 mg, 0.58 mmol) was added to N,N-dimethylformamide (10 mL), followed by addition of (S)-2-(chloromethyl)-1-methylpyrroline (77.8 mg, 0.58 mmol) obtained in the last step and potassium carbonate (402.2 mg, 2.91 mmol). The resulting reaction solution was stirred at 100° C. for 3.0 h, and then cooled to room temperature. The mixture was separated by preparative liquid chromatography to give the target product (39 mg, yield: 22%).
LC-MS: m/z 304 (M+H)+.
(S)-7-Methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4(3H)-one (38.0 mg, 0.13 mmol) was added to dichloromethane (4 mL), followed by addition of 2,4,6-triisopropylsulfonyl chloride (45.5 mg, 0.15 mmol), triethylamine (25.4 mg, 0.25 mmol) and 4-dimethylaminopyridine (1.5 mg, 0.013 mmol). The resulting reaction solution was stirred at room temperature overnight, then poured into water, and extracted with dichloromethane (10 mL). The organic phase was dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EA=5:1) to give the target product (14.0 mg, yield: 20%).
LC-MS: m/z 570(M+H)+.
(S)-7-Methoxy-2-methyl-6-((1-methylpyrrolin-2-yl)methoxy)quinazolin-4-yl-2,4,6-triisopropyl benzenesulfonate (31.0 mg, 0.054 mmol) was added to dimethyl sulfoxide (2 mL), and then (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol (20.2 mg, 0.082 mmol) and triethylamine (0.4 mL) were added. The resulting reaction solution was reacted at 120° C. for 2.0 h in microwave, then cooled to room temperature, quenched with water, and then extracted with ethyl acetate (10 mL). The organic phase was dried and concentrated under reduced pressure, and the resulting residue was separated by preparative liquid chromatography to give the target compound (4 mg, yield: 13.9%).
LC-MS: m/z 533 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.07 (m, 1H), 7.81 (m, 1H), 7.57 (d, J=6.3 Hz, 1H), 7.30 (t, J=7.1 Hz, 1H), 7.25-7.17 (m, 1H), 7.02 (d, J=3.0 Hz, 1H), 5.79 (m, 1H), 5.34 (m, 1H), 4.10-3.97 (m, 1H), 3.87 (m, 3H), 2.43 (m, 2H), 2.34-2.17 (m, 5H), 2.13-1.94 (m, 2H), 1.82-1.66 (m, 2H), 1.58 (m, 3H), 1.24 (m, 9H).
The following compounds were synthesized in the same manner as in Example 1 with different starting materials:
LC-MS: m/z 490 (M+H)+.
LC-MS: m/z 471 (M+H)+.
LC-MS: m/z 460 (M+H)+.
LC-MS: m/z 474 (M+H)+.
LC-MS: m/z 504 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 14.28 (brs, 1H), 9.71 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.17 (m, 3H), 6.88 (d, J=4.3 Hz, 2H), 6.76 (s, 1H), 5.81-5.61 (m, 1H), 4.33 (m, 1H), 4.15 (m, 1H), 3.97 (m, 4H), 2.80 (s, 3H), 2.59 (s, 3H), 2.45 (m, 1H), 2.27-2.13 (m, 2H), 1.91 (m, 1H), 1.64 (d, J=7.0 Hz, 3H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO-d6) δ 7.93 (d, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.86 (d, 1H), 6.69 (s, 1H), 5.57-5.53 (m, 3H), 4.22-4.18 (m, 2H), 3.91-3.84 (m, 5H), 3.44-3.39 (m, 1H), 2.35 (s, 3H), 1.55-1.53 (d, 3H), 0.54-0.44 (m, 4H).
LC-MS: m/z 490 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.02 (s, 1H), 6.87 (d, J=11.5 Hz, 2H), 6.70 (s, 1H), 5.64-5.44 (m, 3H), 4.23-4.07 (m, 2H), 3.86 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.87-1.74 (m, 1H), 1.52 (d, J=8.0 Hz, 3H), 0.51-0.40 (m, 2H), 0.37-0.24 (m, 2H).
LC-MS: m/z 561 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.03 (d, J=7.4 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J=6.7 Hz, 1H), 7.30 (t, J=6.7 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.02 (s, 1H), 5.80 (p, J=7.0 Hz, 1H), 5.31 (s, 1H), 4.16 (m, 2H), 3.86 (s, 3H), 2.78 (t, J=6.0 Hz, 2H), 2.27 (d, J=10.1 Hz, 6H), 2.08-1.95 (m, 2H), 1.93-1.73 (m, 3H), 1.66 (m, 2H), 1.58 (d, J=7.0 Hz, 3H), 1.22 (m, 8H).
LC-MS: m/z 518 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.93 (d, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.02 (s, 1H), 6.87 (d, J=11.0 Hz, 2H), 6.69 (s, 1H), 5.63-5.46 (m, 3H), 4.13 (m, 2H), 3.86 (s, 3H), 2.76 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.34 (s, 3H), 2.25 (s, 3H), 2.00 (m, 2H), 1.90-1.71 (m, 3H), 1.70-1.59 (m, 2H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 504 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.95 (d, J=8.0 Hz, 1H), 7.64 (d, J=9.6 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J=10.4 Hz, 2H), 6.69 (s, 1H), 5.62-5.46 (m, 3H), 3.96 (m, 2H), 3.88 (s, 3H), 2.39-2.10 (m, 11H), 1.54 (d, J=7.1 Hz, 3H), 0.67 (s, 2H), 0.48 (s, 2H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.4 Hz, 1H), 7.67 (s, 1H), 7.58 (t, J=6.6 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.21 (m, 1H), 7.01 (s, 1H), 5.79 (m, 1H), 5.31 (s, 1H), 3.98 (m, 2H), 3.89 (s, 3H), 2.26 (m, 8H), 1.58 (d, J=7.0 Hz, 3H), 1.32-1.12 (m, 9H), 0.68 (m, 2H), 0.48 (m, 2H).
LC-MS: m/z 528 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.99 (d, J=7.7 Hz, 1H), 7.74 (s, 1H), 7.05 (s, 1H), 6.86 (d, J=10.6 Hz, 2H), 6.69 (s, 1H), 5.61-5.43 (m, 3H), 4.20 (t, J=19.3 Hz, 2H), 3.87 (s, 3H), 3.59 (t, J=5.5 Hz, 2H), 2.99 (s, 3H), 2.92 (s, 3H), 2.34 (s, 3H), 1.52 (t, J=17.4 Hz, 3H).
LC-MS: m/z 518 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.92 (d, J=7.4 Hz, 1H), 7.79 (s, 1H), 7.02 (s, 1H), 6.87 (d, J=14.3 Hz, 2H), 6.69 (s, 1H), 5.53 (m, 3H), 4.32 (m, 2H), 4.05 (m, 3H), 3.88 (s, 3H), 2.34 (m, 3H), 2.17 (m, 2H), 1.99 (m, 5H), 1.54 (d, J=7.0 Hz, 3H).
LC-MS: m/z 546 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.92 (d, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.01 (s, 1H), 6.87 (m, 2H), 6.70 (s, 1H), 5.66-5.44 (m, 3H), 4.28-3.93 (m, 2H), 3.87 (s, 3H), 3.60-3.48 (m, 4H), 2.66-2.56 (m, 1H), 2.50 (s, 3H), 2.35 (m, 4H), 2.07-1.95 (m, 1H), 1.56 (t, J=8.6 Hz, 3H), 0.63 (m, 2H), 0.50 (m, 2H).
LC-MS: m/z 579 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.10 (m, 1H), 7.77 (m, 2H), 7.63 (t, J=7.1 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.03 (s, 1H), 5.75 (m, 1H), 4.07 (m, 3H), 3.87 (s, 3H), 2.30 (s, 3H), 1.91 (m, 4H), 1.62 (d, J=7.1 Hz, 3H), 1.40 (m, 11H).
LC-MS: m/z 479 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.14 (t, J=8.6 Hz, 1H), 7.84-7.70 (m, 2H), 7.62 (t, J=6.9 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.03 (s, 1H), 5.85-5.67 (m, 1H), 4.23-3.92 (m, 2H), 3.87 (s, 3H), 3.56 (m, 1H), 2.91 (m, 2H), 2.30 (s, 3H), 2.12-1.67 (m, 4H), 1.62 (d, J=7.1 Hz, 3H).
LC-MS: m/z 493 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 14.61 (brs, 1H), 10.00 (s, 1H), 8.21 (d, J=19.4 Hz, 1H), 7.92 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.0 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.28 (s, 1H), 5.93 (m, 1H), 4.66 (d, J=9.6 Hz, 1H), 4.54-4.37 (m, 1H), 4.23 (m, 1H), 3.98 (s, 3H), 3.71 (m, 2H), 3.03 (s, 3H), 2.54 (s, 3H), 2.37 (m, 1H), 2.25-1.90 (m, 3H), 1.73 (t, J=10.3 Hz, 3H).
LC-MS: m/z 597 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.4 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J=6.7 Hz, 1H), 7.31 (m, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.02 (s, 1H), 5.79 (m, 1H), 5.34 (s, 1H), 4.36 (t, J=5.1 Hz, 2H), 3.83 (s, 3H), 2.83 (t, J=5.7 Hz, 2H), 2.75 (d, J=10.4 Hz, 2H), 2.68-2.56 (m, 4H), 2.39-2.15 (m, 7H), 1.58 (d, J=7.0 Hz, 3H), 1.20 (m, 6H).
LC-MS: m/z 557 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.15 (d, J=6.9 Hz, 1H), 7.79 (t, J=7.1 Hz, 1H), 7.74 (s, 1H), 7.63 (t, J=7.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.04 (s, 1H), 5.75 (p, J=6.9 Hz, 1H), 4.15 (d, J=10.8 Hz, 2H), 4.08-3.95 (m, 1H), 3.87 (s, 3H), 3.32-3.24 (m, 2H), 3.02 (s, 3H), 2.28 (s, 3H), 1.99 (m, 4H), 1.62 (d, J=7.0 Hz, 3H).
