Patent Application
20230026425
The present disclosure belongs to the field of medicinal chemistry, and particularly relates to acylamino bridged heterocyclic compounds, or isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, and to pharmaceutical compositions thereof, and their use in the preparation of medicaments for the treatment of autoimmune diseases, tumors and neurodegenerative diseases related to receptor-interacting protein 1 kinase (RIPK1).
In the early days, it was thought that there are two main ways of cell death, i.e., apoptosis and necrosis. Apoptosis is the autonomous and orderly death of cells controlled by genes in order to maintain the stability of the body's internal environment. It plays an important role in the evolution of the organism, the stability of the internal environment, and the development of the system. Cell necrosis is a pathological process in which cells are affected by physical, chemical and other environmental factors, such as mechanical damage, poisons, microorganisms, radiation, etc., causing cell death. In 2005, Degterev A et al. first discovered and reported an orderly cell necrosis process regulated by a series of biochemical molecules, and named it Necroptosis (also known as programmed necrosis). This process is a kind of programmed cell necrosis produced by stimulating death receptors with TNF-α, FasL or TRAIL. Morphologically, it is manifested as cell swelling, cell volume increasing, organelle dysfunction, damage to cell membrane integrity, release of cell contents, and mass production of ROS.
Receptor-interacting protein 1 kinase (RIPK1) belongs to the TKL family of serine/threonine protein kinases. Members of the RIPK serine/threonine kinase family have the same N-terminal kinase domain, but different binding domains. Studies have shown that receptor-interacting protein 1 can regulate the process of cell apoptosis. The death domain of RIPK-1 binds to death receptors such as TNFR1, Fas, TRAILR1, TRAILR2, etc., and they can also bind to other proteins containing death domains, such as TRADD, FADD, etc. Binding with the latter is a necessary condition for activating caspase-8 and inducing apoptosis. The intermediate structure of RIPK-1 is the RIPK isotype interaction target, through which RIPK-1 can interact with RIPK-3. Kelliher et al. found that mice with congenital defects of RIPK-1 died less than 3 days after birth due to a large number of cell apoptosis, which indicates that RIPK-1 is also involved in regulating cell apoptosis. In addition, cells with congenital RIPK-1 deficiency are quite sensitive to TNF-induced cell death, perhaps because such cells cannot effectively activate NF-kB.
On the other hand, studies have also shown that RIPK-1 and RIPK-3 are also involved in the process of cell necroptosis. In most cell types, death receptors TNFR1, Fas and TRAILR mediate cell apoptosis. Activating TNFR1 can trigger the ubiquitination of RIPK-1 through cIAP1 and cIAP2, and the ubiquitinated RIPK-1 determines whether the cell will continue to survive or die. When the apoptosis pathway is blocked by the pan-caspase inhibitor z-VAD-fmk, cell death will move toward to necroptosis. In this process, the activity of RIPK-1 is a key factor, which is regulated by FasL, TNF and TRAIL death receptors.
Recent studies have shown that the process of necroptosis is related to a variety of diseases, including tumors, autoimmune diseases, degenerative diseases, inflammatory diseases and the like. Based on this, it can be known that RIP family kinases are closely related to the occurrence of tumors, autoimmune diseases, degenerative diseases, inflammatory diseases and other diseases.
For example, in the study of Alzheimer's disease, Claudia Balducci et al. found that activated microglia plays an important role in the evolution of Alzheimer's disease (Pharmacological Research. 2018; 130: 402-413). At the same time, microglias highly expresses RIPK-1, and RIPK-1 inhibitors can protect from Aβ-induced neuronal death in vitro and reduce the proliferation of microglias. Moreover, in Alzheimer-like mouse brains, RIPK-1 inhibitors can improve their learning and memory abilities. In addition to Alzheimer's disease, RIPK-1 inhibitors are expected to be used in a variety of other neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, Huntington disease, etc.
At present, there are not many studies on RIPK-1 inhibitors, and only a small number of studies have entered the clinical stage. There is an urgent need for more research and development of drugs based on RIPK-1 inhibitors.
The present disclosure provides a class of acylamino bridged heterocyclic compounds, which exhibit good RIPK-1 inhibitory activity and can be used as RIPK-1 inhibitors in the preparation of a medicament for the treatment of tumors, autoimmune diseases, degenerative diseases, and inflammatory diseases.
The compound represented by formula (I) provided by the present disclosure, or pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs thereof, can be used to prepare medicaments for the treatment or prevention of diseases related to RIPK1.
In formula (I),
Q is NH, O or S;
A1, A2, and A3 are each independently selected from N or CR4 and at least one of A1, A2, and A3 is N, R4 is H, F, Cl or methyl;
R1 is C3-C8 cycloalkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRaRb,
or 4- to 8-membered heteroalicyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRaRb,
or aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydrogen, C1-C6 alkylthio, —SO2—R5, —SO—R5, —CO—R5, —CONH—R5, —NHCO—R5, —R′—COO—R″, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl and/or C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, and —O—R6,
the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring, the heteroaryl is a monocyclic or bicyclic group having 5 to 10 ring atoms and containing 1 to 3 heteroatoms selected from N, O, or S as ring atoms, the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1-2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, and C1-C6 alkylthio,
R′ is C2-C6 alkenylene, or C1-C6 alkylene,
R″ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R2 is C3-C8 cycloalkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRcRd,
or C7-C12 bridged cyclyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRcRd,
or C1-C10 alkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, cyano, —CONH2, C3-C8 cycloalkyl, and —NRcRd,
or —(CH2)n-Re, wherein Re is aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, C3-C6 cycloalkyl, phenyl, naphthyl, C2-C6 alkynyl, C2-C6 alkenyl, and —NRcRd, wherein n is an integer from 0 to 3,
or —(CH2)m-Rf, wherein Rf is 4- to 8-membered heteroalicyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRcRd, m is an integer from 0 to 3,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring, the heteroaryl is a monocyclic or bicyclic group having 5 to 10 ring atoms and containing 1 to 3 heteroatoms selected from N, O, or S as ring atoms,
Rc and Rd are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R3 is hydrogen, C1-C3 alkyl, hydroxyl, halogen, trifluoromethyl, or cyano.
In some embodiments, alternatively, Q is NH, O or S;
A1, A2, and A3 are each independently selected from N or CR4 and at least one of A1, A2, and A3 is N, R4 is H, F, Cl or methyl;
R1 is C3-C8 cycloalkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRaRb,
or 4- to 8-membered heteroalicyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRaRb,
or aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —SO2—R5, —SO—R5, —CO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, and —O—R6,
the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring, the heteroaryl is a monocyclic or bicyclic group having 5 to 10 ring atoms and containing 1 to 3 heteroatoms selected from N, O, or S as ring atoms, the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, and C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R2 is C3-C8 cycloalkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRcRd,
or C7-C12 bridged cyclyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRcRd,
or C1-C10 alkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, cyano, —CONH2, C3-C8 cycloalkyl, and —NRcRd,
or —(CH2)n-Re, wherein Re is aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, C2-C6 alkynyl, C2-C6 alkenyl, and —NRcRd, wherein n is an integer from 0 to 3,
or —(CH2)m-Rf, wherein Rf is 4- to 8-membered heteroalicyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, —CONH2, oxo (═O) and —NRcRd, m is an integer from 0 to 3,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
the aryl group is a monocyclic or bicyclic group containing 6 to 12 carbon ring atoms and having at least one aromatic ring, the heteroaryl is a monocyclic or bicyclic group having 5 to 10 ring atoms and containing 1 to 3 heteroatoms selected from N, O, or S as ring atoms,
Rc and Rd are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R3 is hydrogen, C1-C3 alkyl, hydroxyl, halogen, trifluoromethyl, or cyano.
In some embodiments, alternatively, A3 is N, A1, and A2 are each independently selected from N or CR4, R4 is H, F, Cl or methyl; still alternatively, A3 is N, A1, and A2 are each independently CH.
In some embodiments, alternatively, A3 is N, A1, A2 are each independently selected from N or CR4, R4 is H or F.
In some embodiments, still alternatively, Q is NH.
In some embodiments, alternatively, R1 is C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or aryl or heteroaryl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —CO—R5, —SO2—R5, —SO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, and —O—R6,
the aryl group is phenyl, naphthyl,
the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 1,5-naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —CO—R5, —SO2—R5, —SO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, or C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl.
In some embodiments, alternatively, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or aryl or heteroaryl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —SO2—R5, —SO—R5, —CO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, and —O—R6,
the aryl group is phenyl,
the heteroaryl group is pyrazolyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, or C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl.
In some embodiments, alternatively, R1 is
R7 is hydrogen, C1-C4 alkyl, C1-C3 alkoxy, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, or C1-C3 acyl;
R8 is hydrogen, C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —CO—R5, —SO2—R5, —SO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, hydroxyl C1-C10 alkyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, or —O—R6,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, and C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl.
In some embodiments, alternatively, R1 is:
R7 is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluorine, chlorine, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, ethynyl, propynyl, vinyl, propenyl, cyclopropyl, cyclobutyl, formyl, or acetyl;
R8 is hydrogen, C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —CO—R5, —SO2—R5, —SO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, or —O—R6,
the 4- to 8-membered heteroalicyclic group is heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, and C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl.
In some embodiments, alternatively, R5 is hydrogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C3 alkyl substituted with hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or C1-C3 alkyl which is substituted with 4-6 membered heteroalicyclic group selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl,
In some embodiments, alternatively, R6 is C1-C8 alkyl, C3-C6 cycloalkyl, 4-6 membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, neopentoxy, cyano, amino, dimethylamino, diethylamino, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, —CONH—R5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxyl, fluorine, chlorine, trifluoromethoxy, trichloromethoxy, methylsulfone, ethylsulfone, —SO—R5, —CO—R5, ethynyl, vinyl, methoxyethoxy, methoxypropoxy, ethoxyethoxy, ethoxypropoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, methylthio, ethylthio, and propylthio. Still alternatively, 4- to 8-membered heteroalicyclic group described herein is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolan-2-yl, etc.
In some embodiments, still alternatively, R6 is 4-ethyl-4-hydroxyhexyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, 2-methyl-2-hydroxypropyl, tetrahydro-2H-pyran-4-ylethyl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-pyran-2-ylmethyl, tetrahydro-2H-pyran-2-ylethyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-2-ylethyl, tetrahydrofuran-3-ylethyl, methoxypropyl, ethoxypropyl, tert-butoxypropyl, isobutoxypropyl, isopropoxypropyl, ethoxyethyl, tert-butoxyethyl, isobutoxyethyl, isopropoxyethyl, methoxyethyl, methoxybutyl, ethoxybutyl, tert-butoxybutyl, isobutoxybutyl, isopropoxybutyl, methoxyethoxyethyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, 1-methylpiperidin-4-ylmethyl, 1-methylpiperidin-4-ylethyl, 1-methylpiperidin-4-ylpropyl, 1-methylpiperazin-4-ylethyl, 1-methylpiperazin-4-ylpropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, 3,3-dimethylbutyl, octyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyoctyl, hydroxyheptyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, 4-cyanopentyl, 4,4,4-trifluorobutyl, N,N-dimethylpropyl, N,N-dimethylethyl, N,N-diethylpropyl, N,N-diethylethyl, methylthiobutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylsulfonylbutyl, methylsulfonylmethyl, methylsulfonylethyl, methylsulfonylpropyl, cycloheptylethyl, cycloheptylpropyl, cyclohexylethyl, cyclohexylpropyl, cyclopentylethyl, cyclopentylpropyl, allyl, penten-1-yl, oxetan-3-yl, tetrahydro-2H-pyran-4-yl, oxetan-3-ylmethyl, oxetan-3-ylethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutoxypropyl, cyclobutoxyethyl, cyclobutoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —CH2CONH2, —(CH2)2CONH2, —(CH2)3CONH2,
In some embodiments, alternatively, Ra and Rb are each independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted with C1-C3 alkoxy, C1-C3 alkyl substituted with hydroxyl, C3-C6 cycloalkyl C1-C3 alkyl, C1-C3 alkyl substituted with 4-6 membered heteroalicyclic group, C1-C3 alkyl substituted with C1-C3 alkylthio, or C1-C3 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl.
In some embodiments, still alternatively, R7 is hydrogen, fluorine, chlorine, methyl, or trifluoromethyl.
In some embodiments, alternatively, R1 is
R7 is hydrogen, C1-C4 alkyl, C1-C3 alkoxy, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, or C1-C3 acyl; still alternatively, R7 is hydrogen, fluorine, chlorine, methyl, or trifluoromethyl.
R8 is hydrogen, C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —CO—R5, —SO2—R5, —SO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, or —O—R6,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, and C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R9 is hydrogen, C1-C4 alkyl, C1-C3 alkoxy, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 Cycloalkyl, or C1-C3 acyl.
In some embodiments, alternatively, R2 is C3-C8 cycloalkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, oxo (═O), amino, dimethylamino, and diethylamino,
or C7-C10 bridged cyclyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, oxo (═O), amino, dimethylamino, and diethylamino,
or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, cyano, —CONH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, dimethylamino, and diethylamino,
or —(CH2)n-Re, wherein Re is aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, ethynyl, vinyl, amino, dimethylamino, and diethylamino, n is an integer from 0 to 3,
or —(CH2)m-Rf, wherein Rf is 4- to 8-membered heteroalicyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, oxo (═O), amino, dimethylamino, and diethylamino, m is an integer from 0 to 3,
the 4- to 8-membered heteroalicyclic group contains 1 to 2 atoms selected from N, O, or S as ring atoms,
the aryl group is phenyl, and the heteroaryl group is pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, or thiazolyl.
In some embodiments, alternatively, R2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptyl, adamantyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, 2-hydroxy-2-methylpropyl, 3,3-dimethylbutyl, 3-hydroxy-3-methylbutyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, benzyl, phenethyl, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-cyanophenyl, 2-ethynylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-cyanophenyl, 3-ethynylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-ethynylphenyl, 3,4-difluorophenyl, 3-cyano-4-methylphenyl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrolyl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, methylpiperazin-4-yl, 1-methylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 4-hydroxypiperidin-1-yl, 4-methyl-4-hydroxypiperidin-1-yl,
Rg is —CH3 or —OH.
In some embodiments, alternatively, R2 is 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,4,5-trifluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-2,4-difluorophenyl, 5-chloro-2,4-difluorophenyl, 3-chloro-2,5-difluorophenyl, 3-chloro-2,6-difluorophenyl, 3-chloro-4,5-difluorophenyl, 2-chloro-4,5-difluorophenyl, 2-chloro-3,4-difluorophenyl, 2-chloro-3,5-difluorophenyl, 2-chloro-3,6-difluorophenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-3,5-difluorophenyl, 4-chloro-2,5-difluorophenyl, 5-chloro-2,3-difluorophenyl, 5-chloro-3,4-difluorophenyl, 6-chloro-2,3-difluorophenyl, 3-fluoro-5-methylphenyl, 4-fluoro-3-methylphenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluoro-5-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 3-fluoro-2-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2-fluoro-5-ethylphenyl, 2-fluoro-5-cyclopropylphenyl, or 2-fluoro-5-phenylphenyl.
In some embodiments, alternatively, R3 is hydrogen, methyl, ethyl, hydroxyl, cyano, trifluoromethyl, fluorine, or chlorine.