LC-MS: m/z 522 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.21-7.98 (brs, 1H), 7.75 (s, 1H), 7.04 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.64-5.49 (m, 3H), 4.21 (m, 2H), 3.88 (s, 3H), 2.91 (m, 4H), 2.46 (s, 3H), 2.36 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 0.99 (m 2H), 0.70 (m, 2H).
LC-MS: m/z 554 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=7.9 Hz, 1H), 7.70 (s, 1H), 7.02 (s, 1H), 6.86 (m, 2H), 6.69 (s, 1H), 5.62-5.48 (m, 3H), 4.14 (m, 2H), 3.86 (s, 3H), 2.80 (m, 2H), 2.75 (m, 1H), 2.69-2.59 (m, 3H), 2.58-2.54 (m, 2H), 2.35 (s, 3H), 2.27 (s, 3H), 2.20 (m, 1H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 535 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 9.02 (brs, 1H), 7.96 (s, 1H), 7.63 (t, J=6.9 Hz, 1H), 7.36 (t, J=6.9 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.11 (s, 1H), 5.96-5.81 (m, 1H), 5.35 (s, 1H), 4.32-4.10 (m, 3H), 4.06 (m, 1H), 3.94 (s, 3H), 3.80 (m, 1H), 3.50-3.38 (m, 2H), 3.26 (m, 1H), 3.05 (m, 2H), 2.45 (s, 3H), 1.64 (d, J=6.9 Hz, 3H), 1.22 (d, J=7.5 Hz, 6H).
LC-MS: m/z 535 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.4 Hz, 1H), 7.73 (s, 1H), 7.65-7.51 (m, 1H), 7.30 (t, J=6.7 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.02 (s, 1H), 5.80 (m, 1H), 5.33 (s, 1H), 4.14-3.94 (m, 2H), 3.87 (s, 3H), 3.78 (m, 2H), 3.51 (m, 1H), 2.97 (m, 1H), 2.68 (m, 2H), 2.60-2.52 (m, 2H), 2.28 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.20 (t, J=17.2 Hz, 6H).
LC-MS: m/z 549 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.4 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J=6.6 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.03 (s, 1H), 5.80 (t, J=7.1 Hz, 1H), 5.32 (s, 1H), 4.25-3.98 (m, 2H), 3.85 (m, 5H), 3.59 (m, 1H), 2.87 (m, 1H), 2.72-2.56 (m, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.04 (m, 1H), 1.94 (m, 1H), 1.58 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.3 Hz, 6H).
LC-MS: m/z 536 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.3 Hz, 1H), 7.74 (s, 1H), 7.58 (t, J=6.9 Hz, 1H), 7.30 (t, J=6.7 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.03 (s, 1H), 5.88-5.70 (m, 1H), 5.32 (s, 1H), 4.17-4.02 (m, 2H), 4.01-3.84 (m, 5H), 3.80 (m, 1H), 3.74-3.62 (m, 2H), 3.60-3.41 (m, 2H), 2.28 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.20 (t, J=17.3 Hz, 6H).
LC-MS: m/z 536 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.05 (d, J=7.2 Hz, 1H), 7.76 (d, J=10.9 Hz, 1H), 7.58 (t, J=6.8 Hz, 1H), 7.30 (t, J=6.7 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.03 (s, 1H), 5.88-5.72 (m, 1H), 5.33 (s, 1H), 4.09 (m, 2H), 4.01-3.84 (m, 5H), 3.80 (m, 1H), 3.76-3.63 (m, 2H), 3.50 (m, 2H), 2.29 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.0 Hz, 7H).
LC-MS: m/z 493 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.05 (d, J=7.1 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.87 (d, J=10.7 Hz, 2H), 6.70 (s, 1H), 5.56 (brs, 2H), 4.15-4.01 (m, 2H), 4.01-3.84 (m, 5H), 3.79 (m, 1H), 3.74-3.60 (m, 2H), 3.58-3.44 (m, 3H), 2.36 (s, 3H), 1.56 (d, J=6.9 Hz, 3H).
LC-MS: m/z 613 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.13 (s, 1H), 7.79 (s, 1H), 7.58 (t, J=6.8 Hz, 1H), 7.30 (t, J=6.7 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.04 (s, 1H), 5.81 (t, J=7.1 Hz, 1H), 5.33 (s, 1H), 4.30-4.08 (m, 2H), 4.09-3.94 (m, 2H), 3.88 (s, 3H), 3.76-3.56 (m, 2H), 3.41 (m, 1H), 3.06-2.72 (m, 5H), 2.29 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.20 (t, J=14.5 Hz, 6H).
LC-MS: m/z 516 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.98 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.02 (s, 1H), 6.85 (t, J=11.2 Hz, 2H), 6.69 (s, 1H), 5.64-5.45 (m, 3H), 4.14-3.98 (m, 2H), 3.86 (s, 3H), 2.91 (m, 1H), 2.61 (m, 1H), 2.53 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H), 2.13 (dd, J=12.6, 8.2 Hz, 1H), 1.67-1.44 (m, 4H), 0.63-0.39 (m, 4H).
LC-MS: m/z 526 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.86 (d, J=10.1 Hz, 2H), 6.69 (s, 1H), 5.66-5.46 (m, 3H), 4.11 (d, J=5.2 Hz, 2H), 3.87 (s, 3H), 3.45-3.34 (m, 1H), 3.05 (t, J=5.3 Hz, 1H), 2.80-2.56 (m, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.30-2.12 (m, 1H), 1.56 (t, J=7.2 Hz, 3H).
LC-MS: m/z 554 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.99 (t, J=13.1 Hz, 1H), 7.71 (s, 1H), 7.06 (d, J=10.1 Hz, 1H), 6.87 (d, J=9.9 Hz, 2H), 6.70 (s, 1H), 5.64-5.45 (m, 3H), 4.09 (t, J=12.0 Hz, 2H), 3.99 (m, 1H), 3.88 (s, 3H), 2.99 (s, 3H), 2.36 (s, 3H), 2.02 (m, 4H), 1.56 (d, J=7.0 Hz, 3H).
LC-MS: m/z 571 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.13 (d, J=6.8 Hz, 1H), 7.79 (d, J=15.0 Hz, 1H), 7.60 (t, J=6.7 Hz, 1H), 7.38-7.25 (m, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.04 (d, J=10.1 Hz, 1H), 5.81 (p, J=6.8 Hz, 1H), 5.33 (s, 1H), 4.27 (t, J=5.0 Hz, 2H), 3.87 (s, 3H), 3.61 (t, J=5.4 Hz, 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.29 (s, 3H), 1.59 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.1 Hz, 6H).
LC-MS: m/z 490 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.93 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.5 Hz, 2H), 6.69 (s, 1H), 5.57 (d, J=11.2 Hz, 3H), 4.19-4.02 (m, 2H), 3.87 (s, 3H), 2.42 (s, 6H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 0.70 (q, J=6.8 Hz, 4H).
LC-MS: m/z 495 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.96 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.04 (s, 1H), 6.89-6.79 (m, 1H), 6.70 (dd, J=5.4, 2.7 Hz, 1H), 5.67 (p, J=6.9 Hz, 1H), 5.33 (s, 2H), 4.35-4.11 (m, 2H), 3.87 (m, 5H), 3.43 (m, 1H), 2.31 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 0.62-0.35 (m, 4H).
LC-MS: m/z 463 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.81 (d, J=4.8 Hz, 1H), 8.14 (d, J=7.1 Hz, 1H), 7.78 (d, J=18.9 Hz, 2H), 7.63 (d, J=4.3 Hz, 1H), 7.04 (s, 1H), 5.68 (m, 1H), 4.22 (d, J=4.4 Hz, 2H), 3.87 (m, 5H), 3.46-3.40 (m, 1H), 2.30 (s, 3H), 1.65 (d, J=6.9 Hz, 3H), 0.49 (m, 4H).
LC-MS: m/z 463 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.70 (d, J=4.6 Hz, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.95 (s, 1H), 7.73 (s, 2H), 7.05 (s, 1H), 5.69-5.51 (m, 1H), 4.23 (d, J=3.8 Hz, 2H), 3.88 (s, 5H), 3.50-3.39 (m, 1H), 2.30 (s, 3H), 1.63 (d, J=6.9 Hz, 3H), 0.64-0.30 (m, 4H).
LC-MS: m/z 478 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.7 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 6.50 (s, 2H), 5.46 (m, 1H), 4.29-4.13 (m, 2H), 3.95-3.80 (m, 5H), 3.42 (m, 1H), 2.32 (s, 3H), 1.55 (d, J=7.1 Hz, 3H), 0.50 (m, 4H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.1 Hz, 2H), 6.69 (s, 1H), 5.57 (m, 3H), 4.31-4.16 (m, 1H), 4.04 (d, J=5.3 Hz, 2H), 3.93-3.76 (m, 4H), 3.71 (m, 1H), 2.35 (s, 3H), 2.13-2.00 (m, 1H), 2.00-1.81 (m, 2H), 1.79-1.67 (m, 1H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.2 Hz, 2H), 6.69 (s, 1H), 5.65-5.44 (m, 3H), 4.33-4.18 (m, 1H), 4.04 (m, 2H), 3.94-3.78 (m, 4H), 3.71 (m, 1H), 2.35 (s, 3H), 2.13-2.04 (m, 1H), 2.02-1.81 (m, 2H), 1.81-1.67 (m, 1H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 478 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 6.49 (s, 2H), 5.48 (m, 1H), 4.29-4.16 (m, 2H), 3.92-3.77 (m, 5H), 3.41 (m, 1H), 2.34 (s, 3H), 1.55 (d, J=7.1 Hz, 3H), 0.64-0.40 (m, 4H).
LC-MS: m/z 451 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.9 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.87 (d, J=10.9 Hz, 2H), 6.69 (s, 1H), 5.56 (m, 3H), 4.30-4.14 (m, 2H), 3.89 (s, 3H), 3.73 (m, 2H), 3.32 (s, 3H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.99 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.06 (s, 1H), 6.88 (d, J=8.1 Hz, 2H), 6.71 (s, 1H), 5.71-5.43 (m, 3H), 4.50 (m, 4H), 4.28 (m, 2H), 3.89 (s, 3H), 3.71 (s, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 1.57 (d, J=7.0 Hz, 3H).
LC-MS: m/z 493 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=7.9 Hz, 1H), 7.72 (s, 1H), 7.04 (s, 1H), 6.86 (d, J=10.5 Hz, 2H), 6.69 (s, 1H), 5.65-5.43 (m, 3H), 4.75-4.60 (m, 3H), 4.44 (m, 2H), 4.28-4.14 (m, 2H), 3.88 (s, 3H), 3.80 (t, J=4.5 Hz, 2H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 515 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.61 (d, J=6.7 Hz, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.80 (t, J=7.0 Hz, 1H), 7.69-7.59 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 5.76 (m, 1H), 4.34 (t, J=14.1 Hz, 2H), 3.87 (m, 2H), 3.44 (m, 1H), 2.33 (s, 3H), 1.66 (d, J=7.1 Hz, 3H), 0.56-0.40 (m, 4H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.04 (s, 1H), 6.88 (d, J=8.6 Hz, 2H), 6.70 (s, 1H), 5.66-5.43 (m, 3H), 4.20 (q, J=11.1 Hz, 2H), 3.89 (s, 3H), 3.34 (s, 3H), 2.36 (s, 3H), 1.56 (d, J=7.0 Hz, 3H), 0.95-0.85 (m, 2H), 0.75 (t, J=5.4 Hz, 2H).
LC-MS: m/z 465 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96 (d, J=7.7 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.4 Hz, 2H), 6.69 (s, 1H), 5.56 (m, 3H), 4.04 (m, 2H), 3.87 (s, 3H), 3.75 (m, 1H), 3.36 (s, 3H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.24 (d, J=6.3 Hz, 3H).
LC-MS: m/z 465 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96 (d, J=7.9 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.3 Hz, 2H), 6.69 (s, 1H), 5.69-5.42 (m, 3H), 4.09 (m, 1H), 3.99 (m, 1H), 3.87 (s, 3H), 3.75 (m, 1H), 3.36 (s, 3H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.24 (d, J=6.3 Hz, 3H).
LC-MS: m/z 491 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.97 (d, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.88 (d, J=10.2 Hz, 2H), 6.71 (s, 1H), 5.68-5.40 (m, 3H), 4.32-4.13 (m, 2H), 4.08-3.96 (m, 1H), 3.88 (s, 3H), 3.70 (t, J=4.8 Hz, 2H), 2.36 (s, 3H), 2.24-2.10 (m, 2H), 1.95-1.78 (m, 2H), 1.69-1.35 (m, 5H).
LC-MS: m/z 495 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.9 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.9 Hz, 2H), 6.69 (s, 1H), 5.64-5.38 (m, 3H), 4.28-4.14 (m, 2H), 3.94-3.77 (m, 5H), 3.69-3.57 (m, 2H), 3.48 (m, 2H), 3.25 (s, 3H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 452 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.7 Hz, 1H), 7.74 (s, 1H), 7.04 (s, 1H), 6.77 (s, 1H), 6.55 (m, 1H), 6.49 (s, 2H), 5.48 (m, 1H), 4.30-4.14 (m, 2H), 3.88 (s, 3H), 3.75 (t, J=4.6 Hz, 2H), 3.35 (d, J=3.1 Hz, 3H), 2.33 (s, 3H), 1.56 (d, J=7.1 Hz, 3H).
LC-MS: m/z 452 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.98 (d, J=7.8 Hz, 1H), 7.77 (s, 1H), 7.05 (s, 1H), 6.76 (d, J=1.7 Hz, 1H), 6.70 (s, 1H), 6.49 (s, 2H), 5.49 (p, J=7.0 Hz, 1H), 4.29-4.17 (m, 2H), 3.88 (s, 3H), 3.76 (t, J=4.6 Hz, 2H), 3.35 (s, 3H), 2.34 (s, 3H), 1.56 (d, J=7.1 Hz, 3H).
LC-MS: m/z 491 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.99 (d, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.87 (d, J=11.3 Hz, 2H), 6.69 (s, 1H), 5.57 (m, 3H), 4.23-4.05 (m, 2H), 3.87 (s, 3H), 3.70-3.58 (m, 2H), 3.29 (m, 1H), 2.35 (s, 3H), 2.02 (p, J=6.1 Hz, 2H), 1.55 (d, J=7.0 Hz, 3H), 0.55-0.36 (m, 4H).
LC-MS: m/z 493 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.00 (s, 1H), 7.90 (t, J=7.2 Hz, 1H), 7.72 (t, J=7.1 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.93 (t, J=7.0 Hz, 1H), 4.09 (m, 2H), 3.98 (s, 3H), 3.08 (m, 2H), 2.63 (s, 3H), 2.54 (s, 3H), 1.70 (d, J=7.0 Hz, 3H), 0.91-0.73 (m, 4H).
LC-MS: m/z 480 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.10 (d, J=6.9 Hz, 1H), 7.83-7.73 (m, 1H), 7.70 (s, 1H), 7.62 (t, J=6.9 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 5.83-5.68 (m, 1H), 4.68 (brs, 1H), 4.03 (m, 2H), 3.87 (s, 3H), 3.45 (m, 2H), 2.26 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 0.58 (s, 4H).
LC-MS: m/z 491 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=7.9 Hz, 1H), 7.67 (s, 1H), 7.02 (s, 1H), 6.86 (d, J=10.2 Hz, 2H), 6.69 (s, 1H), 5.64-5.46 (m, 3H), 3.97 (dd, J=36.2, 9.9 Hz, 2H), 3.88 (s, 3H), 3.36 (dd, J=19.9, 6.9 Hz, 2H), 3.26 (s, 3H), 2.35 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 0.63 (t, J=12.3 Hz, 4H).
LC-MS: m/z 454 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.87 (d, J=10.5 Hz, 2H), 6.70 (s, 1H), 5.67-5.40 (m, 3H), 4.27-4.09 (m, 2H), 3.87 (s, 3H), 3.79-3.68 (m, 2H), 2.36 (s, 3H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 491 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.75 (d, J=7.9 Hz, 1H), 7.54 (s, 1H), 6.84 (s, 1H), 6.68 (d, J=10.3 Hz, 2H), 6.51 (s, 1H), 5.45-5.21 (m, 3H), 4.09-3.94 (m, 2H), 3.68 (s, 3H), 3.62 (t, J=4.8 Hz, 2H), 3.16 (m, 2H), 2.17 (s, 3H), 1.36 (d, J=7.0 Hz, 3H), 0.37-0.20 (m, 2H), 0.01 (m, 2H).
LC-MS: m/z 495 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.07 (s, 1H), 7.85 (s, 1H), 7.04 (s, 1H), 6.86 (d, J=12.9 Hz, 2H), 6.70 (s, 1H), 5.67-5.46 (m, 3H), 4.98-4.77 (m, 1H), 3.87 (s, 3H), 3.67-3.49 (m, 4H), 3.32 (s, 6H), 2.37 (s, 3H), 1.55 (d, J=7.0 Hz, 3H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96 (d, J=7.7 Hz, 1H), 7.74 (s, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 6.48 (s, 2H), 5.57-5.40 (m, 1H), 4.70 (d, J=4.5 Hz, 3H), 4.46 (d, J=5.4 Hz, 2H), 4.23 (d, J=5.0 Hz, 2H), 3.89 (s, 3H), 3.80 (t, J=4.6 Hz, 2H), 2.33 (s, 3H), 1.56 (d, J=7.1 Hz, 3H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96 (d, J=7.9 Hz, 1H), 7.73 (s, 1H), 7.04 (s, 1H), 6.87 (d, J=10.6 Hz, 2H), 6.70 (s, 1H), 5.56 (m, 3H), 4.58 (d, J=6.5 Hz, 2H), 4.32 (d, J=6.6 Hz, 2H), 4.22 (dd, J=10.0, 5.0 Hz, 2H), 3.87 (s, 3H), 3.79 (t, J=5.0 Hz, 2H), 2.36 (s, 3H), 1.62-1.41 (m, 6H).
LC-MS: m/z 514 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.37 (s, 1H), 8.21 (d, J=3.5 Hz, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 7.50 (dd, J=8.4, 1.8 Hz, 1H), 7.37 (dd, J=8.3, 4.6 Hz, 1H), 7.06 (s, 1H), 6.87 (d, J=10.1 Hz, 2H), 6.70 (s, 1H), 5.76-5.47 (m, 3H), 4.60-4.34 (m, 4H), 3.87 (s, 3H), 2.38 (s, 3H), 1.56 (d, J=7.0 Hz, 3H).
LC-MS: m/z 505 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.01 (s, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.02 (s, 1H), 6.97-6.77 (m, 2H), 6.70 (s, 1H), 5.68-5.48 (m, 3H), 4.57 (dd, J=19.7, 6.3 Hz, 1H), 3.86 (s, 3H), 3.52 (t, J=9.7 Hz, 1H), 3.24 (m, 4H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.26 (m, 3H), 0.62 (m, 2H), 0.47 (m, 2H).