Disclosed is a compound represented by formula (I), pharmaceutically acceptable salts, isomer, solvate or prodrug thereof,
wherein, Q is NH;
A3 is N, A1, and A2 are each independently selected from N or CR4, R4 is H, F, Cl or methyl, alternatively H or F;
R1 is
R7 is hydrogen, C1-C4 alkyl, C1-C3 alkoxy, halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, C2-C4 alkynyl, C2-C4 alkenyl, C3-C4 cycloalkyl, or C1-C3 acyl;
R8 is hydrogen, C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —CO—R5, —SO2—R5, —SO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, hydroxyl C1-C10 alkyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, or —O—R6,
the 4- to 8-membered heteroalicyclic group is a 4- to 8-membered heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl, or C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group,
R6 is C1-C10 alkyl, C3-C8 cycloalkyl, 4- to 8-membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C1-C6 alkoxy, cyano, —NRaRb, C3-C8 cycloalkyloxy, —CONH—R5, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxylic, halogen, halogenated C1-C6 alkoxy, —SO2—R5, —SO—R5, —CO—R5, C2-C6 alkynyl, C2-C6 alkenyl, C1-C4 alkoxy C1-C6 alkoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, or C1-C6 alkylthio,
Ra and Rb are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C6 alkoxy, C1-C6 alkyl substituted with hydroxyl, C3-C8 cycloalkyl C1-C6 alkyl, C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, C1-C6 alkyl substituted with C1-C3 alkylthio, or C1-C6 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl,
still alternatively, R1 is
R7 is hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, fluorine, chlorine, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, ethynyl, propynyl, vinyl, propenyl, cyclopropyl, cyclobutyl, formyl, or acetyl; alternatively R7 is hydrogen, fluorine, chlorine, methyl, or trifluoromethyl;
R8 is hydrogen, C1-C10 alkyl, halogen, C3-C8 cycloalkyl, halogenated C1-C10 alkyl, cyano, hydroxyl, C1-C6 alkylthio, —CO—R5, —SO2—R5, —SO—R5, —CONH—R5, —NRaRb, 4- to 8-membered heteroalicyclic group, C2-C6 alkynyl, C2-C6 alkenyl, C1-C3 alkoxy C1-C6 alkylthio, C1-C10 alkyl substituted with hydroxyl, C1-C6 alkoxy C1-C10 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, (C3-C8 cycloalkyl)-O—(C1-C6 alkyl), C1-C6 alkyl substituted with 4- to 8-membered heteroalicyclic group, or —O—R6,
the 4- to 8-membered heteroalicyclic group is heteroalicyclic group containing 1 to 2 atoms selected from N, O, or S as ring atoms,
R5 is hydrogen, hydroxyl, C1-C4 alkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C3 alkyl substituted with hydroxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or C1-C3 alkyl which is substituted with 4-6 membered heteroalicyclic group selected from oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl,
R6 is C1-C8 alkyl, C3-C6 cycloalkyl, 4-6 membered heteroalicyclic group, or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, neopentoxy, cyano, amino, dimethylamino, diethylamino, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, —CONH—R5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, C3-C8 cycloalkyl substituted with hydroxyl and/or C1-C4 alkyl, carboxyl, fluorine, chlorine, trifluoromethoxy, trichloromethoxy, methylsulfone, ethylsulfone, —SO—R5, —CO—R5, ethynyl, vinyl, methoxyethoxy, methoxypropoxy, ethoxyethoxy, ethoxypropoxy, 4- to 8-membered heteroalicyclic group, 4- to 8-membered heteroalicyclic group substituted with oxo, 4- to 8-membered heteroalicyclic group substituted with hydroxyl and/or C1-C4 alkyl, methylthio, ethylthio, and propylthio. Still alternatively, 4- to 8-membered heteroalicyclic group described herein is oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dioxolan-2-yl, etc.,
still alternatively, R6 is 4-ethyl-4-hydroxyhexyl, 4-methyl-4-hydroxypentyl, 5-methyl-5-hydroxyhexyl, 2-methyl-2-hydroxypropyl, tetrahydro-2H-pyran-4-ylethyl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-pyran-2-ylmethyl, tetrahydro-2H-pyran-2-ylethyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, tetrahydrofuran-2-ylethyl, tetrahydrofuran-3-ylethyl, methoxypropyl, ethoxypropyl, tert-butoxypropyl, isobutoxypropyl, isopropoxypropyl, ethoxyethyl, tert-butoxyethyl, isobutoxyethyl, isopropoxyethyl, methoxyethyl, methoxybutyl, ethoxybutyl, tert-butoxybutyl, isobutoxybutyl, isopropoxybutyl, methoxyethoxyethyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, 1-methylpiperidin-4-ylmethyl, 1-methylpiperidin-4-ylethyl, 1-methylpiperidin-4-ylpropyl, 1-methylpiperazin-4-ylethyl, 1-methylpiperazin-4-ylpropyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, 3,3-dimethylbutyl, octyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyoctyl, hydroxyheptyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, 4-cyanopentyl, 4,4,4-trifluorobutyl, N,N-dimethylpropyl, N,N-dimethylethyl, N,N-diethylpropyl, N,N-diethylethyl, methylthiobutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylsulfonylbutyl, methylsulfonylmethyl, methylsulfonylethyl, methylsulfonylpropyl, cycloheptylethyl, cycloheptylpropyl, cyclohexylethyl, cyclohexylpropyl, cyclopentylethyl, cyclopentylpropyl, allyl, penten-1-yl, oxetan-3-yl, tetrahydro-2H-pyran-4-yl, oxetan-3-ylmethyl, oxetan-3-ylethyl, fluoroethyl, fluoropropyl, fluorobutyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutoxypropyl, cyclobutoxyethyl, cyclobutoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —CH2CONH2, —(CH2)2CONH2, —(CH2)3CONH2,
Ra and Rb are each independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted with C1-C3 alkoxy, C1-C3 alkyl substituted with hydroxyl, C3-C6 cycloalkyl C1-C3 alkyl, C1-C3 alkyl substituted with 4-6 membered heteroalicyclic group, C1-C3 alkyl substituted with C1-C3 alkylthio, or C1-C3 alkyl substituted with substituted amino or unsubstituted amino, wherein the substituted amino is substituted with mono- or di-C1-C3 alkyl;
R2 is C3-C8 cycloalkyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, oxo (═O), amino, dimethylamino, and diethylamino,
or C7-C10 bridged cyclyl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, oxo (═O), amino, dimethylamino, and diethylamino,
or C1-C10 alkyl which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, cyano, —CONH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, amino, dimethylamino, and diethylamino,
or —(CH2)n-Re, wherein Re is aryl or heteroaryl, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, ethynyl, vinyl, amino, dimethylamino, and diethylamino, n is an integer from 0 to 3,
or —(CH2)m-Rf, wherein Rf is 4- to 8-membered heteroalicyclic group, which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, formyl, acetyl, hydroxyl, fluorine, chlorine, trifluoromethyl, cyano, —CONH2, oxo (═O), amino, dimethylamino, and diethylamino, m is an integer from 0 to 3,
the 4- to 8-membered heteroalicyclic group contains 1 to 2 atoms selected from N, O, or S as ring atoms,
the aryl group is phenyl, and the heteroaryl group is pyridyl, pyrimidinyl, pyrazolyl, oxazolyl, isoxazolyl, or thiazolyl;
still alternatively, R2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptyl, adamantyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, 2-hydroxy-2-methylpropyl, 3,3-dimethylbutyl, 3-hydroxy-3-methylbutyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, benzyl, phenethyl, phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-methoxyphenyl, 2-cyanophenyl, 2-ethynylphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-cyanophenyl, 3-ethynylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-ethynylphenyl, 3,4-difluorophenyl, 3-cyano-4-methylphenyl, pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrolyl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, methylpiperazin-4-yl, 1-methylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 4-hydroxypiperidin-1-yl, 4-methyl-4-hydroxypiperidin-1-yl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,4-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 3,4,5-trifluorophenyl, 2,4,5-trifluorophenyl, 3-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 5-chloro-2-fluorophenyl, 2-chloro-5-fluorophenyl, 5-chloro-3-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 3-chloro-2,4-difluorophenyl, 5-chloro-2,4-difluorophenyl, 3-chloro-2,5-difluorophenyl, 3-chloro-2,6-difluorophenyl, 3-chloro-4,5-difluorophenyl, 2-chloro-4,5-difluorophenyl, 2-chloro-3,4-difluorophenyl, 2-chloro-3,5-difluorophenyl, 2-chloro-3,6-difluorophenyl, 4-chloro-2,3-difluorophenyl, 4-chloro-3,5-difluorophenyl, 4-chloro-2,5-difluorophenyl, 5-chloro-2,3-difluorophenyl, 5-chloro-3,4-difluorophenyl, 6-chloro-2,3-difluorophenyl, 3-fluoro-5-methylphenyl, 4-fluoro-3-methylphenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methylphenyl, 2-fluoro-5-methylphenyl, 3-fluoro-4-methylphenyl, 3-fluoro-2-methylphenyl, 3-fluoro-5-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-4-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 3-fluoro-2-methoxyphenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 3-fluoro-2-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2-fluoro-5-ethylphenyl, 2-fluoro-5-cyclopropylphenyl, 2-fluoro-5-phenylphenyl,
Rg is —CH3 or —OH.
R3 is hydrogen, methyl, ethyl, hydroxyl, cyano, trifluoromethyl, fluorine, or chlorine, still alternatively hydrogen, fluorine, hydroxyl, or chlorine.
According to some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound is selected from the group consisting of one or more of the following salts: hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, salicylate, hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt.
Another aspect of the present disclosure relates to the application of the compound, pharmaceutically acceptable salt(s), isomer(s), solvate(s), or prodrug(s) thereof in the preparation of a medicament for the treatment of RIP1 related diseases, Wherein, the RIP1 related disease include ocular fundus disease, xerophthalmia, psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary cancer and sarcoma, cholangiocarcinoma, inflammatory bowel disease, ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor related periodic syndrome and periodontitis.
Another aspect of the present disclosure provides a pharmaceutical composition, which includes the acylamino bridged heterocyclic compounds of the present disclosure, or isomers, solvates, pharmaceutically acceptable salts or prodrugs thereof, and one or more pharmaceutically acceptable carriers or excipients.
According to some embodiments of the application, the pharmaceutical composition may also include one or more other therapeutic agents.
The present disclosure also relates to a method for treating diseases or disorders mediated by RIP1 kinase, which comprises administering a therapeutically effective amount of a compound of formula (I) or a salt thereof to a patient (human or other mammals, especially human) in need thereof. The RIP1 kinase-mediated diseases or disorders include those mentioned above.
Unless otherwise stated, the following terms used in this application (including the description and claims) have the definitions given below. In this application, the use of “or” or “and” means “and/or” unless stated otherwise. In addition, the use of the term “comprising” and other forms such as “including”, “containing” and “having” is not limiting. The chapter headings used herein are for organizational purposes only and should not be interpreted as limitations on the topics described.
Unless otherwise specified, alkyl represents a saturated straight-chain, or branched-chain hydrocarbon group with the specified number of carbon atoms. The term C1-C10 alkyl represents an alkyl moiety containing 1 to 10 carbon atoms, similarly C1-C3 alkyl represents an alkyl moiety containing 1 to 3 carbon atoms, such as, C1-C6 alkyl including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl etc.
When substituent terms such as “alkyl” are used in combination with other substituent terms, for example in the term “C1-C3 alkoxy C1-C6 alkylthio” or “C1-C10 alkyl substituted with hydroxyl”, this linking substituent term (e.g. alkyl or alkylthio) is intended to include a divalent moiety, wherein the connection point is through the connection substituent. Examples of “C1-C3 alkoxy C1-C6 alkylthio” include, but are not limited to, methoxymethylthio, methoxyethylthio and ethoxypropylthio, etc. Examples of “C1-C10 alkyl substituted with hydroxyl” include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxyisopropyl.
Alkoxy is an alkyl-O— group formed by the previously described linear or branched alkyl group and —O—, for example, methoxy, ethoxy, etc. Similarly, alkylthio is an alkyl-S— group formed by the previously described linear or branched alkyl group and —S—, for example, methylthio, ethylthio, etc.
Alkenyl and alkynyl include straight chain, or branched alkenyl or alkynyl, the term C2-C6 alkenyl or C2-C6 alkynyl means a straight or branched chain hydrocarbon group having at least one alkenyl or alkynyl group.
The term “halogenated C1-C10 alkyl” represents a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of the alkyl moiety comprising 1 to 10 carbon atoms. Examples of “halogenated C1-C10 alkyl” may include, but are not limited to, —CF3 (trifluoromethyl), —CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl and hexafluoroisopropyl, etc. Similarly, the term “halogenated C1-C10 alkoxy” represents a haloalkyl-O— group formed by the halogenated C1-C10 alkyl group and —O—, for example, trifluoromethoxy, trichloromethoxy, etc.
The term “C1-C3 acyl” includes formyl (—CHO), acetyl (CH3CO—), propionyl (C2H5CO—).
The terms “—CO—R5, —SO2—R5, —SO—R5, —CONH—R5” represent
respectively.
“Cycloalkyl” represents a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term “(C3-C6) cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring with 3-6 ring carbon atoms. Exemplary “(C3-C6) cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “aryl” represents a group or moiety containing an aromatic monocyclic or bicyclic hydrocarbon atom group, which contains 6 to 12 carbon ring atoms and has at least one aromatic ring. Examples of “aryl” are phenyl, naphthyl, indenyl and indanyl. Generally, in the compounds of the present disclosure, the aryl group is a phenyl group.
The term “heteroalicyclic group” as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 4- to 8-membered non-aromatic monocyclic saturated ring system, which consists of carbon atoms and 1 to 3 heteroatoms selected from N, O, or S, wherein, N and S heteroatoms can be arbitrarily oxidized, and N heteroatoms can also be arbitrarily quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, imidazolinyl, oxazolinyl, thiazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl.
The term “heteroaryl” as used herein represents a group or moiety containing an aromatic monocyclic or bicyclic group (which contains 5 to 10 ring atoms), which includes 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The term also includes bicyclic heterocyclic aryl, which contains an aryl ring moiety fused to a heterocycloalkyl ring moiety, or a heteroaryl ring moiety fused to a cycloalkyl ring moiety. Unless otherwise specified, it represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and can also represents an unsubstituted or substituted benzene fused heteroaromatic ring system or bicyclic heteroaromatic ring system with 9 or 10 ring atoms, which are composed of carbon atoms and 1 to 3 heteroatoms selected from N, O, or S, where N, S heteroatoms can be oxidized, and N heteroatoms can also be quaternized. Heteroaryl groups can be connected to any heteroatom or carbon atom to form a stable structure. Illustrative examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indazinyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzisothiazolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, benzotriazolyl, triazolopyridyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridyl.
The term “carbonyl” refers to the —C(O)— group. The terms “halogen” and “halo” represent chlorine, fluorine, bromine or iodine substituents. “Oxo” represents the oxygen moiety with double bond; for example, it forms a carbonyl moiety (C═O) when it is directly attached to a carbon atom. “Hydroxy” is intended to mean the —OH group. As used herein, the term “cyano” refers to the group —CN.
The term “each independently” means that when more than one substituents are selected from a number of possible substituents, those substituents may be the same or different.
It is clear that the compounds of formula I, or isomers, crystal forms or prodrugs and pharmaceutically acceptable salts thereof may exist in solvated and unsolvated forms. For example, the solvated form can be a hydrate form. The present disclosure includes all these solvated forms and unsolvated forms.
The compounds of the present disclosure may have asymmetric carbon atoms. According to their physical and chemical differences, such diastereomeric mixtures can be separated into single diastereomers by known, technically mature methods, such as chromatography or fractional crystallization. The separation of enantiomers can be carried out by first reacting with a suitable optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereoisomers, and then the single diastereomers are transformed (hydrolyzed) into the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered as part of the invention.
The compound of the present disclosure as an active ingredient, and the method of preparing the same, are both included in the present disclosure. Moreover, the crystalline form of some of the compounds may exist as polymorphs, and such forms may also be included in the present disclosure. Additionally, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the disclosure.
The compounds of the disclosure may be used in the free form for treatment or, when appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment. As used herein, the term “pharmaceutically acceptable salt” refers to organic and inorganic salts of the compounds of the present disclosure which are suitable for use in human and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salt can be formed by reacting a compound of the disclosure with a suitable free base or acid, including, but not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid. Or the salts may be obtained by methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butanoate, camphorate, camphorsulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, glyconate, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate, phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include suitable non-toxic salts of ammonium, quaternary ammonium, and amine cations formed from halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
Further, the term “prodrug” as used herein means that a compound can be converted into the compound of the present disclosure represented by formula (I) in vivo. Such transformation is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent compound in the blood or tissue.
Pharmaceutical compositions of this disclosure comprise the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof; an additional agent selected from a kinase inhibitory agent (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer agent, an anti-viral agent, anti-inflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
The compounds of the present disclosure may be used alone or in combination with one or more of other compounds of the present disclosure or with one or more of other agents. When administered in combination, the therapeutic agents can be formulated for simultaneous or sequential administration at different times, or the therapeutic agents can be administered as a single composition. By “combination therapy”, it refers to the use of a compound of the disclosure in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose of achieving the optimal results. Co-administration includes dosage form for simultaneous delivery, as well as separate dosage forms for each compound. Thus, administration of the compounds of the disclosure can be combined with other therapies known in the art, for example, radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like as used in the treatment of cancer, in order to improve the symptoms of cancer. The administration sequence is not limited in the present disclosure. The compounds of the present disclosure may be administered before, simultaneously, or after other anticancer or cytotoxic agents.
To prepare the pharmaceutical ingredient of the present disclosure, one or more compounds of formula (I) or salts thereof as an active ingredient can be intimately mixed with a pharmaceutical carrier, which is carried out according to a conventional pharmaceutical formulation technique. The carrier can be used in a wide variety of forms depending on the form of preparation which is designed for different administration modes (for example, oral or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
The pharmaceutical composition of the present disclosure may have the following forms, for example, those suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; those for parenteral injections such as clear solutions, suspensions, emulsion; or those for topical use such as ointments, creams; or as a suppository for rectal administration. The pharmaceutical ingredients may also be presented in unit dosage form for single administration in a precise dosage. The pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present disclosure, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
Therapeutic compounds can also be administered to mammals other than humans. The drug dosage for a mammal will depend on the species of the animal and its disease condition or its disordered condition. The therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a tablet or liquid. The therapeutic compound can also be introduced into the animal by injection or infusion. These drug forms are prepared in a traditional manner complying with standard veterinary practice. As an alternative, the therapeutic compounds can be mixed with the animal feed and fed to the animal, so that the concentrated feed additive or premix can be prepared by mixing ordinary animal feed.
It is a further object of the present disclosure to provide a method for treating cancer in a subject in need thereof, comprising a method for administering to the subject a therapeutically effective amount of a composition containing the compound of the present disclosure.
The present disclosure also includes the use of the compound of the present disclosure or a pharmaceutically acceptable derivative thereof, in the manufacture of medicaments for treating RIP1 related diseases, including ocular fundus disease, xerophthalmia, psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary cancer and sarcoma, cholangiocarcinoma, inflammatory bowel disease, ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor related periodic syndrome and periodontitis.
The present disclosure also provides a method for preparing the corresponding compounds. A variety of synthetic methods can be used to prepare the compounds described herein, including the method involved in the following examples. The compounds of the present disclosure, or pharmaceutically acceptable salts, isomers or hydrates thereof, can be synthesized using the following methods, synthetic methods known in the field of organic chemical synthesis, or variations of these methods understood by those skilled in the art. Preferred methods include, but are not limited to, the following methods.