LC-MS: m/z 505 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.9 Hz, 2H), 6.69 (s, 1H), 5.56 (d, J=11.3 Hz, 3H), 4.18 (dd, J=10.6, 5.2 Hz, 2H), 3.87 (s, 3H), 3.67 (t, J=5.2 Hz, 2H), 2.35 (s, 3H), 2.17-2.03 (m, 2H), 1.82 (t, J=8.9 Hz, 2H), 1.71-1.47 (m, 5H), 1.33 (s, 3H).
LC-MS: m/z 505 (M+H)+.
LC-MS: m/z 505 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.28 (s, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.86 (d, J=9.7 Hz, 2H), 6.69 (s, 1H), 5.66-5.40 (m, 3H), 4.11 (m, 1H), 3.88 (m, 4H), 3.29 (s, 3H), 3.13 (m, 2H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.20 (d, J=6.4 Hz, 3H), 0.76-0.42 (m, 4H).
LC-MS: m/z 505 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.23 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.02 (s, 1H), 6.86 (d, J=10.9 Hz, 2H), 6.69 (s, 1H), 5.65-5.44 (m, 3H), 4.17 (d, J=10.2 Hz, 1H), 3.87 (s, 3H), 3.81 (d, J=10.2 Hz, 1H), 3.28 (s, 3H), 3.11 (m, 2H), 2.33 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.21 (d, J=6.4 Hz, 3H), 0.73-0.46 (m, 4H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=11.3 Hz, 2H), 6.69 (s, 1H), 5.56 (d, J=10.7 Hz, 3H), 4.32-4.09 (m, 3H), 3.87 (s, 3H), 3.81 (d, J=4.3 Hz, 2H), 3.77-3.61 (m, 4H), 2.35 (s, 3H), 1.95 (m, 2H), 1.54 (d, J=7.0 Hz, 3H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.86 (d, J=10.8 Hz, 2H), 6.69 (s, 1H), 5.55 (d, J=13.1 Hz, 3H), 4.33-4.08 (m, 3H), 3.87 (s, 3H), 3.81 (d, J=4.7 Hz, 2H), 3.70 (dt, J=9.9, 6.4 Hz, 4H), 1.95 (m, 2H), 1.54 (d, J=7.0 Hz, 3H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.04 (s, 1H), 6.86 (d, J=10.1 Hz, 2H), 6.70 (s, 1H), 5.68-5.44 (m, 3H), 4.79 (d, J=5.9 Hz, 1H), 4.75-4.62 (m, 2H), 4.44 (dd, J=9.5, 5.9 Hz, 2H), 4.02 (dd, J=8.9, 2.6 Hz, 2H), 3.88 (s, 4H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H).
LC-MS: m/z 507 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.94 (d, J=7.9 Hz, 1H), 7.68 (s, 1H), 7.04 (s, 1H), 6.87 (d, J=9.8 Hz, 2H), 6.70 (s, 1H), 5.56 (dd, J=14.5, 6.7 Hz, 3H), 4.86-4.75 (m, 1H), 4.69 (dd, J=14.7, 6.7 Hz, 2H), 4.44 (dd, J=9.5, 5.9 Hz, 2H), 4.01 (dd, J=9.5, 5.6 Hz, 2H), 3.89 (d, J=7.1 Hz, 4H), 2.35 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.10 (s, 1H), 7.79 (s, 1H), 7.06 (s, 1H), 6.84-6.65 (m, 2H), 6.49 (s, 2H), 5.58-5.38 (m, 1H), 4.77-4.65 (m, 3H), 4.45 (d, J=5.5 Hz, 2H), 4.22 (d, J=2.6 Hz, 2H), 3.90 (s, 3H), 3.80 (t, J=4.5 Hz, 2H), 2.36 (s, 3H), 1.57 (d, J=7.1 Hz, 3H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.23 (s, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.76 (s, 1H), 7.58 (t, J=6.6 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.22 (m, 1H), 7.03 (s, 1H), 5.80 (p, J=6.9 Hz, 1H), 5.34 (s, 1H), 4.24 (m, 2H), 3.87 (s, 3H), 3.77 (t, J=4.6 Hz, 2H), 3.36 (s, 3H), 2.28 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.3 Hz, 6H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.10 (d, J=7.2 Hz, 1H), 7.81 (s, 1H), 7.64 (t, J=6.5 Hz, 1H), 7.36 (t, J=6.8 Hz, 1H), 7.28 (m, 1H), 7.09 (s, 1H), 6.00-5.77 (m, 1H), 5.39 (s, 1H), 4.30 (d, J=3.4 Hz, 2H), 3.93 (s, 3H), 3.82 (t, J=4.2 Hz, 2H), 3.41 (s, 3H), 2.34 (s, 3H), 1.64 (d, J=6.9 Hz, 3H), 1.28 (d, J=11.1 Hz, 6H).
LC-MS: m/z 506 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.99 (d, J=7.5 Hz, 1H), 7.79 (s, 1H), 7.06 (s, 1H), 6.73 (d, J=22.6 Hz, 2H), 6.49 (s, 2H), 5.57-5.37 (m, 1H), 4.58 (d, J=6.2 Hz, 2H), 4.32 (d, J=6.3 Hz, 2H), 4.23 (s, 2H), 3.88 (s, 3H), 3.80 (s, 2H), 2.34 (s, 3H), 1.56 (d, J=6.9 Hz, 3H), 1.51 (s, 3H).
LC-MS: m/z 491 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.14 (s, 1H), 7.77 (s, 1H), 7.04 (s, 1H), 6.70 (d, J=10.8 Hz, 2H), 6.56 (s, 1H), 5.67-5.46 (m, 1H), 5.19 (s, 2H), 5.08 (s, 1H), 4.30-4.14 (m, 2H), 3.88 (s, 3H), 3.81-3.69 (m, 2H), 3.35 (s, 3H), 2.38 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.63 (d, J=5.0 Hz, 1H), 8.09 (d, J=7.5 Hz, 1H), 7.75 (s, 1H), 7.51 (s, 1H), 7.31 (d, J=4.0 Hz, 1H), 7.02 (s, 1H), 5.61 (t, J=7.2 Hz, 1H), 5.38 (s, 1H), 4.21 (d, J=2.7 Hz, 2H), 3.87 (s, 3H), 3.75 (t, J=4.6 Hz, 2H), 3.35 (s, 3H), 2.29 (s, 3H), 1.64 (d, J=7.1 Hz, 3H), 1.10 (d, J=6.5 Hz, 6H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.4 Hz, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.04 (s, 1H), 5.62 (t, J=7.2 Hz, 1H), 5.28 (s, 1H), 4.29-4.19 (m, 2H), 3.88 (s, 3H), 3.82-3.69 (m, 2H), 3.36 (s, 3H), 2.29 (s, 3H), 1.62 (d, J=7.1 Hz, 3H), 1.18 (d, J=7.7 Hz, 6H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.77 (s, 1H), 8.51 (d, J=1.6 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.03 (s, 1H), 5.69-5.51 (m, 1H), 5.40 (s, 1H), 4.28-4.10 (m, 2H), 3.87 (s, 3H), 3.80-3.68 (m, 2H), 3.35 (s, 3H), 2.33 (s, 3H), 1.66 (d, J=7.1 Hz, 3H), 1.14 (d, J=9.2 Hz, 6H).
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.56 (d, J=5.0 Hz, 1H), 8.06 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.52 (d, J=4.3 Hz, 1H), 7.04 (s, 1H), 5.58 (t, J=7.2 Hz, 1H), 5.26 (s, 1H), 4.22 (d, J=2.8 Hz, 2H), 3.88 (s, 3H), 3.76 (t, J=4.7 Hz, 2H), 3.36 (s, 3H), 2.30 (s, 3H), 1.61 (d, J=7.1 Hz, 3H), 1.18 (d, J=5.4 Hz, 6H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.3 Hz, 1H), 7.75 (s, 1H), 7.65-7.52 (m, 1H), 7.37-7.31 (m, 1H), 7.23 (t, J=9.4 Hz, 1H), 7.02 (s, 1H), 5.75 (t, J=7.1 Hz, 1H), 5.20 (s, 1H), 4.29-4.15 (m, 2H), 3.87 (s, 3H), 3.80-3.71 (m, 2H), 3.36 (s, 3H), 2.29 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 1.08 (s, 3H), 0.99 (s, 3H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.98 (d, J=7.7 Hz, 1H), 7.69 (s, 1H), 7.44-7.32 (m, 2H), 7.10 (d, J=9.3 Hz, 1H), 7.03 (s, 1H), 5.60 (t, J=7.2 Hz, 1H), 5.30 (s, 1H), 4.22 (dd, J=5.3, 3.5 Hz, 2H), 3.87 (s, 3H), 3.82-3.73 (m, 2H), 3.35 (s, 3H), 2.32 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 1.12 (d, J=5.5 Hz, 6H).
LC-MS: m/z 494 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.97 (d, J=7.7 Hz, 1H), 7.68 (s, 1H), 7.55 (m, 2H), 7.21 (dd, J=11.1, 8.6 Hz, 1H), 7.02 (s, 1H), 5.59 (t, J=7.2 Hz, 1H), 5.27 (s, 1H), 4.24-4.16 (m, 2H), 3.87 (s, 3H), 3.81-3.72 (m, 2H), 3.35 (s, 3H), 2.34 (s, 3H), 1.59 (d, J=7.1 Hz, 3H), 1.15 (s, 6H).
LC-MS: m/z 513 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.94 (t, J=18.5 Hz, 1H), 7.75 (s, 1H), 7.04 (s, 1H), 6.85 (t, J=16.3 Hz, 2H), 6.70 (s, 1H), 5.56 (dd, J=16.5, 9.2 Hz, 3H), 4.35-4.19 (m, 2H), 4.08-3.92 (m, 3H), 3.88 (s, 3H), 2.36 (s, 3H), 1.82-1.47 (m, 5H).
LC-MS: m/z 467 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.88 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.60 (s, 1H), 6.47 (d, J=16.9 Hz, 1H), 6.32 (d, J=11.2 Hz, 1H), 5.59-5.40 (m, 3H), 4.28-4.14 (m, 2H), 3.87 (s, 3H), 3.75 (t, J=4.7 Hz, 2H), 3.34 (d, J=12.2 Hz, 3H), 2.35 (s, 3H), 1.51 (t, J=11.5 Hz, 3H).
LC-MS: m/z 447 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.05 (d, J=7.7 Hz, 1H), 7.93 (s, 1H), 7.79-7.61 (m, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.32 (s, 2H), 7.03 (s, 1H), 5.67 (m, 1H), 4.22 (dd, J=7.1, 4.2 Hz, 2H), 3.87 (s, 3H), 3.75 (t, J=4.7 Hz, 2H), 3.35 (s, 3H), 2.35 (s, 3H), 1.61 (d, J=7.1 Hz, 3H).
LC-MS: m/z 448 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.01 (d, J=7.9 Hz, 1H), 7.72 (s, 1H), 7.66-7.52 (m, 2H), 7.51-7.33 (m, 2H), 7.03 (s, 1H), 5.63 (m, 2H), 4.22 (d, J=2.5 Hz, 2H), 3.94-3.71 (m, 7H), 3.35 (s, 3H), 2.35 (s, 3H), 1.60 (d, J=7.1 Hz, 3H).
LC-MS: m/z 538 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.31 (s, 1H), 7.85 (s, 1H), 7.62 (t, J=6.8 Hz, 1H), 7.27 (dt, J=15.5, 7.3 Hz, 2H), 7.06 (s, 1H), 5.91-5.77 (m, 1H), 5.32 (s, 1H), 4.31-4.17 (m, 4H), 3.83-3.66 (m, 4H), 3.38 (m, 6H), 2.32 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 1.23 (d, J=10.7 Hz, 6H).
LC-MS: m/z 506 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.97 (d, J=7.9 Hz, 1H), 7.72 (s, 1H), 7.15 (d, J=13.3 Hz, 2H), 7.04 (s, 1H), 6.87 (s, 1H), 5.68-5.53 (m, 1H), 5.22 (s, 1H), 4.29-4.12 (m, 2H), 3.88 (s, 3H), 3.75 (d, J=7.3 Hz, 5H), 3.36 (s, 3H), 2.35 (s, 3H), 1.61 (d, J=7.0 Hz, 3H), 1.14 (s, 6H).
LC-MS: m/z 510 (M+H)+. H NMR (400 MHZ, DMSO) δ 8.13 (d, J=7.1 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J=6.6 Hz, 1H), 7.43-7.27 (m, 2H), 7.02 (s, 1H), 5.95 (t, J=7.0 Hz, 1H), 5.30 (s, 1H), 4.26 (dd, J=9.7, 4.7 Hz, 2H), 3.87 (s, 3H), 3.77 (t, J=4.6 Hz, 2H), 3.37 (s, 3H), 2.25 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.26 (d, J=13.6 Hz, 6H).
LC-MS: m/z 489 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.52 (d, J=7.1 Hz, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.59 (t, J=6.6 Hz, 1H), 7.32 (t, J=6.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.79 (p, J=6.8 Hz, 1H), 5.30 (s, 1H), 4.40 (dd, J=5.0, 2.9 Hz, 2H), 3.89-3.75 (m, 2H), 3.39 (s, 3H), 2.33 (s, 3H), 1.62 (d, J=7.0 Hz, 3H), 1.22 (d, J=10.4 Hz, 6H).
LC-MS: m/z 490 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.07 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.30-7.14 (m, 2H), 7.01 (s, 1H), 5.79 (t, J=7.1 Hz, 1H), 5.24 (s, 1H), 4.32-4.18 (m, 2H), 3.86 (s, 3H), 3.76 (t, J=4.6 Hz, 2H), 3.36 (s, 3H), 2.63 (s, 3H), 2.30 (s, 3H), 1.52 (d, J=6.9 Hz, 3H), 1.22 (d, J=10.1 Hz, 6H).
LC-MS: m/z 501 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.03 (d, J=10.3 Hz, 2H), 7.87 (s, 1H), 7.70 (d, J=11.1 Hz, 2H), 7.03 (s, 1H), 5.58 (dd, J=14.1, 7.0 Hz, 1H), 5.41 (s, 1H), 4.22 (dd, J=5.5, 3.6 Hz, 2H), 3.87 (s, 3H), 3.82-3.71 (m, 2H), 3.36 (s, 3H), 2.31 (s, 3H), 1.62 (d, J=7.1 Hz, 3H), 1.12 (d, J=10.2 Hz, 6H).
LC-MS: m/z 536 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04 (d, J=7.4 Hz, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.29 (d, J=6.7 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.04 (s, 1H), 5.80 (s, 1H), 5.33 (s, 1H), 4.76-4.62 (m, 3H), 4.46 (dd, J=5.7, 3.6 Hz, 2H), 4.24 (dd, J=8.0, 4.2 Hz, 2H), 3.88 (s, 3H), 3.81 (t, J=4.6 Hz, 2H), 2.29 (s, 3H), 1.58 (d, J=7.0 z, 3H), 1.22 (d, J=11.2 Hz, 6H).
LC-MS: m/z 520 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.02 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.29 (d, J=6.7 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.03 (s, 1H), 5.81 (d, J=7.2 Hz, 1H), 5.32 (s, 1H), 4.23 (dd, J=7.5, 4.4 Hz, 2H), 3.86 (d, J=6.5 Hz, 5H), 3.43 (td, J=5.9, 3.0 Hz, 1H), 2.28 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.0 Hz, 6H).
LC-MS: m/z 464 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.21 (d, J=7.3 Hz, 1H), 7.84 (d, J=2.4 Hz, 1H), 7.59 (t, J=6.6 Hz, 1H), 7.53 (d, J=9.1 Hz, 1H), 7.38 (dd, J=9.1, 2.5 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 5.80 (t, J=7.1 Hz, 1H), 5.32 (s, 1H), 4.25 (d, J=3.1 Hz, 2H), 3.75 (t, J=4.5 Hz, 2H), 3.36 (s, 3H), 2.30 (s, 3H), 1.59 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.3 Hz, 6H).
LC-MS: m/z 542 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.39 (d, J=7.0 Hz, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.59 (t, J=6.6 Hz, 1H), 7.31 (t, J=6.6 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 5.80 (t, J=7.1 Hz, 1H), 5.31 (s, 1H), 4.34 (dd, J=7.2, 4.1 Hz, 2H), 3.81 (t, J=4.6 Hz, 2H), 3.40 (s, 3H), 2.31 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 1.22 (d, J=10.6 Hz, 6H).
LC-MS: m/z 480 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.71 (d, J=7.1 Hz, 1H), 7.59 (d, J=11.6 Hz, 2H), 7.28 (t, J=6.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 6.67 (s, 1H), 5.91-5.60 (m, 1H), 4.20 (d, J=4.0 Hz, 2H), 3.75 (t, J=4.5 Hz, 2H), 3.35-3.19 (m, 3H), 2.19 (s, 3H), 1.54 (d, J=6.9 Hz, 3H), 1.22 (d, J=11.8 Hz, 6H).
LC-MS: m/z 497 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.03 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.29 (d, J=6.8 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.02 (s, 1H), 5.84-5.76 (m, 1H), 5.42-5.20 (m, 1H), 4.24 (dd, J=7.6, 4.3 Hz, 2H), 3.76 (t, J=4.6 Hz, 2H), 3.36 (s, 3H), 2.28 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.22 (d, J=11.0 Hz, 6H).
LC-MS: m/z 508 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.03 (d, J=7.4 Hz, 1H), 7.76 (s, 1H), 7.58 (t, J=6.5 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.00 (s, 1H), 5.79 (t, J=7.1 Hz, 1H), 5.32 (s, 1H), 4.28-4.21 (m, 2H), 4.14 (q, J=6.9 Hz, 2H), 3.77 (t, J=4.7 Hz, 2H), 3.38 (s, 3H), 2.28 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.38 (t, J=6.9 Hz, 3H), 1.22 (d, J=11.2 Hz, 6H).
LC-MS: m/z 522 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.03 (d, J=7.4 Hz, 1H), 7.77 (s, 1H), 7.58 (t, J=6.5 Hz, 1H), 7.30 (t, J=6.6 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H), 7.01 (s, 1H), 5.79 (t, J=7.2 Hz, 1H), 5.31 (s, 1H), 4.79-4.67 (m, 1H), 4.24 (dd, J=6.0, 3.4 Hz, 2H), 3.76 (t, J=4.7 Hz, 2H), 3.38 (s, 3H), 2.28 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 1.32 (dd, J=5.6, 4.9 Hz, 6H), 1.22 (d, J=11.3 Hz, 6H).
LC-MS: m/z 520 (M+H)+.
LC-MS: m/z 541 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.82 (d, J=2.3 Hz, 1H), 8.61-8.56 (m, 1H), 8.32 (d, J=7.4 Hz, 1H), 8.08-8.01 (m, 1H), 7.95 (s, 1H), 7.65-7.58 (m, 2H), 7.49 (dd, J=7.9, 4.8 Hz, 1H), 7.32 (t, J=6.9 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.87-5.79 (m, 1H), 5.32 (s, 1H), 4.38-4.27 (m, 2H), 3.72 (t, J=4.7 Hz, 2H), 3.30 (s, 3H), 2.33 (s, 3H), 1.62 (d, J=7.0 Hz, 3H), 1.24 (s, 3H), 1.22 (s, 3H).