In order to make the objectives, technical solutions and advantages of the present disclosure more clear, the present disclosure will be further described in detail below in conjunction with specific examples. It should be understood that the specific examples described here are only used to explain the present disclosure and are not intended to limit the present disclosure. If no specific technology or conditions are indicated in examples, the technology or conditions described in the literature in the art or the product specification shall be followed. If reagents or instruments used do not indicate manufacturers, they are all conventional products that are commercially available. The term “and/or” as used herein includes any and all combinations of one or more related listed items. The Example provided below can better illustrate the present disclosure, unless otherwise specified, all temperatures are in ° C. The names of some compounds in this disclosure are generated by Chemdraw and translated into Chinese.
I. Preparation of A Series Intermediates
A series intermediates may include A and A′, where A′ can be further formed by hydrolysis of A. A can be prepared by the above two routes. In Route 2, Intermediate A is generated by the reaction of compound 3 and acid chloride 4 in a pyridine solvent at 110 degrees, and in Route 1, Intermediate A is synthesized by refluxing compound 1 and hydrazide 2.
The synthetic method refers to WO2014125444A1.
Step 1: Synthesis of 2-phenylpropionyl chloride
2-phenylpropionic acid (1 g, 6.66 mmol) was dissolved in thionyl chloride (10 mL), and reacted at 85° C. for 1 hour. The reaction solution was diluted with toluene and spin dried. The crude product was used directly in the next step.
Step 2: Synthesis of 2-phenylpropionyl hydrazide
2-phenylpropionyl chloride was dissolved in methanol (20 mL), and reacted at 25° C. for 2 hours. Hydrazine hydrate (10 mL) was then added, and reacted at 80° C. for 16 hours. The reaction solution was cooled, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, to afford 900 mg of colorless oil. MS: 165 [M+H]+
Step 3: Synthesis of A-3 and A-4
2-phenylpropionyl hydrazide (900 mg, 5.5 mmol) was dissolved in ethanol (15 mL), ethyl thiooxamate (805 mg, 6 mmol) was added, and reacted at 70° C. for 3 hours. The reaction solution was cooled and filtered to afford 800 mg of white solid. Xylene (20 mL) was added to the solid, and reacted at 160° C. under refluxing to remove water for 24 hours. The reaction solution was cooled and concentrated, the crude product was rinsed with mixture of petroleum ether/ethyl acetate (10:1), to afford 300 mg of ethyl 5-(1-phenylethyl)-4H-1,2,4-triazol-3-carboxylate as white solid. MS: 246 [M+H]+. The mother liquor was evaporated to dryness to afford 200 mg of ethyl 5-(1-phenylethyl)-1,3,4-oxadiazol-2-carboxylate as yellow solid. MS: 247 [M+H]+.
The preparation was carried out in a similar manner to intermediate A-3 and A-4 (step 2 to step 3), except that in step 2, cyclopentylacetyl chloride was used in place of 2-phenylpropionyl chloride.
Step 1: Tert-butyl 2-(2-ethoxy-1-imino-2-oxoethyl)hydrazine-1-carboxylate and 2-(benzyloxy)acetyl chloride in pyridine were reacted at 110° C. to afford ethyl 5-((benzyloxy)methyl)-4H-1,2,4-triazol-3-carboxylate (see M. V. Chudinov et al./Bioorg. Med. Chem. Lett. 26(2016) 3223-3225 for detailed operations)
Step 2: Synthesis of Ethyl 5-(hydroxymethyl)-4H-1,2,4-triazol-3-carboxylate
Ethyl 5-((benzyloxy)methyl)-4H-1,2,4-triazole-3-carboxylate (250 mg, 1 mmol) was dissolved in a mixture of ethanol and ethyl acetate (2:1, 3 mL), palladium on carbon (10%, 25 mg) was added, and was reacted for 5 hours under hydrogen atmosphere. The reaction was filtered through diatomaceous earth and the filtrate was evaporated to get 150 mg of yellow solid. MS: 172 [M+H]+
Step 3: Synthesis of ethyl 5-(chloromethyl)-4H-1,2,4-triazole-3-carboxylate
Ethyl 5-(hydroxymethyl)-4H-1,2,4-triazole-3-carboxylate (150 mg, 0.9 mmol) was dissolved in thionyl chloride (2 mL), and reacted at 85° C. for 7 hours. The reaction was cooled and diluted with toluene, and the resultant was spin dried to afford 160 mg of yellow oil. MS: 190 [M+H]+
Step 4: Synthesis of ethyl 5-(morpholinomethyl)-4H-1,2,4-triazole-3-carboxylate
Ethyl 5-(chloromethyl)-4H-1,2,4-triazole-3-carboxylate (160 mg, 0.9 mmol) was dissolved in tetrahydrofuran (2 mL), diisopropylethylamine (220 mg, 1.7 mmol) and morpholine (150 mg, 1.7 mmol) were added, and reacted at 25° C. for 5 hours. The reaction solution was evaporated to dryness, and purified by column chromatography to get 180 mg of yellow solid. MS: 241 [M+H]+
Table 1 below shows the structure and synthesis of intermediates A-8 to A-28 and mass spectral data thereof, wherein intermediates A-8 to A-12 were prepared in a similar manner to intermediate A-3, without collecting the oxadiazole by-product, and the synthesis of intermediates A-13 and A-28 were carried out in a similar manner to the first step of synthesis of intermediate A-7.
Phenylacetylhydrazine (5 g, 33.3 mmol) was dissolved in anhydrous dichloromethane (100 mL), triethylamine (6.74 g, 66.7 mmol) was added, and under argon protection, methyl oxalyl chloride (4.1 g, 33.5 mmol) was added dropwise at 0° C. The reaction solution was slowly warmed to 25° C. After 16 hours reaction, the solvent was evaporated to dryness, rinsed with mixture of petroleum ether/ethyl acetate, filtered, and the filter cake was re-dissolved in toluene (100 mL), Lawson's reagent (26.9 g, 66.5 mmol) was added, heated to 110° C. and reacted for 6 hours. The reaction was cooled and diluted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate and brine, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to get 4 g product. MS: 235 [M+H]+.
Step 1: Synthesis of 4-phenylpyridin-2-amine
4-Bromopyridin-2-amine (173 mg, 1 mmol), phenylboronic acid (146 mg, 1.2 mmol), Pd(dppf)Cl2 (73 mg, 0.1 mmol) and sodium carbonate (160 mg, 1.5 mmol) were placed in a mixture of dioxane (4 mL) and water (0.8 mL), which was reacted at 100° C. for 16 hours under argon protection. After cooling, the reaction solution was evaporated to dryness and subjected to column chromatography to afford 120 mg of brown solid. MS: 171 [M+H]+.
Step 2: Synthesis of 5-benzyl-N-(4-phenylpyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
4-Phenylpyridin-2-amine (120 mg, 0.7 mmol) was placed in dry xylene (3 mL), to which trimethyl aluminum (3M, 0.7 mL) was slowly added under argon protection, and reacted at 25° C. for 1 hour. Then, intermediate 1 (197 mg, 0.9 mmol) was added, and reacted at 100° C. for 16 hours. The reaction solution was cooled and diluted with methanol, evaporated to dryness and subjected to column chromatography and preparative liquid chromatography to afford 50 mg of white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.90 (s, 1H), 8.49-8.38 (m, 2H), 7.82-7.71 (m, 2H), 7.62-7.45 (m, 4H), 7.40-7.30 (m, 4H), 7.30-7.18 (m, 1H), 4.18 (s, 2H). MS: 356 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, o-methylphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.51-7.34 (m, 3H), 7.34-7.30 (m, 4H), 7.30-7.23 (m, 2H), 7.21 (d, J=5.1 Hz, 1H), 4.19 (s, 2H), 2.28 (s, 3H). MS: 370 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, o-methoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.82 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.33-8.17 (m, 1H), 7.60-6.91 (m, 10H), 4.18 (s, 2H), 3.81 (s, 3H). MS: 386 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, o-ethoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.80 (s, 1H), 8.62-8.40 (m, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.60-6.94 (m, 10H), 4.18 (s, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.32 (t, J=6.9 Hz, 3H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-isopropyloxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.74 (s, 1H), 8.56-8.26 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.29 (m, 5H), 7.27 (d, J=7.3 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.09-7.02 (m, 1H), 4.69 (p, J=6.0 Hz, 1H), 4.19 (s, 2H), 1.27 (d, J=6.0 Hz, 6H). MS: 414 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-(trifluoromethoxy)phenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.96 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.30 (d, J=1.5 Hz, 1H), 7.70-7.51 (m, 4H), 7.41-7.18 (m, 6H), 4.18 (s, 2H). MS: 440 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-chlorophenylboronic acid was used in place of phenylboronic acid. 1H NMR (600 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.95 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 7.68-7.60 (m, 1H), 7.56-7.46 (m, 3H), 7.39-7.30 (m, 4H), 7.30-7.21 (m, 2H), 4.18 (s, 2H). MS: 390 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-cyclopropylphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.87 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 7.42-7.30 (m, 5H), 7.30-7.20 (m, 4H), 7.10-7.01 (m, 1H), 4.18 (s, 2H), 1.91-1.77 (m, 1H), 0.95-0.81 (m, 2H), 0.79-0.63 (m, 2H). MS: 396 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 4-methoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.82 (s, 1H), 8.48-8.29 (m, 2H), 7.80-7.66 (m, 2H), 7.47 (dd, J=5.2, 1.8 Hz, 1H), 7.42-7.18 (m, 5H), 7.18-6.98 (m, 2H), 4.18 (s, 2H), 3.83 (s, 3H). MS: 386 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 4-methoxy-2-methylphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.85 (s, 1H), 8.38 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.47-7.02 (m, 7H), 7.04-6.76 (m, 2H), 4.18 (s, 2H), 3.80 (s, 3H), 2.29 (s, 3H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 4-chloro-2-methylphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.93 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.43-7.11 (m, 8H), 4.18 (s, 2H), 2.28 (s, 3H). MS: 404 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 4-cyano-2-methylphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 10.00 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.41-7.29 (m, 4H), 7.29-7.15 (m, 2H), 4.18 (s, 2H), 2.30 (s, 3H). MS: 395 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-chloro-5-methoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (600 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.91 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.45-7.30 (m, 4H), 7.30-7.19 (m, 2H), 7.08 (dd, J=8.8, 3.1 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 4.18 (s, 2H), 3.81 (s, 3H). MS: 420 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 5-fluoro-2-methoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.87 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 7.51-7.03 (m, 9H), 4.18 (s, 2H), 3.80 (s, 3H). MS: 404 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 5-chloro-2-methoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.86 (s, 1H), 8.39 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 7.50 (dd, J=8.8, 2.7 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.40-7.29 (m, 5H), 7.29-7.15 (m, 2H), 4.18 (s, 2H), 3.81 (s, 3H). MS: 420 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-methoxy-5-methylphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.79 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 7.38-7.29 (m, 5H), 7.29-7.21 (m, 2H), 7.20 (d, J=2.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 4.18 (s, 2H), 3.77 (s, 3H), 2.31 (s, 3H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 5-isopropyl-2-methoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.84 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 7.41-7.19 (m, 8H), 7.09 (d, J=8.5 Hz, 1H), 4.18 (s, 2H), 3.78 (s, 3H), 2.91 (p, J=6.9 Hz, 1H), 1.21 (d, J=6.9 Hz, 6H). MS: 428 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2,5-dimethoxyphenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.83 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 7.45-7.29 (m, 5H), 7.29-7.22 (m, 1H), 7.12 (d, J=9.0 Hz, 1H), 7.02 (dd, J=9.0, 3.1 Hz, 1H), 6.95 (d, J=3.1 Hz, 1H), 4.18 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H). M S: 416 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-methoxy-5-(trifluoromethyl)phenylboronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.83 (dd, J=8.9, 2.3 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.46-7.18 (m, 7H), 4.19 (s, 2H), 3.90 (s, 3H). MS: 454 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.99 (s, 1H), 8.57 (dd, J=4.9, 1.7 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 7.73 (dd, J=7.7, 1.8 Hz, 1H), 7.44-7.32 (m, 5H), 7.32-7.24 (m, 2H), 4.21 (s, 2H), 2.50 (s, 3H). MS: 371 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, (2-methoxypyridin-3-yl)boronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.88 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.28 (dd, J=5.0, 1.9 Hz, 1H), 7.88 (dd, J=7.4, 1.9 Hz, 1H), 7.40 (dd, J=5.2, 1.6 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.21 (m, 1H), 7.17 (dd, J=7.4, 4.9 Hz, 1H), 4.18 (s, 2H), 3.92 (s, 3H). MS: 387 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, (2-ethoxypyridin-3-yl)boronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.83 (s, 1H), 8.48 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.26 (dd, J=4.9, 1.9 Hz, 1H), 7.90 (dd, J=7.4, 1.9 Hz, 1H), 7.42 (dd, J=5.2, 1.6 Hz, 1H), 7.39-7.30 (m, 4H), 7.30-7.21 (m, 1H), 7.15 (dd, J=7.4, 4.9 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 4.18 (s, 2H), 1.34 (t, J=7.0 Hz, 3H). MS: 401 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, (2-isopropyloxypyridin-3-yl)boronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.81 (s, 1H), 8.52 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.25 (dd, J=4.9, 1.9 Hz, 1H), 7.89 (dd, J=7.4, 1.9 Hz, 1H), 7.40 (dd, J=5.2, 1.6 Hz, 1H), 7.38-7.30 (m, 4H), 7.29-7.21 (m, 1H), 7.12 (dd, J=7.4, 4.9 Hz, 1H), 5.39 (p, J=6.2 Hz, 1H), 4.18 (s, 2H), 1.33 (d, J=6.2 Hz, 6H). MS: 415 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, (3-methylpyridin-4-yl)boronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.97 (s, 1H), 8.58 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.39-7.30 (m, 5H), 7.30-7.22 (m, 2H), 4.18 (s, 2H), 2.28 (s, 3H). MS: 371 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, (3-methoxypyridin-4-yl)boronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.91 (s, 1H), 8.56 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.38-8.33 (m, 2H), 7.44 (d, J=4.8 Hz, 1H), 7.39 (dd, J=5.2, 1.6 Hz, 1H), 7.37-7.29 (m, 4H), 7.29-7.21 (m, 1H), 4.18 (s, 2H), 3.94 (s, 3H). MS: 387 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.00 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.28 (d, J=1.4 Hz, 1H), 7.55 (d, J=1.9 Hz, 1H), 7.40 (dd, J=5.2, 1.5 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.21 (m, 1H), 6.63 (d, J=1.9 Hz, 1H), 4.18 (s, 2H), 3.96 (s, 3H). MS: 360 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.97 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.42-7.29 (m, 5H), 7.29-7.20 (m, 1H), 6.40 (s, 1H), 4.18 (s, 2H), 3.87 (s, 3H), 2.19 (s, 3H). MS: 374 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.08 (s, 1H), 8.65-8.41 (m, 1H), 8.31 (d, J=3.7 Hz, 1H), 7.63-7.41 (m, 1H), 7.41-7.19 (m, 5H), 7.15 (d, J=3.8 Hz, 1H), 4.19 (s, 2H), 4.04 (s, 3H). MS: 428 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, o-methylphenylboronic acid was used in place of phenylboronic acid, and 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.80 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.27-8.11 (m, 1H), 7.57-7.12 (m, 9H), 4.17 (s, 2H), 2.27 (s, 3H). MS: 370 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-chlorophenylboronic acid was used in place of phenylboronic acid, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.84 (s, 1H), 9.04 (s, 1H), 8.53-8.23 (m, 2H), 7.66-7.58 (m, 1H), 7.54-7.45 (m, 3H), 7.37-7.31 (m, 2H), 7.31-7.28 (m, 2H), 7.28-7.22 (m, 1H), 4.18 (s, 2H). MS: 390 [M+H]+.
The preparation was carried out in a similar manner to Example 1, except that in step 1, 2-chloro-5-methoxyphenylboronic acid was used in place of phenylboronic acid, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.82 (s, 1H), 9.04 (d, J=2.4 Hz, 1H), 8.49-8.23 (m, 2H), 7.59-7.44 (m, 1H), 7.37-7.31 (m, 2H), 7.31-7.27 (m, 2H), 7.27-7.22 (m, 1H), 7.07-7.02 (m, 2H), 4.18 (s, 2H), 3.81 (s, 3H). MS: 420 [M+H]+.
Step 1: Synthesis of 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole
3-(Trifluoromethyl)-1H-pyrazole (1.09 g, 8 mmol) was dissolved in anhydrous tetrahydrofuran (24 mL), and under argon protection at 0° C., sodium hydride was added in batches (60%, 385 mg, 9.6 mmol). After reacting for 40 minutes, 2-bromopropane (1.28 g, 10.4 mmol) was added dropwise, and the reaction was warmed to 25° C. and reacted for 16 hours. The reaction solution was quenched with saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to afford 300 mg of product, MS: 179 [M+H]+.
Step 2: Synthesis of (1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid
1-Isopropyl-3-(trifluoromethyl)-1H-pyrazole (300 mg, 1.7 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL), and under argon protection at −78° C., n-butyllithium (2.5M, 1 mL, 2.5 mmol) was added dropwise. After reacting at this temperature for 1 hour, trimethyl borate (351 mg, 3.4 mmol) was added, and slowly warmed up overnight. The reaction solution was quenched with saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to afford 70 mg of product, MS: 223 [M+H]+.