LC-MS: m/z 544 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.30 (s, 1H), 8.21 (d, J=7.4 Hz, 1H), 8.10 (s, 1H), 7.85 (s, 2H), 7.64-7.57 (m, 1H), 7.35-7.27 (m, 1H), 7.21 (t, J=7.7 Hz, 1H), 5.88-5.76 (m, 1H), 5.32 (s, 1H), 4.42-4.29 (m, 2H), 3.92-3.85 (m, 5H), 3.43 (s, 3H), 2.31 (s, 3H), 1.61 (d, J=7.1 Hz, 3H), 1.24 (s, 3H), 1.22 (s, 3H).
LC-MS: m/z 536 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.13 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.28 (d, J=6.5 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 6.63 (s, 1H), 5.78 (d, J=7.0 Hz, 1H), 5.42-5.30 (m, 1H), 4.99 (t, J=6.4 Hz, 2H), 4.58 (dd, J=12.2, 5.1 Hz, 2H), 4.27 (d, J=2.5 Hz, 2H), 3.79 (t, J=4.7 Hz, 2H), 3.39 (s, 4H), 2.26 (s, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.22 (d, J=11.0 Hz, 6H).
LC-MS: m/z 635 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.09 (d, J=7.4 Hz, 1H), 7.84 (s, 1H), 7.59 (t, J=6.6 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 6.77 (s, 1H), 5.88-5.72 (m, 1H), 5.10 (s, 1H), 4.63 (d, J=6.1 Hz, 1H), 4.44-4.21 (m, 4H), 3.81 (dd, J=13.2, 8.4 Hz, 4H), 3.40 (s, 3H), 2.30 (s, 3H), 1.59 (d, J=7.0 Hz, 3H), 1.40 (d, J=5.9 Hz, 9H), 1.23 (d, J=11.2 Hz, 6H).
LC-MS: m/z 535 (M+H)+.
LC-MS: m/z 549 (M+H)+.
LC-MS: m/z 577 (M+H)+.
LC-MS: m/z 557 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.52-8.37 (m, 1H), 8.24 (d, J=16.4 Hz, 1H), 8.02 (s, 1H), 7.60 (s, 1H), 7.45 (s, 2H), 7.31 (s, 1H), 7.23 (s, 1H), 7.05 (s, 1H), 5.79 (s, 1H), 5.32 (s, 1H), 4.26 (s, 2H), 3.62 (s, 2H), 3.22 (s, 3H), 2.28 (s, 3H), 1.59 (s, 3H), 1.21-1.14 (m, 6H).
LC-MS: m/z 482 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.28 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.59 (t, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.21 (d, J=8.0 Hz, 1H), 5.80 (m, 1H), 5.33 (s, 1H), 4.36-4.33 (m, 2H), 3.79 (t, J=4.0 Hz, 2H), 3.34 (s, 3H), 2.31 (s, 3H), 1.60 (d, J=8.0 Hz, 3H), 1.24 (s, 3H), 1.21 (s, 3H).
LC-MS: m/z 498 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.41 (d, J=8.0 Hz, 1H), 7.99 (s, 1H), 7.69 (s, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.24-7.20 (m, 1H), 5.80 (m, 1H), 5.34 (s, 1H), 4.36-4.33 (m, 2H), 3.81 (t, J=4.0 Hz, 2H), 3.39 (s, 3H), 2.51 (s, 3H), 1.61 (d, J=7.2 Hz, 3H), 1.24 (s, 3H), 1.21 (s, 3H).
LC-MS: m/z 532 (M+H)+.
LC-MS: m/z 548 (M+H)+.
LC-MS: m/z 535 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.89 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.03 (s, 1H), 6.70 (d, J=12.1 Hz, 2H), 6.56 (d, J=4.9 Hz, 1H), 5.61-5.47 (m, 1H), 5.15 (s, 3H), 4.27-4.14 (m, 4H), 3.83-3.62 (m, 4H), 3.36 (s, 3H), 3.34 (s, 3H), 2.34 (s, 3H), 1.53 (d, J=7.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 496 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.95 (d, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 6.46 (s, 2H), 5.54-5.36 (m, 1H), 4.23 (dt, J=10.2, 5.2 Hz, 4H), 3.74 (dt, J=11.1, 4.5 Hz, 4H), 3.36 (s, 3H), 3.34 (s, 3H), 2.32 (s, 3H), 1.56 (d, J=7.1 Hz, 3H).
LC-MS: m/z 554 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.37 (d, J=2.9 Hz, 1H), 8.20 (dd, J=4.6, 1.1 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.50 (dd, J=8.4, 1.7 Hz, 1H), 7.36 (dd, J=8.4, 4.6 Hz, 1H), 7.04 (s, 1H), 6.70 (d, J=10.3 Hz, 2H), 6.55 (s, 1H), 5.60-5.48 (m, 1H), 5.18 (s, 2H), 4.47 (dd, J=20.2, 3.9 Hz, 4H), 3.86 (s, 3H), 2.35 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 517 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.89 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.02 (s, 1H), 6.74-6.66 (m, 2H), 6.56 (t, J=1.9 Hz, 1H), 5.59-5.47 (m, 1H), 5.16 (s, 2H), 5.08 (s, 1H), 4.19 (dd, J=5.9, 4.0 Hz, 2H), 3.87 (s, 3H), 3.92-3.81 (m, 2H), 3.46-3.38 (m, 1H), 2.35 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.12 (s, 6H), 0.56-0.41 (m, 4H).
LC-MS: m/z 533 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.90 (d, J=8.1 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.74-6.66 (m, 2H), 6.56 (t, J=1.9 Hz, 1H), 5.59-5.47 (m, 1H), 5.17 (s, 2H), 5.09 (s, 1H), 4.76-4.62 (m, 3H), 4.50-4.40 (m, 2H), 4.20 (dd, J=5.8, 3.8 Hz, 2H), 3.88 (s, 3H), 3.79 (dd, J=5.8, 3.7 Hz, 2H), 2.35 (s, 3H), 1.54 (d, J=7.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 553 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.89 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.03 (s, 1H), 6.69 (d, J=11.5 Hz, 2H), 6.55 (s, 1H), 5.62-5.46 (m, 1H), 5.16 (s, 2H), 5.07 (s, 1H), 4.23 (d, J=4.5 Hz, 2H), 4.11-3.95 (m, 3H), 3.87 (s, 3H), 2.34 (s, 3H), 1.81-1.44 (m, 5H), 1.19-1.07 (m, 6H).
LC-MS: m/z 535 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.89 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.02 (s, 1H), 6.70 (d, J=11.6 Hz, 2H), 6.55 (s, 1H), 5.59-5.42 (m, 1H), 5.16 (s, 2H), 4.20 (t, J=4.8 Hz, 2H), 3.92-3.77 (m, 5H), 3.63 (dd, J=5.6, 3.9 Hz, 2H), 3.48 (dd, J=5.6, 3.8 Hz, 2H), 3.26 (s, 3H), 2.34 (s, 4H), 1.53 (d, J=7.0 Hz, 3H), 1.10 (d, J=10.9 Hz, 6H).
LC-MS: m/z 533 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 10.01 (s, 1H), 8.03 (s, 1H), 7.75 (d, J=12.1 Hz, 2H), 7.61 (s, 1H), 7.26 (s, 1H), 7.04 (s, 1H), 5.65-5.51 (m, 1H), 5.19 (s, 1H), 4.27-4.15 (m, 2H), 3.88 (s, 3H), 3.81-3.70 (m, 2H), 3.37 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H), 1.60 (d, J=7.1 Hz, 3H), 1.14 (s, 6H).
LC-MS: m/z 549 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 9.70 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.72 (s, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 5.65-5.51 (m, 1H), 5.17 (s, 1H), 4.30-4.15 (m, 2H), 3.87 (s, 3H), 3.79-3.71 (m, 2H), 3.64 (s, 3H), 2.34 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 535 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.90 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.03 (s, 1H), 6.72 (d, J=12.9 Hz, 2H), 6.58 (s, 1H), 5.56 (d, J=7.3 Hz, 1H), 5.16 (s, 2H), 5.06 (s, 1H), 4.96-4.83 (m, 1H), 3.88 (s, 3H), 3.69-3.52 (m, 4H), 3.30 (s, 6H), 2.36 (s, 3H), 1.55 (d, J=7.0 Hz, 3H), 1.13 (d, J=2.7 Hz, 6H).
LC-MS: m/z 527 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 13.05 (s, 1H), 8.14 (s, 2H), 7.82 (d, J=23.4 Hz, 2H), 6.98 (s, 1H), 6.73 (d, J=10.4 Hz, 2H), 6.57 (s, 1H), 5.64-5.50 (m, 1H), 5.16 (s, 2H), 5.08 (s, 1H), 4.34 (s, 2H), 3.85 (s, 2H), 3.39 (s, 3H), 2.39 (s, 3H), 1.58 (d, J=6.9 Hz, 3H), 1.13 (s, 6H).
LC-MS: m/z 486 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.41 (d, J=7.9 Hz, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 6.74-6.66 (m, 2H), 6.57 (t, J=1.9 Hz, 1H), 5.60-5.50 (m, 1H), 5.19 (s, 2H), 5.10 (s, 1H), 4.41-4.33 (m, 2H), 3.83-3.76 (m, 2H), 3.38 (s, 3H), 2.39 (s, 3H), 1.57 (d, J=7.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 509 (M+H)+.
LC-MS: m/z 535 (M+H)+.
LC-MS: m/z 551 (M+H)+.
LC-MS: m/z 525 (M+H)+.
LC-MS: m/z 535 (M+H)+.
LC-MS: m/z 567 (M+H)+.
LC-MS: m/z 476 (M+H)+.
LC-MS: m/z 502 (M+H)+.
LC-MS: m/z 518 (M+H)+.
LC-MS: m/z 438 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.86 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.04 (s, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.79 (s, 2H), 5.38-5.34 (m, 1H), 4.23-4.21 (m, 2H), 3.88 (s, 3H), 3.76-3.74 (m, 2H), 3.35 (s, 3H), 2.35 (s, 3H), 1.50 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.24-1.12 (m, 2H), 0.65 (m, 2H).
LC-MS: m/z 464 (M+H)+. 1H NMR (400 MHZ, DMSO) & 7.86 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.04 (s, 1H), 6.37 (d, J=1.6 Hz, 1H), 6.29 (s, 1H), 5.79 (s, 2H), 5.46-5.17 (m, 1H), 4.28-4.13 (m, 2H), 3.95-3.78 (m, 5H), 3.46-3.35 (m, 1H), 2.35 (s, 3H), 1.50 (d, J=6.9 Hz, 3H), 1.38 (s, 3H), 1.15 (m 2H), 0.65 (m, 2H), 0.56-0.36 (m, 4H).
LC-MS: m/z 480 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.88 (m, 1H), 7.64 (s, 1H), 7.05 (s, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.79 (s, 2H), 5.37 (m, 1H), 4.72-4.69 (m, 3H), 4.46-4.42 (m, 2H), 4.22 (m, 2H), 3.89 (s, 3H), 3.81-3.79 (m, 2H), 2.35 (s, 3H), 1.49 (d, J=8.0 Hz, 3H), 1.38 (s, 3H), 1.19 (m, 2H), 0.66 (m, 2H).
LC-MS: m/z 442 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96-7.94 (m, 2H), 7.74 (s, 1H), 6.97 (s, 1H), 6.52 (d, J=8.0 Hz, 1H), 6.24 (d, J=8.0 Hz, 1H), 6.14 (s, 2H), 4.19 (m, 2H), 3.85 (s, 3H), 3.74-3.72 (m, 2H), 3.35 (s, 3H), 2.28 (s, 3H), 1.88 (m, 1H), 1.62-1.57 (m, 2H), 1.48 (d, J=8.0 Hz, 3H), 0.93 (m, 1H).
LC-MS: m/z 480 (M+H)+.
LC-MS: m/z 506 (M+H)+.
LC-MS: m/z 522 (M+H)+.
LC-MS: m/z 506 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.04-8.01 (m, 1H), 7.75 (s, 1H), 7.64-7.60 (m, 1H), 7.40-7.37 (m, 1H), 7.25-7.22 (m, 1H), 7.03 (s, 1H), 5.81-5.75 (m, 1H), 4.54-4.48 (m, 1H), 4.26-4.23 (m, 2H), 3.87 (s, 3H), 3.78-3.74 (m, 4H), 3.36 (s, 3H), 2.29 (s, 3H), 2.03-1.94 (m, 2H), 1.85-1.82 (m, 2H), 1.59 (d, J=4 Hz, 2H)
LC-MS: m/z 506 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.03-8.01 (m, 1H), 7.75 (s, 1H), 7.64-7.60 (m, 1H), 7.40-7.37 (m, 1H), 7.25-7.22 (m, 1H), 7.03 (s, 1H), 5.81-5.75 (m, 1H), 4.54-4.48 (m, 1H), 4.26-4.23 (m, 2H), 3.87 (s, 3H), 3.76-3.74 (m, 4H), 3.36 (s, 3H), 2.29 (s, 3H), 2.03-1.94 (m, 2H), 1.86-1.82 (m, 2H), 1.59 (d, J=4 Hz, 2H)
LC-MS: m/z 536 (M+H)+.
LC-MS: m/z 512 (M+H)+.
LC-MS: m/z 538 (M+H)+.
LC-MS: m/z 554 (M+H)+.
Step 1: Methyl 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate (1.2 g), ethyl cyanoformate (0.932 g) and a 2 M solution of HCl in dioxane (20 mL) were heated in a sealed tube for 20 h, and then concentrated under reduced pressure. DMF and DBU were added to the residue to dissolve the solid. The mixture was then separated by preparative liquid chromatography to give the target product (230 mg, yield: 15%). LC-MS: m/z 323 (M+H)+.
Step 2: Ethyl 4-hydroxy-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-carboxylate (230 mg) was dissolved in DMF (5 mL), DBU (540 mg) was added, and BOP (628 mg) was added slowly in an ice-water bath. The mixture was stirred at room temperature for 1 h, and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (201 mg) was then added. The mixture was stirred at 100° C. for 16 h, and then separated by preparative liquid chromatography to give the target product (150 mg, yield: 39%). LC-MS: m/z 540 (M+H)+.
Step 3: Ethyl 4-hydroxy-7-methoxy-6-(2-methoxyethoxy)quinazoline-2-carboxylate (20 mg, 0.04 mmol) was added to ethanol (5 mL) and water (2 mL), and ammonium chloride (42 mg, 0.80 mmol) and iron powder (23 mg, 0.40 mmol) were added successively. The mixture was heated to 80° C., stirred for 3 h, and then separated by preparative liquid chromatography to give the target product.
LC-MS: m/z 495 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.29 (d, J=7.5 Hz, 1H), 7.81 (s, 1H), 7.27 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.56 (m, 3H), 4.28 (d, J=6.6 Hz, 4H), 3.93 (s, 3H), 3.77 (m, 2H), 3.36 (s, 3H), 1.58 (d, J=6.6 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H).
LC-MS: m/z 467 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.39 (d, J=7.4 Hz, 1H), 7.83 (s, 1H), 7.29 (s, 1H), 6.90 (s, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 5.80-5.67 (m, 1H), 5.54 (s, 2H), 4.27 (d, J=4.5 Hz, 2H), 3.92 (s, 3H), 3.77 (t, J=4.4 Hz, 2H), 3.51 (s, 3H), 1.58 (d, J=7.0 Hz, 3H).
LC-MS: m/z 466 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.22 (d, J=8.0 Hz, 1H), 7.82 (s, 2H), 7.46 (s, 1H), 7.23 (s, 1H), 6.91 (s, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 5.73-5.58 (m, 1H), 5.51 (s, 2H), 4.27 (d, J=4.1 Hz, 2H), 3.92 (s, 3H), 3.77 (t, J=4.5 Hz, 2H), 3.36 (s, 3H), 1.57 (d, J=7.1 Hz, 3H).
Methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (10 g) was dispersed in MeOH (100 mL), and palladium on carbon (10% wt, 1.5 g) was added. The system was purged three times with hydrogen. The mixture was stirred at room temperature overnight. THF was added to the reaction solution to dissolve the solid, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the target product (8.0 g, yield: 92%). which was used directly in the next step without purification. LC-MS: m/z 198 (M+H)+.
A mixture of methyl 2-amino-5-hydroxy-4-methylbenzoate (6 g), cyclopropanecarbonitrile (6.1 g) and a 4 M solution of HCl in dioxane (100 mL) was heated to 110° C. and stirred overnight. The resulting reaction solution was cooled and filtered. The filter cake was collected and air-dried to give the target product (6.0 g, yield: 85%). which was used directly in the next step without purification. LC-MS: m/z 233 (M+H)+.
A mixture of 2-cyclopropyl-7-methoxyquinazoline-4,6-diol (400 mg), methyl p-toluenesulfonate (500 mg), potassium carbonate (476 mg) and DMF (5 mL) was heated to 100° C. and stirred overnight. The resulting mixture was separated by medium-pressure column chromatography to give the target product (50 mg, yield: 12%). LC-MS: m/z 247 (M+H)+.
2-Cyclopropyl-6,7-dimethoxyquinazolin-4-ol (50 mg) was dissolved in DMF (5 mL), DBU (152 mg) was added, and then BOP (177 mg) was added slowly with cooling in an ice-water bath. The resulting mixture was stirred at room temperature for 1 h, and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (49 mg) was then added. The reaction mixture was stirred at 100° C. for 16 h, then cooled, and separated by preparative chromatography to give the target product (21 mg, yield: 26%). LC-MS: m/z 433 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.96 (d, J=6.9 Hz, 1H), 7.68 (s, 1H), 6.98 (s, 1H), 6.83 (s, 1H), 6.79-6.76 (m, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 5.39-5.22 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 1.86 (dd, J=8.2, 3.6 Hz, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.98 (d, J=4.6 Hz, 1H), 0.85-0.55 (m, 3H).
The following compounds were synthesized in the same manner as the compound of Example 149 with different starting materials:
LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 7.93 (d, J=7.1 Hz, 1H), 7.70 (s, 1H), 6.99 (s, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 5.30 (t, J=7.0 Hz, 1H), 4.21 (dd, J=8.5, 4.3 Hz, 2H), 3.87 (s, 3H), 3.75 (t, J=4.6 Hz, 2H), 1.86 (m, 1H), 1.53 (d, J=7.0 Hz, 3H), 0.98 (m, 1H), 0.84-0.57 (m, 3H).
LC-MS: m/z 527 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.38 (s, 1H), 7.90 (s, 1H), 7.09 (s, 1H), 6.87 (d, J=14.5 Hz, 2H), 6.69 (s, 1H), 5.59-5.35 (m, 3H), 4.27 (dd, J=9.9, 4.8 Hz, 2H), 3.89 (s, 3H), 3.76 (t, J=4.6 Hz, 2H), 3.35 (s, 4H), 2.91-2.72 (m, 4H), 1.60 (d, J=7.0 Hz, 3H).
LC-MS: m/z 567 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.06 (d, J=7.3 Hz, 1H), 7.75 (s, 1H), 7.07 (s, 1H), 6.69 (s, 2H), 6.56 (s, 1H), 5.58-5.38 (m, 1H), 5.13 (s, 2H), 5.05 (s, 1H), 4.22 (d, J=5.3 Hz, 2H), 3.89 (s, 3H), 3.81-3.70 (m, 2H), 3.37 (s, 3H), 3.26-3.20 (m, 1H), 2.94-2.72 (m, 4H), 1.56 (d, J=7.0 Hz, 3H), 1.09 (s, 6H).