Step 3 to Step 4: 5-benzyl-N-(4-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
The preparation was carried out in a similar manner to Example 1, except that in step 1, (1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)boronic acid was used in place of phenylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.08 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.26 (s, 1H), 7.41-7.29 (m, 5H), 7.29-7.21 (m, 1H), 7.04 (s, 1H), 4.86-4.60 (m, 1H), 4.18 (s, 2H), 1.45 (d, J=6.5 Hz, 6H). MS: 456 [M+H]+.
Step 1: Synthesis of 4-(5-fluoro-2-methylphenyl)pyridin-2-amine
4-Bromopyridin-2-amine (400 mg, 2.3 mmol), pinacol diborate (645 mg, 2.5 mmol), Pd(dppf)Cl2 (170 mg, 0.2 mmol) and potassium acetate (564 mg, 5.8 mmol) were placed in dioxane (12 mL), and reacted at 85° C. for 16 hours under argon protection. The reaction solution was cooled to 25° C., and 2-bromo-4-fluoro-1-methylbenzene (321 mg, 1.7 mmol), Pd(dppf)Cl2 (150 mg, 0.2 mmol) and an aqueous solution (1 mL) of sodium carbonate (360 mg, 3.4 mmol) was added, and continued to react under argon protection at 100° C. for 5 hours. The reaction solution was cooled and evaporated to dryness, and subjected to column chromatography to afford 240 mg of brown solid. MS: 203 [M+H]+.
Step 2: Synthesis of 5-benzyl-N-(4-(5-fluoro-2-methylphenyl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
4-(5-Fluoro-2-methylphenyl)pyridin-2-amine (0.7 mmol) was placed in dry xylene (3 mL), and trimethyl aluminum (3M, 0.7 mL) was slowly added under argon protection. After reacting at 25° C. for 1 hour, intermediate 1 (197 mg, 0.9 mmol) was added, and reacted at 100° C. for 16 hours. The reaction solution was cooled and diluted with methanol, evaporated to dryness and subjected to column chromatography and preparative liquid chromatography to prepare the product. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.96 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.54-7.00 (m, 9H), 4.18 (s, 2H), 2.24 (s, 3H). MS: 388 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-4-chloro-1-methylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.50 (s, 1H), 9.96 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.57-7.06 (m, 9H), 4.17 (s, 2H), 2.24 (s, 3H). MS: 404 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-4-cyano-1-methylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.93 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.74 (dd, J=8.1, 2.0 Hz, 1H), 7.68-7.53 (m, 2H), 7.38-7.30 (m, 4H), 7.30-7.23 (m, 2H), 4.20 (s, 2H), 2.35 (s, 3H). MS: 395 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-4-trifluoromethyl-1-methylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.93 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.74 (dd, J=8.1, 2.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.39-7.23 (m, 6H), 4.20 (s, 2H), 2.35 (s, 3H). MS: 438 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-4-methylsulfonyl-1-methylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.00 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.91 (dd, J=8.0, 2.1 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.40-7.21 (m, 6H), 4.18 (s, 2H), 3.26 (s, 3H), 2.37 (s, 3H). MS: 448 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 7-bromo-2,3-dihydrobenzofuran was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (600 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.78 (s, 1H), 8.53 (s, 1H), 8.39 (d, J=5.3 Hz, 1H), 7.52 (d, J=5.3 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.38-7.30 (m, 5H), 7.27 (d, J=7.2 Hz, 1H), 7.03-6.98 (m, 1H), 4.63 (t, J=8.7 Hz, 2H), 4.18 (s, 2H), 3.27 (t, J=8.7 Hz, 2H). MS: 398 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 4-bromo-2,3-dihydro-1H-indene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.27 (d, J=1.5 Hz, 1H), 7.60-7.12 (m, 9H), 4.18 (s, 2H), 3.04-2.88 (m, 4H), 2.11-1.95 (m, 2H). MS: 396 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 5-bromochroman was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.44-7.30 (m, 4H), 7.30-7.14 (m, 3H), 6.91-6.76 (m, 2H), 4.27-4.09 (m, 4H), 2.61 (t, J=6.5 Hz, 2H), 1.95-1.78 (m, 2H). MS: 412 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 4-bromobenzo[d][1,3]dioxole was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (600 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.85 (s, 1H), 8.57 (s, 1H), 8.44 (d, J=5.3 Hz, 1H), 7.55 (d, J=5.3 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.08-6.97 (m, 2H), 6.15 (s, 2H), 4.18 (s, 2H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 5-bromo-2,3-dihydrobenzo[b][1,4]dioxine was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (600 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.84 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.39-7.29 (m, 5H), 7.29-7.21 (m, 1H), 7.02-6.92 (m, 3H), 4.34-4.25 (m, 4H), 4.17 (s, 2H). MS: 414 [M+H]+.
Step 1: Synthesis of 5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate
5,6,7,8-tetrahydronaphthalen-1-ol was dissolved in dichloromethane (600 mg, 4 mmol) and pyridine (480 mg, 6.1 mmol), trifluoromethanesulfonic anhydride (1.37 g, 4.8 mmol) was added dropwise under argon protection at 0° C., and the reaction was warmed to 25° C. and reacted for 5 hours. The reaction solution was diluted with dichloromethane, washed with 1M HCl, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford 444 mg of colorless oil. MS: 281 [M+H]+.
Step 2 to Step 3: The preparation was carried out in a similar manner to Example 33, except that in step 1, 5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.88 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.07 (s, 1H), 7.40-7.29 (m, 4H), 7.29-7.12 (m, 4H), 7.03 (dd, J=7.3, 1.6 Hz, 1H), 4.17 (s, 2H), 2.81 (t, J=6.4 Hz, 2H), 2.56 (t, J=6.2 Hz, 2H), 1.81-1.71 (m, 2H), 1.71-1.59 (m, 2H). MS: 410 [M+H]+.
Step 1: Synthesis of 3-chloro-5-cyclopropyl-2-methoxypyridine
5-bromo-3-chloro-2-methoxypyridine (500 mg, 2.2 mmol), cyclopropylboronic acid (212 mg, 2.5 mmol), Pd(dppf)Cl2 (145 mg, 0.2 mmol) and potassium carbonate (930 mg, 6.7 mmol) were placed in a mixture of dioxane (8 mL) and water (2 mL), and reacted for 16 hours under argon protection at 80° C. The reaction solution was evaporated to dryness and subjected to column chromatography to afford 165 mg of product, MS: 184 [M+H]+.
Step 2 to Step 3: The preparation was carried out in a similar manner to Example 33, except that in step 1, 3-chloro-5-cyclopropyl-2-methoxypyridine was used in place of 2-bromo-4-fluoro-1-methylbenzene, and reacted at 120° C. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.87 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.43-7.30 (m, 5H), 7.30-7.21 (m, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 2.05-1.90 (m, 1H), 1.04-0.88 (m, 2H), 0.82-0.67 (m, 2H). MS: 427 [M+H]+.
Step 1: Synthesis of 5-cyclopropyl-2-methylphenol
The operation is the same as step 1 of Example 44, but 5-bromo-2-methylphenol was used in place of 5-bromo-3-chloro-2-methoxypyridine. MS: 149 [M+H]+.
Step 2 to Step 4:
The preparation was carried out in a similar manner to Example 43, except that in step 1, but 5-cyclopropyl-2-methylphenol was used in place of 5,6,7,8-tetrahydronaphthalen-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.46-7.11 (m, 7H), 7.11-6.87 (m, 2H), 4.17 (s, 2H), 2.21 (s, 3H), 2.02-1.84 (m, 1H), 1.00-0.87 (m, 2H), 0.76-0.56 (m, 2H). MS: 410 [M+H]+.
Step 1: Synthesis of 4-(5-bromo-2-methoxyphenyl)pyridin-2-amine
The operation is the same as step 1 of Example 1, but (5-bromo-2-methoxyphenyl)boronic acid was used in place of phenylboronic acid. MS: 279 [M+H]+.
Step 2: Synthesis of 4-(5-cyclopropyl-2-methoxyphenyl)pyridin-2-amine
The operation is the same as step 1 of Example 44, but 4-(5-bromo-2-methoxyphenyl)pyridin-2-amine was used in place of 5-bromo-3-chloro-2-methoxypyridine. MS: 241 [M+H]+.
Step 3: Synthesis of 5-benzyl-N-(4-(5-cyclopropyl-2-methoxyphenyl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
The operation is the same as step 2 of Example 1, but 4-(5-cyclopropyl-2-methoxyphenyl)pyridin-2-amine was used in place of 4-phenylpyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.79 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.27 (s, 1H), 7.40-7.29 (m, 5H), 7.29-7.21 (m, 1H), 7.14 (dd, J=8.5, 2.3 Hz, 1H), 7.11-7.03 (m, 2H), 4.18 (s, 2H), 3.76 (s, 3H), 2.00-1.88 (m, 1H), 0.97-0.86 (m, 2H), 0.70-0.58 (m, 2H). MS: 426 [M+H]+.
Step 1: Synthesis of 4-(cyclopent-1-en-1-yl)pyridin-2-amine
The operation is the same as step 1 of Example 1, but cyclopent-1-en-1-ylboronic acid was used in place of phenylboronic acid. MS: 161 [M+H]+.
Step 2: Synthesis of 4-cyclopentylpyridin-2-amine
4-(Cyclopent-1-en-1-yl)pyridin-2-amine (160 mg, 1 mmol) was dissolved in a mixture of ethanol (2 mL) and ethyl acetate (1 mL), to which a drop of hydrochloric acid and palladium on carbon (10%, 10 mg) was added, and reacted for 16 hours under hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth. The filtrate was evaporated to dryness, diluted with dichloromethane, washed with saturated aqueous solution of sodium carbonate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford 140 mg of yellow oil. MS: 163 [M+H]+.
Step 3: Synthesis of 5-benzyl-N-(4-cyclopentylpyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
The operation is the same as step 2 of Example 1, but 4-cyclopentylpyridin-2-amine was used in place of 4-phenylpyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.70 (s, 1H), 8.23 (d, J=5.1 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.42-7.29 (m, 4H), 7.29-7.18 (m, 1H), 7.09 (dd, J=5.1, 1.5 Hz, 1H), 4.16 (s, 2H), 3.11-2.95 (m, 1H), 2.15-1.97 (m, 2H), 1.86-1.73 (m, 2H), 1.73-1.60 (m, 2H), 1.60-1.44 (m, 2H). MS: 348 [M+H]+.
The preparation was carried out in a similar manner to Example 47, except that in step 1, cyclohex-1-en-1-ylboronic acid was used in place of cyclopent-1-en-1-ylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.68 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.39-7.28 (m, 4H), 7.28-7.19 (m, 1H), 7.12-7.03 (m, 1H), 4.15 (s, 2H), 2.64-2.53 (m, 1H), 1.89-1.74 (m, 4H), 1.75-1.64 (m, 1H), 1.48-1.31 (m, 4H), 1.30-1.18 (m, 1H). MS: 362 [M+H]+.
The preparation was carried out in a similar manner to Example 47, except that in step 1, (3,6-dihydro-2H-pyran-4-yl)boronic acid was used in place of cyclopent-1-en-1-ylboronic acid. 1H NMR (400 MHz, DMSO-d6) δ 14.53 (s, 1H), 9.69 (s, 1H), 8.27 (d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.42-7.18 (m, 5H), 7.12 (d, J=5.3 Hz, 1H), 4.19 (s, 2H), 4.02-3.86 (m, 2H), 3.53-3.37 (m, 2H), 2.95-2.78 (m, 1H), 1.81-1.52 (m, 4H). MS: 364 [M+H]+.
Step 1: Synthesis of 3-bromo-2-methoxy-5-methylpyridine
Anhydrous methanol (100 mg, 3.1 mmol) was dissolved in anhydrous DMF (3 mL), and sodium hydride (60%, 115 mg, 2.9 mmol) was added under argon protection at 0° C. After reacting for 1 hour, 3-bromo-2-chloro-5-methylpyridine (400 mg, 1.9 mmol) in DMF (1 mL) was added dropwise, and reacted at 60° C. for 16 hours. MS: 202 [M+H]+.
Step 2 to Step 3: The preparation was carried out in a similar manner to Example 33, except that in step 1, 3-bromo-2-methoxy-5-methylpyridine was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.86 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.39 (dd, J=5.2, 1.6 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.21 (m, 1H), 4.18 (s, 2H), 3.88 (s, 3H), 2.30 (s, 3H). MS: 401 [M+H]+.
The preparation was carried out in a similar manner to Example 50, except that in step 1, anhydrous ethanol was used in place of anhydrous methanol. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.80 (s, 1H), 8.47 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.07 (dd, J=2.3, 1.0 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.41 (dd, J=5.2, 1.6 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.21 (m, 1H), 4.37 (q, J=7.1 Hz, 2H), 4.18 (s, 2H), 2.29 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS: 415 [M+H]+.
The preparation was carried out in a similar manner to Example 50, except that in step 1, anhydrous isopropanol was used in place of anhydrous methanol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.91-9.71 (m, 1H), 8.51 (s, 1H), 8.40 (d, J=5.2 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.44-7.18 (m, 6H), 5.34 (p, J=6.2 Hz, 1H), 4.18 (s, 2H), 2.28 (s, 3H), 1.31 (d, J=6.2 Hz, 6H). MS: 429 [M+H]+.
Step 1: Synthesis of 6-chloro-2-ethoxy-3-methylpyridine
Anhydrous ethanol (830 mg, 18 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and sodium hydride (60%, 600 mg, 15 mmol) was added at 0° C. After reacting for 30 minutes, 2,6-dichloro-3-methylpyridine (810 mg, 5 mmol) in tetrahydrofuran (5 mL) was added, and reacted at 40° C. for 24 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to afford 300 mg of product. MS: 172 [M+H]+.
Step 2 to Step 3: The preparation was carried out in a similar manner to Example 33, except that in step 1, 6-chloro-2-ethoxy-3-methylpyridine was used in place of 2-bromo-4-fluoro-1-methylbenzene, and reacted at 120° C. 1H NMR (400 MHz, DMSO-d6) δ 14.21 (s, 1H), 9.86 (s, 1H), 8.86 (d, J=3.6 Hz, 1H), 8.53-8.32 (m, 1H), 7.84-7.77 (m, 1H), 7.71 (dd, J=7.8, 3.6 Hz, 1H), 7.59 (dd, J=7.8, 3.8 Hz, 1H), 7.40-7.30 (m, 4H), 7.27 (d, J=7.0 Hz, 1H), 4.56-4.43 (m, 2H), 4.18 (s, 2H), 2.21 (s, 3H), 1.52-1.36 (m, 3H). MS: 415 [M+H]+.
The preparation was carried out in a similar manner to Example 53, except that in step 1, 2-methoxyethanol was used in place of anhydrous ethanol. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.87 (s, 1H), 8.85 (d, J=1.3 Hz, 1H), 8.44 (d, J=5.3 Hz, 1H), 7.81 (dd, J=5.3, 1.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.20 (m, 1H), 4.64-4.51 (m, 2H), 4.18 (s, 2H), 3.82-3.73 (m, 2H), 3.45 (s, 3H), 2.22 (s, 3H). MS: 445 [M+H]+.
Step 1: Synthesis of tert-butyl (3-bromo-4-methylphenyl)carbamate
3-Bromo-4-methylaniline (1.86 g, 10 mmol) was placed in dichloromethane (25 mL), 4-dimethylaminopyridine (120 mg, 1 mmol) and triethylamine (2 g, 20 mmol) were added, a solution of di-tert-butyl dicarbonate (2.4 g, 11 mmol) in dichloromethane (5 mL) was added dropwise under argon protection at 0° C., and reacted at 25° C. for 4 hours after the addition. The reaction solution was diluted with dichloromethane, washed with saturated aqueous solution of ammonium chloride, washed with brine, dried over anhydrous sodium sulfate, evaporated to dryness and filtered to afford 2.84 g crude product.
Step 2: Synthesis of tert-butyl (3-bromo-4-methylphenyl)(methyl)carbamate
Tert-butyl (3-bromo-4-methylphenyl)carbamate (2.84 g, 9.9 mmol) was dissolved in DMF, and sodium hydride (60%, 475 mg, 11.9 mmol) was added in batches at 0° C. After reacting at 0° C. for 30 minutes, iodomethane (2.1 g, 14.8 mmol) was added dropwise, and reacted at 25° C. for 3 hours. The reaction solution was quenched with saturated aqueous solution of ammonium chloride, diluted with ethyl acetate, washed with saturated aqueous solution of ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, purified by column chromatography to afford 2.5 g.
Step 3: Synthesis of 3-bromo-N,4-dimethylaniline
Tert-butyl (3-bromo-4-methylphenyl)(methyl)carbamate (2.5 g, 8.3 mmol) was dissolved in dichloromethane (25 mL), trifluoroacetic acid (10 mL) was added dropwise at 0° C., and reacted at 25° C. for 3 hours. The reaction solution was concentrated, an aqueous solution of sodium carbonate was added dropwise to adjust the pH to 9, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford 1.5 g of crude product. MS: 200 [M+H]+.