In an argon atmosphere, (R)-1-(3-(1-(7-bromo-6-(2-methoxyethoxy)-2-methylquinazoline-4-amino)ethyl)-2-fluoropheny 1)-1,1-difluoro-2-methylpropan-2-ol (100 mg, 0.18 mmol) was added to dioxane (5 mL), and triethylamine (56 mg, 0.55 mmol), cuprous iodide (20 mg), Pd(PPh3)2Cl2 (20 mg), and ethynyltrimethylsilane (54 mg, 0.55 mmol) were added at room temperature. The reaction solution was microwaved to 80° C., reacted for 2 h, and then concentrated under reduced pressure to give the target product (120 mg). which was used directly in the next step without purification.
(R)-1,1-difluoro-1-(2-fluoro-3-(1-((6-(2-methoxyethoxy)-2-methyl-7-((trimethylsilyl)ethynyl)q uinazolin-4-yl)amino)ethyl)phenyl)-2-methylpropan-2-ol (120 mg, 0.21 mmol) obtained in the last step was added to methanol (5 mL) at room temperature, and potassium fluoride (38 mg, 0.64 mmol) was then added. The resulting reaction solution was stirred at room temperature for 1 h, and then concentrated under reduced pressure. The residue was separated by preparative liquid chromatography to give the target product (65 mg, yield: 64%).
LC-MS: m/z 488 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.32 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.72-7.52 (m, 3H), 7.31 (t, J=6.6 Hz, 1H), 7.23 (dd, J=24.6, 16.9 Hz, 1H), 5.79 (t, J=7.1 Hz, 1H), 5.31 (s, 1H), 4.48 (s, 1H), 4.38-4.22 (m, 2H), 3.79 (t, J=4.7 Hz, 2H), 3.39 (s, 3H), 2.30 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 1.22 (d, J=10.9 Hz, 6H).
The following compounds were synthesized in the same manner as the compound of Example 153 with different starting materials:
LC-MS: m/z 502 (M+H)+.
LC-MS: m/z 528 (M+H)+.
LC-MS: m/z 514 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.32 (d, J=7.2 Hz, 1H), 7.84 (s, 1H), 7.64 (s, 1H), 7.59 (t, J=6.6 Hz, 1H), 7.31 (t, J=6.7 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 5.78 (dd, J=14.1, 7.0 Hz, 1H), 5.30 (s, 1H), 4.48 (s, 1H), 4.28 (t, J=6.7 Hz, 2H), 3.89 (t, J=4.6 Hz, 2H), 3.49 (m, 1H), 2.30 (s, 3H), 1.60 (d, J=7.0 Hz, 3H), 1.22 (d, J=10.8 Hz, 6H), 0.65-0.39 (m, 4H).
LC-MS: m/z 530 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.34 (d, J=8 Hz, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.59 (m, 1H), 7.31 (m, 1H), 7.23-7.21 (m, 1H), 5.79 (m, 1H), 5.37 (brs, 1H), 4.74-4.72 (m, 3H), 4.53 (s, 1H), 4.48-4.46 (m, 2H), 4.31-4.30 (m, 2H), 3.84 (t, J=4.0 Hz, 2H), 2.30 (s, 3H), 1.60 (d, J=8.0 Hz, 3H), 1.22 (d, J=8.0 Hz, 6H).
LC-MS: m/z 500 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.32 (d, J=6.5 Hz, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.58 (t, J=6.6 Hz, 1H), 7.31 (t, J=6.6 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.80 (t, J=7.1 Hz, 1H), 5.30 (d, J=8.2 Hz, 1H), 5.28 (m, 1H), 4.49 (s, 1H), 4.04 (dd, J=10.2, 4.6 Hz, 1H), 3.97-3.77 (m, 3H), 2.43-2.24 (m, 4H), 2.11-1.97 (m, 1H), 1.61 (d, J=7.0 Hz, 3H), 1.22 (d, J=10.5 Hz, 6H).
LC-MS: m/z 551 (M+H)+.
LC-MS: m/z 565 (M+H)+.
LC-MS: m/z 521 (M+H)+.
LC-MS: m/z 569 (M+H)+.
LC-MS: m/z 485 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.18 (d, J=8 Hz, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 6.71-6.68 (m, 2H), 6.56 (s, 1H), 5.56-5.52 (m, 1H), 5.17 (s, 2H), 5.06 (s, 1H), 4.45 (s, 1H), 4.28-4.26 (m, 2H), 3.78-3.76 (m, 2H), 3.38 (s, 3H), 2.36 (s, 3H), 1.56 (d, J=4.0 Hz, 3H), 1.12 (s, 6H).
LC-MS: m/z 497 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.22 (m, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 6.56 (s, 1H), 5.57 (m, 1H), 5.23-5.20 (m, 3H), 5.08 (s, 1H), 4.00 (m, 1H), 3.92-3.82 (m, 3H), 2.37 (s, 3H), 2.32-2.30 (m, 1H), 1.56 (d, J=8.0 Hz, 3H), 1.11 (s, 6H).
LC-MS: m/z 506 (M+H)+.
LC-MS: m/z 445 (M+H)+.
LC-MS: m/z 457 (M+H)+.
LC-MS: m/z 471 (M+H)+.
LC-MS: m/z 487 (M+H)+.
LC-MS: m/z 539 (M+H)+. 1H NMR (400 MHZ, DMSO) δ 8.67 (d, J=7.3 Hz, 1H), 8.27 (s, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.74 (dd, J=9.4, 2.6 Hz, 1H), 7.60 (t, J=6.7 Hz, 1H), 7.32 (t, J=6.8 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H), 6.52 (d, J=9.4 Hz, 1H), 5.81 (t, J=7.1 Hz, 1H), 5.32 (s, 1H), 4.81 (s, 1H), 3.54 (s, 3H), 2.39 (s, 3H), 1.58 (d, J=7.0 Hz, 3H), 1.22 (d, J=10.0 Hz, 6H).
The following biological test examples are further described to explain the present invention, but these examples are not intended to limit the scope of the present invention.
(2) 5 μL of Tag1-SOS1 solution was added to the test plate, and 5 μL of dilution buffer was added to the control group.
(3) 5 μL of Tag2-KRASG12C solution was added to the test plate.
(4) 10 μL of Anti-Tag1-Tb3+ and Anti-Tag2-XL665 detection solution were added to the test plate. The plate was centrifuged at 1000 rpm for 1 min and incubated at room temperature for 2 h.
(5) The plate was read.
(6) The IC50 values for the compounds were finally calculated using GraphPad Prism software, and a curve was fit and plotted.
The inhibitory activity of the compounds of the examples of the present invention on the binding of KRASG12C enzyme to SOS1 is shown in Table 1.
As can be seen from Table 1:
The compounds of the examples of the present invention showed good inhibitory activity against the binding of KRASG12C to SOS1.
The diluted test compounds were added to a 384-well cell culture plate using a nanoliter pipetting system, and duplicate wells were set. An equal volume of medium was added to the positive control group; an equal volume of DMSO was added to the negative control group. The plate was centrifuged at 1000 rpm at room temperature for 1 min.
The cells were inoculated into a) 384-well culture plate, an equal volume of cells was added to the negative control group, and only an equal volume of medium was added to the positive control group. The plate was centrifuged at 1000 rpm at room temperature for 1 min. The final concentration of DMSO in the final compounds was 0.5%. The plate was incubated in a thermostatic incubator at 37° C. with 5% CO2 for 7 days.
CellTiter-Glo® 3D was added to b) 384-well cell culture plate at 20 μL/well. The plate was shaken at 320 rpm in the dark for 20 min, and incubated at room temperature in the dark for 2 h. The luminescence values were read using an Envision multi-mode microplate reader.
The inhibition rates (IRs) of the test compounds were calculated according to the following formula: IR (%)=(1−(RLU compound−RLU blank control)/(RLU vehicle control−RLU blank control))×100%. The inhibition rates of the compounds at different concentrations were calculated in Excel, and then inhibition curves were plotted and relevant parameters including minimum inhibition rate, maximum inhibition rate and IC50 were calculated using GraphPad Prism software. The experimental results are shown in Table 3.
Male SD rats weighing about 220 g were fasted overnight and then intragastrically administered solutions of the compounds of the present invention [CMC/TW80 as a carrier] at 10 mg/kg. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 36, and 48 h after administration of the compounds of the present invention, and the plasma concentrations of the compounds of the present invention were determined by LC/MS/MS.
As can be seen from the results, the compounds of the present invention have good pharmacokinetic properties.
100 μL of a suspension containing 5×106 MIA PaCa-2 tumor cells was subcutaneously inoculated into the right posterior abdomens of nude mice. The health of the mice was monitored daily, and measurements were started when tumors grew to be palpable. The tumor volume was calculated as follows: 0.5×L×W2, where L and W represent the length and width of the tumor, respectively. When the tumors grew to about 100 mm3, the mice were randomized into groups. The mice were intragastrically administered a corresponding dose (50 mg/kg) of compound suspension in CMC-Na twice daily, and their general states were monitored at the same time. The tumors were measured 3 times a week, and the body weight was measured twice a week. The test results are shown in Table 4.
The structure of the reference compound BI3406:
As can be seen from the results, the compounds of the present invention have better anti-tumor effects than the reference compound BI3406.
All documents mentioned in the present invention are incorporated as references, just as each document is individually cited as a reference. In addition, it should be understood that various modifications or changes may be made by those skilled in the art after reading the above teachings of the present invention, and these equivalent forms also fall within the scope defined by the claims appended hereto.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011128302.9 | Oct 2020 | CN | national |
| 202110178999.9 | Feb 2021 | CN | national |
| 202110790488.2 | Jul 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/125084 | 10/20/2021 | WO |