Step 4: Synthesis of 3-bromo-N-(2-methoxyethyl)-N,4-dimethylaniline
3-Bromo-N,4-dimethylaniline (200 mg, 1 mmol) was dissolved in DMF, potassium carbonate (275 mg, 1.5 mmol) and 1-bromo-2-methoxyethane (180 mg, 1.3 mmol) were added, and reacted for 24 hours at 70° C. in sealed tube. The reaction solution was cooled, diluted with ethyl acetate, washed with saturated ammonium chloride and brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford 180 mg of the product. MS: 258 [M+H]+.
Step 5 to Step 6: The preparation was carried out in a similar manner to Example 33, except that in step 1, 3-bromo-N-(2-methoxyethyl)-N,4-dimethylaniline was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.86 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.38-7.29 (m, 4H), 7.27 (dd, J=6.1, 2.5 Hz, 1H), 7.19 (dd, J=5.1, 1.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.72 (dd, J=8.5, 2.8 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 4.17 (s, 2H), 3.54-3.43 (m, 4H), 3.24 (s, 3H), 2.90 (s, 3H), 2.13 (s, 3H). MS: 457 [M+H]+.
The operation is the same as Example 55, but 1-bromo-2-ethoxyethane was used in place of 1-bromo-2-methoxyethane in step 4. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.85 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.46-7.29 (m, 4H), 7.27 (d, J=6.5 Hz, 1H), 7.19 (dd, J=5.2, 1.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.72 (dd, J=8.5, 2.8 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 4.18 (s, 2H), 3.56-3.45 (m, 4H), 3.41 (q, J=7.0 Hz, 2H), 2.90 (s, 3H), 2.13 (s, 3H), 1.07 (t, J=7.0 Hz, 3H). MS: 471 [M+H]+.
The operation is the same as Example 55, but 3-bromo-1-propanol was used in place of 1-bromo-2-methoxyethane in step 4. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.88 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.42-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.19 (dd, J=5.1, 1.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.72 (dd, J=8.5, 2.7 Hz, 1H), 6.54 (d, J=2.7 Hz, 1H), 4.49 (t, J=5.0 Hz, 1H), 4.17 (s, 2H), 3.51-3.36 (m, 4H), 2.86 (s, 3H), 2.13 (s, 3H), 1.73-1.55 (m, 2H). MS: 457 [M+H]+.
The operation is the same as Example 55, but 1-bromo-3-methoxypropane was used in place of 1-bromo-2-methoxyethane in step 4. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.88 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.43-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.19 (dd, J=5.1, 1.6 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.70 (dd, J=8.5, 2.8 Hz, 1H), 6.54 (d, J=2.8 Hz, 1H), 4.17 (s, 2H), 3.40-3.34 (m, 4H), 3.19 (s, 3H), 2.86 (s, 3H), 2.13 (s, 3H), 1.77-1.63 (m, 2H). MS: 471 [M+H]+.
Step 1: Synthesis of 3-bromo-4-methylbenzenethiol
3-bromo-4-methylaniline (1.12 g, 6 mmol) was dissolved in 6M hydrochloric acid solution, and at −10° C., an aqueous solution (6 mL) of sodium nitrite (1.04 g, 15 mmol) was slowly added dropwise. After reacting for 30 minutes, this mixture was added dropwise to an aqueous solution (15 mL) of potassium ethylxanthate (3.36 g, 21 mmol), reacted at 80° C. for 20 minutes, and then cooled. The reaction solution was diluted with water, extracted with ether, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was dissolved in ethanol (30 mL), and potassium hydroxide (3.36 g, 60 mmol) in water (10 mL) was added dropwise at 0° C., and reacted at 50° C. for 3 hours. The reaction solution was concentrated, diluted with water, adjusted to pH 4 with 6M hydrochloric acid, and extracted with ether. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford 1 g of crude product. MS: 203 [M+H]+.
Step 2 to Step 4: Synthesis of 5-benzyl-N-(4-(5-((3-methoxypropyl)thio)-2-methylphenyl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
The operation is the same as steps 4 to 6 of Example 55, but 3-bromo-4-methylbenzenethiol was used in place of 3-bromo-N,4-dimethylaniline in the fourth step, and 1-bromo-3-methoxypropane was used in place of 1-bromo-2-methoxyethane in the fourth step. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.92 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.41-7.29 (m, 6H), 7.29-7.13 (m, 3H), 4.18 (s, 2H), 3.40 (t, J=6.1 Hz, 2H), 3.19 (s, 3H), 3.00 (t, J=7.2 Hz, 2H), 2.23 (s, 3H), 1.84-1.72 (m, 2H). MS: 474 [M+H]+.
Step 1: Synthesis of 5-methoxy-2-methylpyridine
The operation is the same as step 4 of Example 55, but iodomethane was used in place of 1-bromo-2-methoxyethane, and reacted at 50° C. in sealed tube. MS: 124 [M+H]+.
Step 2 to Step 5: Synthesis of 2-bromo-3-methoxy-6-methylpyridine
Synthesis was made with reference to the method in Gonzalez, Javier et al/PCT Int. Appl., 2006018725, 23 Feb. 2006. In the third step, the separated 3-methoxy-6-methyl-2-nitropyridine N-oxide was used for the subsequent reaction.
Step 6 and 7: The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-3-methoxy-6-methylpyridine was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.82 (s, 1H), 8.71 (s, 1H), 8.41 (d, J=5.3 Hz, 1H), 7.68 (dd, J=5.3, 1.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.40-7.29 (m, 5H), 7.29-7.22 (m, 1H), 4.18 (s, 2H), 3.87 (s, 3H), 3.33 (s, 3H). MS: 401 [M+H]+.
The operation is the same as step of Example 60, but 5-methoxy-2-methyl-4-nitropyridine N-oxide separated in the third step was used for the subsequent reaction. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.93 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.43-7.33 (m, 5H), 7.33-7.26 (m, 2H), 4.21 (s, 2H), 3.92 (s, 3H), 2.50 (s, 3H). MS: 401 [M+H]+.
The operation is the same as Example 60, but bromoethane was used in place of iodomethane in the first step, and in the third step, the nitration process only gets 3-ethoxy-6-methyl-2-nitropyridine N-oxide. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.80 (s, 1H), 8.84 (s, 1H), 8.41 (d, J=5.3 Hz, 1H), 7.74 (dd, J=5.3, 1.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.39-7.29 (m, 5H), 7.29-7.22 (m, 1H), 4.25-4.08 (m, 4H), 2.48 (s, 3H), 1.39 (t, J=6.9 Hz, 3H). MS: 415 [M+H]+.
The preparation was carried out in a similar manner to Example 33, except that in step 1, 4-bromo-2-ethyl-5-methoxypyridine (see Gonzalez, Javier et al/PCT Int. Appl., 2006018725, 23 Feb. 2006 for its synthetic method) was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.93 (s, 1H), 8.50-8.38 (m, 2H), 8.33 (d, J=1.4 Hz, 1H), 7.43-7.30 (m, 5H), 7.30-7.21 (m, 2H), 4.18 (s, 2H), 3.90 (s, 3H), 2.76 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H). MS: 415 [M+H]+.
Step 1: Synthesis of 2-bromo-4-(2-(tert-butoxy)ethoxy)-1-methylbenzene
3-Bromo-4-methylphenol (187 mg, 1 mmol), 2-(tert-butoxy)ethan-1-ol (142 mg, 1.2 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were placed in anhydrous tetrahydrofuran (3 mL), diisopropyl azodicarboxylate (303 mg, 1.5 mmol) was added dropwise under argon protection at 0° C., and after the addition, reacted at 25° C. for 16 hours. The reaction solution was evaporated to dryness and purified by column chromatography to afford 230 mg of colorless oil. MS: 287 [M+H]+.
Step 2 to Step 3: The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-4-(2-(tert-butoxy)ethoxy)-1-methylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.90 (s, 1H), 8.48-8.37 (m, 1H), 8.12 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.18 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.12-3.99 (m, 2H), 3.69-3.58 (m, 2H), 2.19 (s, 3H), 1.15 (s, 9H). MS: 486 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, tetrahydro-2H-pyran-4-ol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.40-7.29 (m, 4H), 7.29-7.14 (m, 3H), 6.99 (dd, J=8.5, 2.7 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 4.65-4.54 (m, 1H), 4.20 (s, 2H), 3.89-3.76 (m, 2H), 3.52-3.41 (m, 2H), 2.18 (s, 3H), 2.02-1.88 (m, 2H), 1.66-1.50 (m, 2H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, oxetan-3-yl methanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.45-7.14 (m, 7H), 6.97 (dd, J=8.4, 2.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 4.78-4.64 (m, 2H), 4.48-4.36 (m, 2H), 4.22 (d, J=6.8 Hz, 2H), 4.18 (s, 2H), 3.46-3.34 (m, 1H), 2.20 (s, 3H). MS: 456 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.42-7.29 (m, 4H), 7.29-7.12 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 3.92-3.79 (m, 4H), 3.33-3.27 (m, 2H), 2.19 (s, 3H), 2.05-1.90 (m, 1H), 1.72-1.62 (m, 2H), 1.38-1.23 (m, 2H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 2-fluoro-1-ethanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.93 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.44-7.14 (m, 7H), 6.98 (dd, J=8.4, 2.8 Hz, 1H), 6.87 (d, J=2.7 Hz, 1H), 4.84-4.75 (m, 1H), 4.72-4.61 (m, 1H), 4.33-4.26 (m, 1H), 4.26-4.20 (m, 1H), 4.18 (s, 2H), 2.20 (s, 3H). MS: 432 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 2-cyclopropyl-1-ethanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.0 Hz, 1H), 8.12 (s, 1H), 7.39-7.30 (m, 4H), 7.30-7.19 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.69-1.55 (m, 2H), 0.89-0.75 (m, 1H), 0.50-0.37 (m, 2H), 0.20-0.06 (m, 2H). MS: 454 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 2-isobutoxy-1-ethanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.45-7.15 (m, 7H), 6.95 (dd, J=8.4, 2.8 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.15-4.06 (m, 2H), 3.74-3.61 (m, 2H), 3.21 (d, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.88-1.68 (m, 1H), 0.84 (d, J=6.7, 2.5 Hz, 6H). MS: 486 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 1-(2-hydroxyethyl)pyrrolidin-2-one was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.23 (m, 2H), 7.21 (dd, J=5.0, 1.6 Hz, 1H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.09 (t, J=5.5 Hz, 2H), 3.53 (t, J=5.5 Hz, 2H), 3.45 (t, J=7.0 Hz, 2H), 2.26-2.13 (m, 5H), 1.95-1.83 (m, 2H). MS: 497 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-(methylthio)-1-propanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.42-7.29 (m, 4H), 7.29-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.06 (t, J=6.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.19 (s, 3H), 2.05 (s, 3H), 2.02-1.90 (m, 2H). MS: 474 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-(methylsulfonyl)-1-propanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.88 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.41-7.15 (m, 7H), 6.96 (dd, J=8.4, 2.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.11 (t, J=6.2 Hz, 2H), 3.31-3.23 (m, 2H), 3.01 (s, 3H), 2.20 (s, 3H), 2.17-2.05 (m, 2H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 2-chloro-4-hydroxybenzonitrile was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.02 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.34 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.42 (d, J=4.9 Hz, 1H), 7.39-7.30 (m, 4H), 7.30-7.18 (m, 3H), 4.23 (t, J=4.6 Hz, 2H), 4.18 (s, 2H), 3.67 (t, J=4.7 Hz, 2H), 1.15 (s, 9H). MS: 497 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.32-7.13 (m, 2H), 6.95 (dd, J=8.4, 2.8 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.09-4.00 (m, 2H), 3.67-3.57 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.39-2.22 (m, 1H), 2.20 (s, 3H), 1.80-1.66 (m, 2H), 1.66-1.44 (m, 4H), 1.29-1.17 (m, 2H), 1.15 (s, 9H). MS: 478 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 3, ethyl 5-(cyclopentylmethyl)-1,3,4-oxadiazol-2-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.33-7.20 (m, 2H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.10-3.99 (m, 2H), 3.67-3.58 (m, 2H), 2.97 (d, J=7.4 Hz, 2H), 2.37-2.24 (m, 1H), 2.20 (s, 3H), 1.86-1.73 (m, 2H), 1.70-1.44 (m, 4H), 1.33-1.18 (m, 2H), 1.15 (s, 9H). MS: 479 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.93-9.76 (m, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.32-7.15 (m, 2H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.04 (t, J=4.8 Hz, 2H), 3.63 (t, J=4.9 Hz, 2H), 2.66 (d, J=7.0 Hz, 2H), 2.20 (s, 3H), 1.83-1.53 (m, 6H), 1.30-1.06 (m, 12H), 1.06-0.88 (m, 2H). MS: 492 [M+H]+.
Step 1: Synthesis of 2-bromo-4-(2-(tert-butoxy)ethoxy)benzaldehyde
The operation is the same as step 1 of Example 64, but 2-bromo-4-hydroxybenzaldehyde was used in place of 2-bromo-3-methylphenol in step 1.
Step 2: Synthesis of 2-bromo-4-(2-(tert-butoxy)ethoxy)-1-vinylbenzene
Methyltriphenylphosphonium bromide (1.25 g, 3.5 mmol) was placed in anhydrous tetrahydrofuran (7 mL), and n-butyl lithium was added dropwise at −20° C. under argon protection. After reacting at 0° C. for 1 hour, 2-bromo-4-(2-(tert-butoxy)ethoxy)benzaldehyde (700 mg, 2.3 mmol) in anhydrous tetrahydrofuran (2.5 mL) solution was added, heated to 25° C. and reacted for 5 hours. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the crude product was directly used in the next step.
Step 3 to Step 4: The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-4-(2-(tert-butoxy)ethoxy)-1-vinylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.92 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.38-7.30 (m, 4H), 7.29-7.22 (m, 1H), 7.17 (dd, J=5.0, 1.5 Hz, 1H), 7.06 (dd, J=8.7, 2.6 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.55 (dd, J=17.4, 11.0 Hz, 1H), 5.71 (d, J=17.4 Hz, 1H), 5.15 (d, J=11.1 Hz, 1H), 4.17 (s, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.64 (dd, J=5.6, 4.0 Hz, 2H), 1.15 (s, 9H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 3.93-3.86 (m, 1H), 3.86-3.78 (m, 3H), 3.32-3.23 (m, 2H), 2.77 (d, J=7.4 Hz, 2H), 2.35-2.22 (m, 1H), 2.19 (s, 3H), 2.06-1.92 (m, 1H), 1.79-1.44 (m, 8H), 1.40-1.12 (m, 4H). MS: 476 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.84 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.34-7.12 (m, 2H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 3.93-3.79 (m, 4H), 3.40-3.31 (m, 3H), 2.72-2.62 (m, 2H), 2.19 (s, 3H), 2.07-1.92 (m, 1H), 1.84-1.70 (m, 1H), 1.70-1.53 (m, 6H), 1.41-1.05 (m, 5H), 1.05-0.90 (m, 2H). MS: 490 [M+H]+.
Step 1 to Step 2: Synthesis of 4-(5-(3-bromopropoxy)-2-methylphenyl)pyridin-2-amine
The operation is the same as steps 1 to 2 of Example 64, but 3-bromopropyl-1-ol was used in place of 2-(tert-butoxy)ethan-1-ol in step 1.
Step 3: Synthesis of 4-(5-(3-cyclobutoxypropoxy)-2-methylphenyl)pyridin-2-amine
Cyclobutanol (115 mg, 1.6 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and sodium hydride (60%, 65 mg, 1.6 mmol) was added under argon protection at 0° C. After 30 minutes of reaction, 4-(5-(3-bromopropoxy)-2-methylphenyl)pyridin-2-amine (200 mg, 0.6 mmol) in tetrahydrofuran was added dropwise, and reacted at 50° C. for 4 hours. The reaction was cooled, quenched with saturated ammonium chloride, the reaction solution was evaporated, and purified by column chromatography to afford 40 mg of product and 20 mg of by-product 4-(5-allyloxy)-2-methylphenyl)pyridin-2-amine. MS: 313 [M+H]+ and MS: 241 [M+H]+
Step 4: Synthesis of 5-benzyl-N-(4-(5-(3-cyclobutoxypropoxy)-2-methylphenyl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
The operation is the same as step 2 of Example 1, but 4-(5-(3-cyclobutoxypropoxy)-2-methylphenyl)pyridin-2-amine was used in place of 4-phenylpyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.88 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.49-7.30 (m, 4H), 7.30-7.17 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.93-3.81 (m, 1H), 3.42-3.39 (m, 2H), 2.19 (s, 3H), 2.16-2.06 (m, 2H), 1.96-1.85 (m, 2H), 1.85-1.71 (m, 2H), 1.66-1.53 (m, 1H), 1.50-1.36 (m, 1H). MS: 498 [M+H]+.
The operation is the same as Example 81, but the by-product 4-(5-allyloxy)-2-methylphenyl)pyridin-2-amine obtained in the third step was used for the subsequent reaction. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.92 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.96 (dd, J=8.4, 2.8 Hz, 1H), 6.85 (d, J=2.8 Hz, 1H), 6.11-5.96 (m, 1H), 5.45-5.32 (m, 1H), 5.32-5.19 (m, 1H), 4.64-4.53 (m, 2H), 4.17 (s, 2H), 2.19 (s, 3H). MS: 426 [M+H]+.
The operation is the same as Example 81, but isopropanol was used in place of cyclobutanol in the third step. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.89 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.48-7.10 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.58-3.44 (m, 3H), 2.19 (s, 3H), 1.95-1.80 (m, 2H), 1.06 (d, J=6.1 Hz, 6H). MS: 486 [M+H]+.
The operation is the same as Example 81, but piperidin-2-one was used in place of cyclobutanol in the third step. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.46-7.11 (m, 7H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.28-3.20 (m, 4H), 2.26-2.13 (m, 5H), 1.91 (t, J=6.8 Hz, 2H), 1.77-1.61 (m, 4H). MS: 525 [M+H]+.
Step 1: Synthesis of 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate
2-(2-methoxyethoxy)ethan-1-ol (1 g, 8.3 mmol) and triethylamine (2.1 g, 20.8 mmol) were dissolved in dichloromethane (30 mL), p-toluenesulfonyl chloride (1.75 g, 9.2 mmol) was added at 0° C., and reacted at 25° C. for 2 hours. Saturated aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford 1.8 g of yellow oil.
Step 2 to Step 4: 5-benzyl-N-(4-(5-(2-(2-methoxyethoxy)ethoxy)-2-methylphenyl)pyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide
The operation is the same as steps 4 to 6 of Example 55, but 3-bromo-4-methylphenol was used in place of 3-bromo-N,4-dimethylaniline in the fourth step, 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate was used in place of 1-bromo-2-methoxyethane in the fourth step. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.4 Hz, 1H), 7.37-7.29 (m, 4H), 7.29-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.95 (dd, J=8.4, 2.8 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.14-4.05 (m, 2H), 3.76-3.67 (m, 2H), 3.61-3.53 (m, 2H), 3.47-3.41 (m, 2H), 3.23 (s, 3H), 2.19 (s, 3H). MS: 488 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, oxetan-3-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.92 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.43-7.30 (m, 4H), 7.30-7.23 (m, 2H), 7.20 (dd, J=5.1, 1.5 Hz, 1H), 6.80 (dd, J=8.4, 2.7 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 5.36-5.26 (m, 1H), 4.96-4.86 (m, 2H), 4.61-4.50 (m, 2H), 4.18 (s, 2H), 2.19 (s, 3H). MS: 442 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.89 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.49-7.14 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.02 (t, J=6.3 Hz, 2H), 3.89-3.75 (m, 2H), 3.30-3.19 (m, 2H), 2.19 (s, 3H), 1.77-1.55 (m, 5H), 1.26-1.12 (m, 2H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.84 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.30-7.16 (m, 2H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.09-3.98 (m, 2H), 3.88-3.76 (m, 2H), 3.32-3.21 (m, 2H), 2.85-2.72 (m, 2H), 2.36-2.22 (m, 1H), 2.19 (s, 3H), 1.79-1.45 (m, 11H), 1.31-1.14 (m, 4H). MS: 490 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.31-7.15 (m, 2H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.03 (t, J=6.3 Hz, 2H), 3.87-3.75 (m, 2H), 3.32-3.21 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.83-1.72 (m, 1H), 1.71-1.54 (m, 9H), 1.31-1.09 (m, 6H), 1.05-0.88 (m, 2H). MS: 504 [M+H]+.
Step 1: Synthesis of 5-(3-bromo-4-methylphenoxy)valeronitrile
The operation is the same as step 4 of Example 55, but 3-bromo-4-methylphenol was used in place of 3-bromo-N,4-dimethylaniline in the fourth step, and 5-chlorovaleronitrile was used in place of 1-bromo-2-methoxyethane in the fourth step.
Step 2: Synthesis of 5-(3-bromo-4-methylphenoxy)-2-methylvaleronitrile
5-(3-Bromo-4-methylphenoxy)valeronitrile (268 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and LDA (2M, 0.8 mL, 1.6 mmol) was added dropwise at −78° C. under argon protection. After reacting for 1 hour, iodomethane (215 mg, 1.5 mmol) was added dropwise at the same temperature, the reaction was gradually warmed to 25° C., and reacted for 16 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried, and purified by column chromatography to afford 210 mg of product.
Step 3 to Step 4: The preparation was carried out in a similar manner to Example 33, except that in step 1, 5-(3-bromo-4-methylphenoxy)-2-methylvaleronitrile was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.47-7.16 (m, 7H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.02 (t, J=6.2 Hz, 2H), 2.99-2.84 (m, 1H), 2.19 (s, 3H), 1.93-1.74 (m, 2H), 1.74-1.60 (m, 2H), 1.24 (d, J=7.0 Hz, 3H). MS: 481 [M+H]+.
The operation is the same as step of Example 90, but the product of the first step 5-(3-bromo-4-methylphenoxy)valeronitrile was used directly to carry out the third to fourth step reaction. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.0 Hz, 1H), 8.11 (d, J=1.4 Hz, 1H), 7.41-7.30 (m, 4H), 7.29-7.18 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.02 (t, J=6.1 Hz, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.93-1.59 (m, 4H). MS: 467 [M+H]+.
Step 1: Synthesis of 2-bromo-1-methoxy-3-methylbenzene
2-Bromo-3-methylphenol (374 mg, 2 mmol) was placed in acetonitrile (6 mL), potassium carbonate (553 mg, 4 mmol) was added and stirred at 25° C. for 1 hour. Iodomethane (426 mg, 3 mmol) was added, and reacted at 80° C. for 16 hours in sealed tube. The reaction solution was diluted with ethyl acetate, and filtered. The filtrate was evaporated to dryness, and subjected to column chromatography to afford 340 mg of yellow oil. MS: 201 [M+H]+
Step 2 to Step 3: The preparation was carried out in a similar manner to Example 33, except that in step 1, 2-bromo-1-methoxy-3-methylbenzene was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.84 (s, 1H), 8.40 (dd, J=5.0, 0.8 Hz, 1H), 7.96 (s, 1H), 7.46-7.30 (m, 5H), 7.30-7.17 (m, 1H), 7.04 (dd, J=5.1, 1.5 Hz, 1H), 7.01-6.85 (m, 2H), 4.18 (s, 2H), 3.67 (s, 3H), 2.04 (s, 3H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoethane was used in place of iodomethane. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.83 (s, 1H), 8.39 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.43-7.29 (m, 4H), 7.29-7.16 (m, 2H), 7.05 (dd, J=5.1, 1.5 Hz, 1H), 7.01-6.89 (m, 2H), 4.18 (s, 2H), 3.98 (q, J=7.0 Hz, 2H), 2.05 (s, 3H), 1.13 (t, J=7.0 Hz, 3H). MS: 414 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane. 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 9.80 (s, 1H), 8.39 (d, J=5.1 Hz, 1H), 8.00 (s, 1H), 7.39-7.30 (m, 4H), 7.30-7.20 (m, 2H), 7.06 (d, J=5.1 Hz, 1H), 7.01-6.87 (m, 2H), 4.19 (s, 2H), 4.09-3.98 (m, 2H), 3.52-3.41 (m, 2H), 3.10 (s, 3H), 2.07 (s, 3H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromo-1-ethanol was used in place of iodomethane, and 3-bromo-2-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.93 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 8.10 (d, J=1.4 Hz, 1H), 7.50-7.21 (m, 6H), 7.16 (dd, J=5.1, 1.6 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 5.16-4.62 (m, 1H), 4.18 (s, 2H), 4.05 (t, J=5.0 Hz, 2H), 3.76 (t, J=5.0 Hz, 2H), 2.11 (s, 3H). MS: 430 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, and 3-bromo-2-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.21 (s, 1H), 9.93 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.54-7.20 (m, 6H), 7.16 (dd, J=5.0, 1.5 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 4.28-4.06 (m, 4H), 3.75-3.66 (m, 2H), 3.33 (s, 3H), 2.09 (s, 3H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-1-propanol was used in place of iodomethane, and 3-bromo-2-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.08 (d, J=1.4 Hz, 1H), 7.44-7.21 (m, 6H), 7.17 (dd, J=5.1, 1.5 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.58 (t, J=5.0 Hz, 1H), 4.17 (s, 2H), 4.09 (t, J=6.2 Hz, 2H), 3.64-3.56 (m, 2H), 2.08 (s, 3H), 1.95-1.84 (m, 2H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, and 3-bromo-2-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.92 (s, 1H), 8.51-8.31 (m, 1H), 8.20-7.99 (m, 1H), 7.42-7.30 (m, 4H), 7.30-7.20 (m, 2H), 7.16 (dd, J=5.1, 1.6 Hz, 1H), 7.04 (dd, J=8.4, 1.1 Hz, 1H), 6.85 (dd, J=7.7, 1.1 Hz, 1H), 4.17 (s, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.51 (t, J=6.3 Hz, 2H), 3.25 (s, 3H), 2.08 (s, 3H), 2.04-1.91 (m, 2H). MS: 458 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, and 3-bromo-2-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 8.09 (s, 1H), 7.40-7.21 (m, 6H), 7.17 (d, J=5.1 Hz, 1H), 7.04 (d, J=8.2 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.53-4.41 (m, 1H), 4.17 (s, 2H), 4.04 (t, J=6.3 Hz, 2H), 3.51-3.44 (m, 2H), 2.09 (s, 3H), 1.87-1.73 (m, 2H), 1.68-1.55 (m, 2H). MS: 458 [M+H]+.
Step 1 to Step 2: Synthesis of 4-(2-methyl-5-(octyloxy)phenyl)pyridin-2-amine
The operation is the same as steps 1 to 2 of Example 92, but 3-bromo-2-methylphenol was used in place of 2-bromo-3-methylphenol in step 1, and 1-bromooctane was used in place of iodomethane in step 1. MS: 313 [M+H]+.
Step 3: Intermediate 2 (98 mg, 0.48 mmol) was dissolved in DMF (3 mL), 1-propanephosphonic acid cyclic anhydride (50%, 305 mg, 0.48 mmol), diisopropylethylamine (124 mg, 0.96 mmol) and 4-(2-methyl-5-(octyloxy)phenyl)pyridin-2-amine (100 mg, 0.3 mmol) were added, and reacted at 25° C. for 16 hours. The reaction solution was diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and subjected to column chromatography and preparative liquid chromatography to afford 30 mg of white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.74 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.4 Hz, 1H), 7.41-7.29 (m, 4H), 7.29-7.13 (m, 3H), 6.91 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.6 Hz, 1H), 4.17 (s, 2H), 3.95 (t, J=6.5 Hz, 2H), 2.18 (s, 3H), 1.76-1.57 (m, 2H), 1.45-1.33 (m, 2H), 1.33-1.14 (m, 8H), 0.91-0.76 (m, 3H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.42-7.31 (m, 4H), 7.31-7.23 (m, 2H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.94 (dd, J=8.4, 2.8 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 4.18 (s, 2H), 3.77 (s, 3H), 2.19 (s, 3H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.21 (d, J=5.1 Hz, 1H), 6.95 (dd, J=8.5, 2.8 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 3.77 (s, 3H), 2.78 (d, J=7.5 Hz, 2H), 2.34-2.22 (m, 1H), 2.20 (s, 3H), 1.80-1.66 (m, 2H), 1.66-1.43 (m, 4H), 1.30-1.13 (m, 2H). MS: 392 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.34-7.16 (m, 2H), 7.03-6.88 (m, 1H), 6.83 (d, J=2.9 Hz, 1H), 3.77 (s, 3H), 2.66 (d, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.83-1.52 (m, 6H), 1.30-1.06 (m, 3H), 1.06-0.86 (m, 2H). MS: 406 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromo-4-ethylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.83 (s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.29 (d, J=1.4 Hz, 1H), 7.54-7.16 (m, 8H), 7.09 (d, J=8.4 Hz, 1H), 4.17 (s, 2H), 3.78 (s, 3H), 2.61 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H). MS: 414 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 2, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 10.82 (s, 1H), 9.03 (d, J=2.3 Hz, 1H), 8.44-8.29 (m, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.39-7.20 (m, 5H), 7.08-6.97 (m, 2H), 4.17 (s, 2H), 4.08 (q, J=7.0 Hz, 2H), 1.33 (t, J=6.9 Hz, 3H). MS: 434 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoethane was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.40-7.30 (m, 4H), 7.30-7.20 (m, 2H), 7.06 (dd, J=8.8, 3.1 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.18 (s, 2H), 4.08 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H). MS: 434 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoethane was used in place of iodomethane, and 3-bromo-4-methoxyphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.79 (s, 1H), 8.43-8.24 (m, 2H), 7.47-7.29 (m, 5H), 7.27 (d, J=6.5 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 7.01 (dd, J=9.0, 3.1 Hz, 1H), 6.94 (d, J=3.1 Hz, 1H), 4.19 (s, 2H), 4.03 (q, J=6.9 Hz, 2H), 3.75 (s, 3H), 1.32 (t, J=6.9 Hz, 3H). MS: 430 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoethane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.30 (m, 4H), 7.30-7.22 (m, 2H), 7.20 (dd, J=5.1, 1.5 Hz, 1H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.04 (q, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS: 414 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoethane was used in place of iodomethane, and 5-bromo-3-methyl-1H-pyrazole was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.98 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.35-8.14 (m, 1H), 7.51-7.15 (m, 6H), 6.35 (s, 1H), 4.29-3.95 (m, 4H), 2.21 (s, 3H), 1.36 (t, J=7.2 Hz, 3H). MS: 388 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromopropane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 2, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.83 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.49-8.20 (m, 2H), 7.48 (dd, J=8.6, 1.9 Hz, 1H), 7.41-7.31 (m, 2H), 7.31-7.28 (m, 2H), 7.28-7.22 (m, 1H), 7.07-6.98 (m, 2H), 4.74-4.64 (m, 1H), 4.18 (s, 2H), 1.28 (dd, J=6.1, 1.9 Hz, 6H). MS: 448 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromopropane was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.50 (dd, J=8.8, 2.8 Hz, 1H), 7.41-7.30 (m, 4H), 7.30-7.22 (m, 2H), 7.09-7.02 (m, 1H), 6.99 (d, J=3.0 Hz, 1H), 4.69 (p, J=6.0 Hz, 1H), 4.17 (s, 2H), 1.28 (d, J=6.1, 2.7 Hz, 6H). MS: 448 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromopropane was used in place of iodomethane, and 3-bromo-4-methoxyphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.84 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.30 (s, 1H), 7.40-7.29 (m, 5H), 7.29-7.22 (m, 1H), 7.09 (d, J=9.0 Hz, 1H), 7.00 (dd, J=8.9, 3.0 Hz, 1H), 6.93 (d, J=3.0 Hz, 1H), 4.56 (p, J=6.0 Hz, 1H), 4.18 (s, 2H), 3.75 (s, 3H), 1.25 (d, J=6.0 Hz, 6H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromopropane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 2, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 10.79 (s, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.25-8.08 (m, 1H), 7.42-7.16 (m, 6H), 6.88 (dd, J=8.4, 2.7 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 4.62 (p, J=6.0 Hz, 1H), 4.17 (s, 2H), 2.17 (s, 3H), 1.26 (d, J=6.0 Hz, 6H). MS: 428 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromopropane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.90 (s, 1H), 8.58-8.29 (m, 1H), 8.11 (s, 1H), 7.63-7.29 (m, 4H), 7.29-7.06 (m, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.78 (d, J=3.5 Hz, 1H), 4.67-4.54 (m, 1H), 4.17 (s, 2H), 2.18 (s, 3H), 1.26 (d, J=6.3, 3.3 Hz, 6H). MS: 428 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3,3-dimethylbutane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.48-7.13 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.02 (t, J=7.2 Hz, 2H), 2.18 (s, 3H), 1.65 (t, J=7.2 Hz, 2H), 0.95 (s, 9H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-chloroacetamide was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.91 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.54 (s, 1H), 7.42-7.30 (m, 5H), 7.30-7.22 (m, 2H), 7.20 (dd, J=5.1, 1.6 Hz, 1H), 6.96 (dd, J=8.4, 2.8 Hz, 1H), 6.88 (d, J=2.8 Hz, 1H), 4.44 (s, 2H), 4.18 (s, 2H), 2.20 (s, 3H). MS: 443 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-chloro-2-methylpropyl-2-ol was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.91-14.25 (m, 1H), 9.90 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.45-7.13 (m, 7H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.61 (s, 1H), 4.18 (s, 2H), 3.73 (s, 2H), 2.19 (s, 3H), 1.19 (s, 6H). MS: 458 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-chloro-2-methylpropyl-2-ol was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.87 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H), 7.32-7.17 (m, 2H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.63 (s, 1H), 3.73 (s, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.33-2.22 (m, 1H), 2.20 (s, 3H), 1.80-1.66 (m, 2H), 1.66-1.42 (m, 4H), 1.30-1.10 (m, 8H). MS: 450 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-chloro-2-methylpropyl-2-ol was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.34-7.14 (m, 2H), 6.95 (dd, J=8.5, 2.7 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.63 (s, 1H), 3.73 (s, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.20 (s, 3H), 1.84-1.53 (m, 6H), 1.31-1.05 (m, 9H), 1.05-0.88 (m, 2H). MS: 464 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromoacetonitrile was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.41-7.29 (m, 5H), 7.29-7.18 (m, 2H), 7.08 (dd, J=8.4, 2.8 Hz, 1H), 6.99 (d, J=2.8 Hz, 1H), 5.20 (s, 2H), 4.18 (s, 2H), 2.22 (s, 3H). MS: 425 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-(bromomethyl)tetrahydrofuran was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.44-7.29 (m, 4H), 7.29-7.12 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.26-4.07 (m, 3H), 4.02-3.86 (m, 2H), 3.82-3.72 (m, 1H), 3.72-3.61 (m, 1H), 2.19 (s, 3H), 2.06-1.92 (m, 1H), 1.92-1.73 (m, 2H), 1.73-1.58 (m, 1H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-(bromomethyl)tetrahydrofuran was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.30 (m, 4H), 7.30-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.00-3.84 (m, 2H), 3.83-3.70 (m, 2H), 3.70-3.58 (m, 1H), 3.57-3.47 (m, 1H), 2.71-2.57 (m, 1H), 2.19 (s, 3H), 2.07-1.92 (m, 1H), 1.72-1.57 (m, 1H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-(bromomethyl)tetrahydro-2H-pyran was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.94 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.15 (m, 3H), 6.93 (dd, J=8.6, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 3.97-3.81 (m, 3H), 3.63-3.56 (m, 2H), 2.18 (s, 3H), 1.85-1.73 (m, 1H), 1.68-1.57 (m, 1H), 1.55-1.39 (m, 3H), 1.37-1.16 (m, 1H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromo-1-ethanol was used in place of iodomethane, and 2-bromophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.78 (s, 1H), 8.47-8.26 (m, 2H), 7.46-7.39 (m, 3H), 7.37-7.31 (m, 4H), 7.26 (d, J=7.3 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.12-7.07 (m, 1H), 4.76 (t, J=5.5 Hz, 1H), 4.18 (s, 2H), 4.08 (t, J=5.2 Hz, 2H), 3.78-3.67 (m, 2H). MS: 416 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromo-1-ethanol was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.85 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.44-7.14 (m, 7H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.85 (t, J=5.5 Hz, 1H), 4.19 (s, 2H), 4.00 (t, J=5.0 Hz, 2H), 3.77-3.62 (m, 2H), 2.19 (s, 3H). MS: 430 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, and 2-bromophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (600 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.81 (s, 1H), 8.42-8.32 (m, 2H), 7.46-7.40 (m, 2H), 7.39 (dd, J=5.1, 1.6 Hz, 1H), 7.37-7.30 (m, 4H), 7.29-7.23 (m, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.12-7.08 (m, 1H), 4.22-4.14 (m, 4H), 3.69-3.63 (m, 2H), 3.22 (s, 3H). MS: 430 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 2, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.49 (s, 1H), 10.72 (s, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H), 8.25-8.16 (m, 1H), 7.39-7.19 (m, 6H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.13-4.05 (m, 2H), 3.69-3.61 (m, 2H), 3.30 (s, 3H), 2.18 (s, 3H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.85 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.16 (m, 3H), 6.95 (dd, J=8.4, 2.8 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.19 (s, 2H), 4.11 (t, J=4.6 Hz, 2H), 3.65 (t, J=4.6 Hz, 2H), 3.30 (s, 3H), 2.19 (s, 3H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, and 5-bromo-6-methylpyridin-3-ol (for the synthetic method refers to Lin, Nan-Horng et al/U.S. Pat. No. 6,437,138, 20 Aug. 2002) was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.97 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.16 (s, 1H), 7.42-7.20 (m, 7H), 4.28-4.11 (m, 4H), 3.66 (s, 2H), 3.30 (s, 3H), 2.39 (s, 3H). MS: 445 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, methyl 5-benzyl-1,3,4-thiodiazol-2-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.47 (dd, J=5.1, 0.7 Hz, 1H), 8.00 (dd, J=1.6, 0.8 Hz, 1H), 7.44-7.20 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.58 (s, 2H), 4.14-4.05 (m, 2H), 3.69-3.60 (m, 2H), 3.30 (s, 3H), 2.19 (s, 3H). MS: 461 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.45-7.13 (m, 7H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.14-4.02 (m, 2H), 3.76-3.64 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.12 (t, J=7.0 Hz, 3H). MS: 458 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, and 5-bromo-6-methylpyridin-3-ol (for the synthetic method refers to Lin, Nan-Horng et al/U.S. Pat. No. 6,437,138, 20 Aug. 2002) was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.98 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.16 (s, 1H), 7.41-7.18 (m, 7H), 4.26-4.07 (m, 4H), 3.69 (s, 2H), 3.61 (p, J=6.1 Hz, 1H), 2.39 (s, 3H), 1.09 (d, J=6.0 Hz, 6H). MS: 473 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.90 (s, 1H), 8.42 (dd, J=5.1, 0.8 Hz, 1H), 8.12 (s, 1H), 7.39-7.29 (m, 4H), 7.29-7.18 (m, 3H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.17 (s, 2H), 4.12-4.01 (m, 2H), 3.74-3.65 (m, 2H), 3.61 (p, J=6.1 Hz, 1H), 2.19 (s, 3H), 1.10 (d, J=6.1 Hz, 6H). MS: 472 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromo-N,N-dimethyl-1-ethylamine hydrochloride was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.89-14.02 (m, 1H), 9.90 (s, 1H), 8.42 (dd, J=5.1, 0.8 Hz, 1H), 8.15-8.07 (m, 1H), 7.39-7.30 (m, 4H), 7.30-7.17 (m, 3H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.06 (t, J=5.8 Hz, 2H), 2.62 (t, J=5.8 Hz, 2H), 2.21 (s, 6H), 2.19 (s, 3H). MS: 457 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-bromo-N,N-dimethyl-1-ethylamine hydrochloride was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.20 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.41-7.29 (m, 4H), 7.29-7.18 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.05 (t, J=6.0 Hz, 2H), 2.83 (t, J=6.1 Hz, 2H), 2.60 (q, J=7.1 Hz, 4H), 2.19 (s, 3H), 0.98 (t, J=7.1 Hz, 6H). MS: 485 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)-4-methylpiperazine dihydrochloride was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 13.97 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 7.40-7.15 (m, 7H), 6.94 (dd, J=8.6, 2.8 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 4.17 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.8 Hz, 2H), 2.46 (s, 4H), 2.30 (s, 4H), 2.19 (s, 3H), 2.13 (s, 3H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-(2-bromoethyl)-1,3-dioxolane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.45-7.15 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.98 (t, J=4.9 Hz, 1H), 4.18 (s, 2H), 4.08 (t, J=6.6 Hz, 2H), 3.96-3.84 (m, 2H), 3.84-3.71 (m, 2H), 2.19 (s, 3H), 2.10-1.95 (m, 2H). MS: 486 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1,1,1-trifluorobutane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 7.41-7.30 (m, 4H), 7.30-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.05 (t, J=6.2 Hz, 2H), 2.47-2.31 (m, 2H), 2.19 (s, 3H), 1.99-1.85 (m, 2H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-N,N-dimethyl-1-propylamine hydrochloride was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.39-7.29 (m, 4H), 7.29-7.14 (m, 3H), 6.92 (dd, J=8.4, 2.6 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 3.99 (t, J=6.4 Hz, 2H), 2.36 (t, J=7.1 Hz, 2H), 2.18 (s, 3H), 2.14 (s, 6H), 1.89-1.77 (m, 2H). MS: 471 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-1-propanol was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.80 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.38-7.30 (m, 4H), 7.26 (dd, J=7.5, 4.8 Hz, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.54 (t, J=5.1 Hz, 1H), 4.17 (s, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.57-3.52 (m, 2H), 2.19 (s, 3H), 1.91-1.79 (m, 2H). MS: 444 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.41 (dd, J=5.2, 2.1 Hz, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.45-7.15 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.6 Hz, 1H), 4.17 (s, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.48-3.44 (m, 2H), 3.23 (d, J=2.1 Hz, 3H), 2.19 (d, J=2.1 Hz, 3H), 2.02-1.85 (m, 2H). MS: 458 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(1-phenylethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.44-7.28 (m, 4H), 7.29-7.17 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.41 (q, J=7.2 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.19 (s, 3H), 1.98-1.87 (m, 2H), 1.67 (d, J=7.2 Hz, 3H). MS: 472 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, in step 3, ethyl 5-(1-phenylethyl)-1,3,4-oxadiazol-2-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 7.96 (s, 1H), 7.43-7.20 (m, 7H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.63 (q, J=7.2 Hz, 1H), 4.02 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.3 Hz, 2H), 3.34 (s, 3H), 2.18 (s, 3H), 1.98-1.87 (m, 2H), 1.71 (d, J=7.2 Hz, 3H). MS: 473 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.84 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.33-7.14 (m, 2H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.84-2.74 (m, 2H), 2.36-2.22 (m, 1H), 2.20 (s, 3H), 2.00-1.88 (m, 2H), 1.79-1.66 (m, 2H), 1.66-1.56 (m, 2H), 1.56-1.45 (m, 2H), 1.27-1.18 (m, 2H). MS: 450 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.97-9.76 (m, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.34-7.12 (m, 2H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 4.03 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.67 (d, J=7.0 Hz, 2H), 2.19 (s, 3H), 2.01-1.86 (m, 2H), 1.84-1.53 (m, 6H), 1.30-1.06 (m, 3H), 1.06-0.87 (m, 2H). MS: 464 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, methyl 5-benzyl-1,3,4-thiodiazol-2-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.47 (dd, J=5.1, 0.8 Hz, 1H), 7.99 (dd, J=1.6, 0.8 Hz, 1H), 7.46-7.17 (m, 7H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.58 (s, 2H), 4.02 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.23 (s, 3H), 2.18 (s, 3H), 2.00-1.87 (m, 2H). MS: 475 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-ethoxypropane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.46-7.29 (m, 4H), 7.29-7.14 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.49 (t, J=6.3 Hz, 2H), 3.41 (q, J=7.0 Hz, 2H), 2.19 (s, 3H), 2.00-1.86 (m, 2H), 1.08 (t, J=7.0 Hz, 3H). MS: 472 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanenitrile was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.45-7.14 (m, 7H), 6.96 (dd, J=8.4, 2.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.05 (t, J=6.0 Hz, 2H), 2.65 (t, J=7.1 Hz, 2H), 2.19 (s, 3H), 2.06-1.96 (m, 2H). MS: 453 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentene was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.97 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.44-7.16 (m, 7H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 5.94-5.77 (m, 1H), 5.62-5.40 (m, 1H), 5.12-4.91 (m, 1H), 4.18 (s, 2H), 4.06-3.91 (m, 2H), 2.44-2.32 (m, 1H), 2.19 (s, 3H), 1.87-1.72 (m, 1H), 1.69-1.55 (m, 2H). MS: 454 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, (4-bromobutyl)(methyl)sulfane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.00 (t, J=6.4 Hz, 2H), 2.58-2.52 (m, 2H), 2.19 (s, 3H), 2.03 (s, 3H), 1.85-1.73 (m, 2H), 1.73-1.61 (m, 2H). MS: 488 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.39-7.29 (m, 4H), 7.29-7.22 (m, 2H), 7.21 (dd, J=5.2, 1.6 Hz, 1H), 6.93 (dd, J=8.4, 2.8 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.51-4.35 (m, 1H), 4.17 (s, 2H), 3.98 (t, J=6.5 Hz, 2H), 3.44 (t, J=6.4 Hz, 2H), 2.19 (s, 3H), 1.80-1.67 (m, 2H), 1.62-1.49 (m, 2H). MS: 458 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-4-methoxybutane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.91 (s, 1H), 8.47-8.34 (m, 1H), 8.18-8.03 (m, 1H), 7.43-7.13 (m, 7H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 3.98 (t, J=6.4 Hz, 2H), 3.35 (t, J=6.3 Hz, 2H), 3.22 (s, 3H), 2.19 (s, 3H), 1.81-1.68 (m, 2H), 1.68-1.56 (m, 2H). MS: 472 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.42-7.30 (m, 4H), 7.30-7.13 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.45-4.31 (m, 1H), 4.18 (s, 2H), 3.97 (t, J=6.5 Hz, 2H), 3.46-3.36 (m, 2H), 2.19 (s, 3H), 1.70 (t, J=6.9 Hz, 2H), 1.54-1.36 (m, 4H). MS: 472 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 8-bromo-1-octanol was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.42-7.11 (m, 7H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.46-4.24 (m, 1H), 4.17 (s, 2H), 3.96 (t, J=6.5 Hz, 2H), 3.37-3.34 (m, 2H), 2.18 (s, 3H), 1.78-1.60 (m, 2H), 1.50-1.34 (m, 4H), 1.34-1.13 (m, 6H). MS: 514 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromocyclopropane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.39-7.30 (m, 4H), 7.30-7.23 (m, 2H), 7.23-7.18 (m, 1H), 7.05 (dd, J=8.4, 2.7 Hz, 1H), 6.93 (d, J=2.7 Hz, 1H), 4.19 (s, 2H), 3.91-3.82 (m, 1H), 2.20 (s, 3H), 0.83-0.71 (m, 2H), 0.71-0.60 (m, 2H). MS: 426 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, bromocyclobutane was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.89 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.40-7.29 (m, 4H), 7.29-7.15 (m, 3H), 6.84 (dd, J=8.4, 2.7 Hz, 1H), 6.72 (d, J=2.7 Hz, 1H), 4.77-4.64 (m, 1H), 4.18 (s, 2H), 2.46-2.35 (m, 2H), 2.18 (s, 3H), 2.11-1.94 (m, 2H), 1.83-1.70 (m, 1H), 1.70-1.54 (m, 1H). MS: 440 [M+H]+.
Step 1: Synthesis of methyl 4-(3-bromo-4-methylphenoxy)butanoate
The operation is the same as step 1 of Example 92, but methyl 4-bromobutanoate was used in place of iodomethane in step 1, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol in step 1.
Step 2: Synthesis of 4-(3-bromo-4-methylphenoxy)butanamide
Methyl 4-(3-bromo-4-methylphenoxy)butanoate (287 mg, 1 mmol) was dissolved in 7M ammonia in methanol, and reacted at 80° C. for 36 hours in sealed tube. The reaction solution was cooled, evaporated to dryness, and used directly in the next step.
Step 3 to Step 4: The preparation was carried out in a similar manner to Example 33, except that in step 1, 4-(3-bromo-4-methylphenoxy)butanamide was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.30 (m, 5H), 7.26 (dd, J=7.6, 5.2 Hz, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.88-6.67 (m, 2H), 4.18 (s, 2H), 3.97 (t, J=6.4 Hz, 2H), 2.28-2.12 (m, 5H), 1.97-1.83 (m, 2H). MS: 471 [M+H]+.
The operation is the same as steps 2 to 4 of Example 157, but methyl 3-bromo-4-methylbenzoate was used in place of methyl 4-(3-bromo-4-methylphenoxy)butanoate in step 2. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.95 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.15 (d, J=5.3 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.81 (d, J=5.4 Hz, 1H), 7.51-7.42 (m, 1H), 7.42-7.30 (m, 5H), 7.30-7.18 (m, 2H), 4.18 (s, 2H), 2.33 (s, 3H). MS: 413 [M+H]+.
Step 1: Synthesis of methyl 2-(3-bromo-4-methylphenoxy)acetate
The operation is the same as step 1 of Example 92, but methyl bromoacetate was used in place of iodomethane in step 1, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol in step 1.
Step 2: Synthesis of 1-((3-bromo-4-methylphenoxy)methyl)cyclopropane-1-ol
Methyl 2-(3-bromo-4-methylphenoxy)acetate (259 mg, 1 mmol) and tetraisopropyl titanate (57 mg, 0.2 mmol) were dissolved in anhydrous tetrahydrofuran, and ethyl Grignard reagent (1M in THF, 2.5 mL, 2.5 mmol) slowly added at 0° C. under argon protection. Then the mixture was slowly warmed to 25° C. after the addition, and reacted for 4 hours. The reaction solution is quenched with saturated solution of ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and used directly in the next step.
Step 3 to Step 4: The preparation was carried out in a similar manner to Example 33, except that in step 1, 1-((3-bromo-4-methylphenoxy)methyl)cyclopropan-1-ol was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.41-7.30 (m, 4H), 7.30-7.14 (m, 3H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.8 Hz, 1H), 5.59 (s, 1H), 4.18 (s, 2H), 3.97 (s, 2H), 2.19 (s, 3H), 0.73-0.63 (m, 2H), 0.63-0.53 (m, 2H). MS: 456 [M+H]+.
Step 1: Synthesis of methyl 4-(3-bromo-4-methylphenoxy)butanoate
The operation is the same as step 4 of Example 55, but 3-bromo-4-methylphenol was used in place of 3-bromo-N,4-dimethylaniline in the fourth step, and methyl 4-bromobutanoate was used in place of 1-bromo-2-methoxyethane in the fourth step.
Step 2: Synthesis of 5-(3-bromo-4-methylphenoxy)-2-methylpentan-2-ol
Methyl 4-(3-bromo-4-methylphenoxy)butanoate (287 mg, 1 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), to which methylmagnesium bromide (3M, 1 mL, 3 mmol) was added dropwise under argon protection at 0° C., and reacted at 25° C. for 2 hours. The reaction was quenched with saturated aqueous solution of ammonium chloride, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and subjected to column chromatography to afford 260 mg of product. MS: 287 [M+H]+.
Step 3 to Step 4: The preparation was carried out in a similar manner to Example 33, except that in step 1, 5-(3-bromo-4-methylphenoxy)-2-methylpentan-2-ol was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.88 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.30 (m, 4H), 7.30-7.16 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.26-4.10 (m, 3H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.82-1.68 (m, 2H), 1.54-1.40 (m, 2H), 1.09 (s, 6H). MS: 486 [M+H]+.
The operation is the same as steps 2 to 4 of Example 160, but methyl 4-bromo-3-methylbenzoate was used in place of methyl 4-(3-bromo-4-methylphenoxy)butanoate in step 2 of Example 160 to carry out the reaction. In this step of reaction, two products of 2-(3-bromo-4-methylphenyl)propan-2-ol and 1-(3-bromo-4-methylphenyl)ethan-1-one were obtained, and 2-(3-bromo-4-methylphenyl)propan-2-ol was used for the subsequent reactions in the present Example. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.87 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.51-7.14 (m, 9H), 5.07 (s, 1H), 4.18 (s, 2H), 2.29 (s, 3H), 1.45 (s, 6H). MS: 428 [M+H]+.
The operation is the same as Example 161, but the product 1-(3-bromo-4-methylphenyl)ethan-1-one obtained in the first step was used for the subsequent reactions. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.95 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.99-7.93 (m, 1H), 7.93-7.84 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.20 (m, 2H), 4.18 (s, 2H), 2.62 (s, 3H), 2.35 (s, 3H). MS: 412 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, (butane-1,4-diyl)dimagnesium dibromide was used in place of methylmagnesium bromide. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 7.47-7.29 (m, 4H), 7.29-7.13 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.05 (s, 1H), 3.98 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.87-1.33 (m, 12H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, (pentane-1,5-diyl)dimagnesium dibromide was used in place of methylmagnesium bromide. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.49-7.29 (m, 4H), 7.29-7.12 (m, 3H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.01-3.86 (m, 3H), 2.19 (s, 3H), 1.75 (t, J=8.3 Hz, 2H), 1.63-1.49 (m, 2H), 1.49-1.38 (m, 5H), 1.38-1.24 (m, 5H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide. 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 8.11 (s, 1H), 7.40-7.28 (m, 4H), 7.28-7.22 (m, 2H), 7.21 (dd, J=5.1, 1.5 Hz, 1H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 3.96 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 2.19 (s, 3H), 1.74-1.63 (m, 2H), 1.48-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 0.77 (t, J=7.4 Hz, 6H). MS: 514 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.32-7.12 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 3.96 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.21 (m, 1H), 2.19 (s, 3H), 1.79-1.47 (m, 8H), 1.47-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 1.28-1.11 (m, 2H), 0.77 (t, J=7.4 Hz, 6H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.41-7.29 (m, 4H), 7.29-7.22 (m, 2H), 7.21 (dd, J=5.1, 1.5 Hz, 1H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.10 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.68 (t, J=6.9 Hz, 2H), 1.50-1.33 (m, 4H), 1.06 (s, 6H). MS: 500 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, tert-butyl (3-bromo-4-methylphenyl)(methyl)carbamate was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.88 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.46-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.18 (dd, J=5.0, 1.5 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 6.70 (dd, J=8.5, 2.8 Hz, 1H), 6.52 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 4.12 (s, 1H), 3.28 (t, J=7.4 Hz, 2H), 2.86 (s, 3H), 2.13 (s, 3H), 1.63-1.46 (m, 2H), 1.42-1.27 (m, 2H), 1.05 (s, 6H). MS: 499 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-isobutyl-4H-1,2,4-triazol-5-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.33-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.19 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 2.72-2.62 (m, 2H), 2.19 (s, 3H), 2.16-2.02 (m, 1H), 1.84-1.68 (m, 2H), 1.56-1.41 (m, 2H), 1.09 (s, 6H), 0.93 (d, J=6.6 Hz, 6H). MS: 452 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-neopentyl-4H-1,2,4-triazol-5-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.31-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 2.67 (s, 2H), 2.20 (s, 3H), 1.83-1.66 (m, 2H), 1.57-1.39 (m, 2H), 1.09 (s, 6H), 0.97 (s, 9H). MS: 466 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(cyclopropylmethyl)-4H-1,2,4-triazol-5-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 9.88 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.37-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.6 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.72 (d, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.83-1.66 (m, 2H), 1.55-1.39 (m, 2H), 1.18-1.03 (m, 7H), 0.59-0.46 (m, 2H), 0.33-0.22 (m, 2H). MS: 450 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(cyclobutylmethyl)-4H-1,2,4-triazol-5-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.34-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.88 (d, J=7.5 Hz, 2H), 2.79-2.62 (m, 1H), 2.19 (s, 3H), 2.12-1.97 (m, 2H), 1.94-1.79 (m, 2H), 1.79-1.64 (m, 4H), 1.55-1.42 (m, 2H), 1.09 (s, 6H). MS: 464 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.33-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.19 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.34-2.22 (m, 1H), 2.19 (s, 3H), 1.83-1.66 (m, 4H), 1.66-1.55 (m, 2H), 1.55-1.41 (m, 4H), 1.27-1.18 (m, 2H), 1.09 (s, 6H). MS: 478 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(cyclopentylmethyl)-1,3,4-oxadiazol-2-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.99 (s, 1H), 7.32-7.20 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.97 (d, J=7.4 Hz, 2H), 2.38-2.24 (m, 1H), 2.19 (s, 3H), 1.87-1.69 (m, 4H), 1.69-1.39 (m, 6H), 1.32-1.20 (m, 2H), 1.09 (s, 6H). MS: 479 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.85 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.31-7.17 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.19 (s, 3H), 1.84-1.70 (m, 3H), 1.70-1.56 (m, 5H), 1.54-1.41 (m, 2H), 1.29-1.15 (m, 3H), 1.09 (s, 6H), 1.05-0.89 (m, 2H). MS: 492 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(2-cyclopentylethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.32 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.33-7.15 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.79 (t, J=7.2 Hz, 2H), 2.19 (s, 3H), 1.84-1.66 (m, 7H), 1.66-1.39 (m, 6H), 1.18-0.98 (m, 8H). MS: 492 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-((tetrahydro-2H-pyran-4-yl)methyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.87 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.34-7.14 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.89-3.78 (m, 2H), 3.31-3.19 (m, 2H), 2.73 (d, J=7.1 Hz, 2H), 2.19 (s, 3H), 2.07-1.92 (m, 1H), 1.81-1.68 (m, 2H), 1.61-1.51 (m, 2H), 1.51-1.42 (m, 2H), 1.30-1.22 (m, 2H), 1.09 (s, 6H). MS: 494 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-((4,4-difluorocyclohexyl)methyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.87 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.32-7.13 (m, 2H), 6.93 (dd, J=8.5, 2.6 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 2.75 (d, J=7.0 Hz, 2H), 2.19 (s, 3H), 2.09-1.64 (m, 9H), 1.55-1.40 (m, 2H), 1.35-1.23 (m, 2H), 1.09 (s, 6H). MS: 528 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(bicyclo[2.2.1]heptan-2-ylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.32 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.35-7.12 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 3.17 (d, J=4.1 Hz, 1H), 2.74 (dd, J=14.6, 8.0 Hz, 1H), 2.59 (dd, J=14.6, 7.7 Hz, 1H), 2.28-2.16 (m, 4H), 1.96-1.85 (m, 1H), 1.81-1.68 (m, 2H), 1.54-1.33 (m, 6H), 1.29-1.20 (m, 2H), 1.19-1.12 (m, 2H), 1.09 (s, 6H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(adamantan-1-ylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.32 (s, 1H), 9.83 (s, 1H), 8.39 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.30-7.13 (m, 2H), 6.90 (dd, J=8.4, 2.7 Hz, 1H), 6.78 (d, J=2.7 Hz, 1H), 4.17 (s, 1H), 3.94 (t, J=6.6 Hz, 2H), 2.51 (s, 2H), 2.17 (s, 3H), 1.95-1.83 (m, 3H), 1.79-1.66 (m, 2H), 1.66-1.57 (m, 3H), 1.57-1.38 (m, 11H), 1.06 (s, 6H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(morpholinomethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.09 (s, 1H), 9.95 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.32-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.20 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.71 (s, 2H), 3.59 (t, J=4.6 Hz, 4H), 2.49-2.40 (m, 4H), 2.19 (s, 3H), 1.81-1.67 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 495 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(phenethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 9.89 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 7.40-7.10 (m, 7H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 3.22-2.99 (m, 4H), 2.20 (s, 3H), 1.84-1.66 (m, 2H), 1.57-1.37 (m, 2H), 1.09 (s, 6H). MS: 500 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.44-7.29 (m, 2H), 7.28-7.13 (m, 4H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.29-4.09 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.18 (s, 3H), 1.83-1.68 (m, 2H), 1.52-1.39 (m, 2H), 1.09 (s, 6H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 13.74 (s, 1H), 9.93 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.50-7.30 (m, 2H), 7.30-7.06 (m, 4H), 6.92 (d, J=8.6 Hz, 1H), 6.80 (s, 1H), 4.34-4.06 (m, 3H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.84-1.66 (m, 2H), 1.47 (t, J=8.1 Hz, 2H), 1.09 (s, 6H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(3-chlorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.95 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.49-7.13 (m, 6H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.31-4.07 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.83-1.66 (m, 2H), 1.54-1.38 (m, 2H), 1.09 (s, 6H). MS: 520 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(3-methoxybenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.41-7.12 (m, 3H), 7.05-6.70 (m, 5H), 4.26-4.05 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 3.74 (s, 3H), 2.19 (s, 3H), 1.83-1.65 (m, 2H), 1.56-1.37 (m, 2H), 1.09 (s, 6H). MS: 516 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(3-cyanobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.98 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.62-7.51 (m, 1H), 7.30-7.17 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.27 (s, 2H), 4.19 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.81-1.68 (m, 2H), 1.53-1.40 (m, 2H), 1.09 (s, 6H). MS: 511 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.93 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.46-7.31 (m, 2H), 7.31-7.10 (m, 4H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.29-4.08 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.83-1.65 (m, 2H), 1.54-1.40 (m, 2H), 1.09 (s, 6H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(4-chlorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.93 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 7.51-7.29 (m, 4H), 7.29-7.13 (m, 2H), 6.93 (dd, J=8.5, 2.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 4.28-4.07 (m, 3H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.75 (t, J=8.2 Hz, 2H), 1.54-1.39 (m, 2H), 1.09 (s, 6H). MS: 520 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(4-methoxybenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.89 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.40-7.09 (m, 4H), 7.04-6.70 (m, 4H), 4.18 (s, 1H), 4.10 (s, 2H), 3.96 (t, J=6.8 Hz, 2H), 2.19 (s, 3H), 1.83-1.64 (m, 2H), 1.57-1.35 (m, 2H), 1.09 (s, 6H). MS: 516 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(4-cyanobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.95 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.91-7.76 (m, 2H), 7.62-7.47 (m, 2H), 7.32-7.13 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.29 (s, 2H), 4.18 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.81-1.67 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 511 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, ethyl 5-(3,4-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.96 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.4 Hz, 1H), 7.51-7.32 (m, 2H), 7.32-7.13 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.25-4.12 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.82-1.67 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 2-chloro-4-hydroxybenzonitrile was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 10.04 (s, 1H), 8.52 (d, J=5.1 Hz, 1H), 8.34 (d, J=1.4 Hz, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.41 (dd, J=5.1, 1.6 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.15 (m, 3H), 4.27-4.08 (m, 5H), 1.87-1.72 (m, 2H), 1.56-1.41 (m, 2H), 1.10 (s, 6H). MS: 497 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.96 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.43-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.22-7.11 (m, 2H), 6.97 (d, J=2.5 Hz, 1H), 4.26-4.13 (m, 3H), 4.09 (t, J=6.6 Hz, 2H), 1.86-1.69 (m, 2H), 1.54-1.39 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 2-bromo-4-hydoxylbenzaldehyde was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.99 (s, 1H), 9.80 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.43-7.29 (m, 5H), 7.29-7.15 (m, 2H), 7.05 (d, J=2.5 Hz, 1H), 4.28-4.20 (m, 2H), 4.18 (s, 2H), 3.73-3.61 (m, 2H), 1.15 (s, 9H). MS: 500 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 2, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 14.54 (s, 1H), 10.75 (s, 1H), 9.02 (s, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 7.43-7.18 (m, 6H), 6.91 (d, J=8.2 Hz, 1H), 6.83 (s, 1H), 4.18 (s, 2H), 3.76 (s, 3H), 2.18 (s, 3H). MS: 400 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, bromoethane was used in place of iodomethane, and in step 2, 5-bromopyridin-3-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ 14.49 (s, 1H), 10.70 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.41-8.08 (m, 2H), 7.48-7.12 (m, 6H), 6.90 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 4.03 (q, J=7.0 Hz, 2H), 2.18 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS: 414 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and 1-bromobutane was used in place of iodomethane. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.48-7.10 (m, 7H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.17 (s, 2H), 3.97 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.83-1.54 (m, 2H), 1.54-1.27 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). MS: 442 [M+H]+.
The preparation was carried out in a similar manner to Example 161, except that in step 1, methyl 3-bromo-4-methylbenzoate was used in place of methyl 4-bromo-3-methylbenzoate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (d, J=1.3 Hz, 1H), 7.42 (dd, J=7.9, 2.0 Hz, 1H), 7.39-7.30 (m, 5H), 7.30-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.6 Hz, 1H), 5.05 (s, 1H), 4.17 (s, 2H), 2.25 (s, 3H), 1.43 (s, 6H). MS: 428 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(3,5-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.29-7.03 (m, 5H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.26 (s, 2H), 4.18 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.81-1.67 (m, 2H), 1.53-1.40 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,4-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.57-7.38 (m, 1H), 7.38-7.17 (m, 3H), 7.17-7.01 (m, 1H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.28-4.11 (m, 3H), 3.97 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.83-1.66 (m, 2H), 1.56-1.40 (m, 2H), 1.10 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,3-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.47-7.30 (m, 1H), 7.30-7.12 (m, 4H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.27 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.82-1.66 (m, 2H), 1.55-1.40 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,5-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 9.94 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.42-7.11 (m, 5H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.22 (s, 2H), 4.17 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.80-1.70 (m, 2H), 1.54-1.42 (m, 2H), 1.10 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(5-chloro-2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.93 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.53 (dd, J=6.6, 2.7 Hz, 1H), 7.48-7.36 (m, 1H), 7.36-7.14 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.22 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.83-1.68 (m, 2H), 1.55-1.42 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(5-chloro-3-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.91 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.43-7.14 (m, 5H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.24 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.82-1.68 (m, 2H), 1.52-1.42 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(3-chloro-4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.95 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.59 (dd, J=7.2, 2.1 Hz, 1H), 7.47-7.29 (m, 2H), 7.29-7.15 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.24-4.14 (m, 3H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.83-1.66 (m, 2H), 1.54-1.41 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(3-fluoro-5-methylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.32-7.14 (m, 2H), 7.03-6.86 (m, 4H), 6.80 (d, J=2.7 Hz, 1H), 4.22-4.10 (m, 3H), 3.96 (t, J=6.6 Hz, 2H), 2.30 (s, 3H), 2.19 (s, 3H), 1.82-1.68 (m, 2H), 1.54-1.42 (m, 2H), 1.09 (s, 6H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(4-fluoro-3-methylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.53 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.34-7.00 (m, 5H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.24-4.04 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.27-2.12 (m, 6H), 1.83-1.67 (m, 2H), 1.56-1.41 (m, 2H), 1.09 (s, 6H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(4-fluoro-3-methoxybenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.30-7.08 (m, 4H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.90-6.83 (m, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.22-4.09 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 3.83 (s, 3H), 2.19 (s, 3H), 1.81-1.69 (m, 2H), 1.54-1.41 (m, 2H), 1.09 (s, 6H). MS: 534 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2-fluoro-3-trifluoromethylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.88-7.64 (m, 2H), 7.49-7.34 (m, 1H), 7.30-7.13 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.32 (s, 2H), 4.16 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.81-1.69 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 572 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2-fluoro-5-trifluoromethylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.76 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.90 (dd, J=6.7, 2.4 Hz, 1H), 7.83-7.67 (m, 1H), 7.56-7.37 (m, 1H), 7.33-7.12 (m, 2H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.32 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.18 (s, 3H), 1.80-1.68 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 572 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(4-fluoro-3-trifluoromethylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.55 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.84-7.76 (m, 1H), 7.76-7.67 (m, 1H), 7.50 (dd, J=10.6, 8.8 Hz, 1H), 7.29-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.30 (s, 2H), 4.16 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.82-1.66 (m, 2H), 1.52-1.42 (m, 2H), 1.09 (s, 6H). MS: 572 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(3-fluoro-5-trifluoromethylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.70-7.50 (m, 3H), 7.30-7.15 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.36 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.82-1.67 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (s, 6H). MS: 572 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,3,4-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.87 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.40-7.15 (m, 4H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.26 (s, 2H), 4.16 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.80-1.66 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,3,5-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.75 (s, 1H), 9.96 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.58-7.41 (m, 1H), 7.33-7.13 (m, 3H), 7.01-6.87 (m, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.28 (s, 2H), 4.16 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.81-1.67 (m, 2H), 1.52-1.42 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,3,6-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.75 (s, 1H), 9.89 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 7.59-7.42 (m, 1H), 7.31-7.12 (m, 3H), 6.92 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.25 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.18 (s, 3H), 1.80-1.68 (m, 2H), 1.55-1.41 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(3,4,5-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.00 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.45-7.28 (m, 2H), 7.28-7.15 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.26-4.13 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.81-1.67 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(2,4,5-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.92 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.73-7.46 (m, 2H), 7.30-7.14 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.24-4.13 (m, 3H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.81-1.67 (m, 2H), 1.53-1.40 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.89 (s, 1H), 8.54-8.45 (m, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.84-7.75 (m, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.34-7.17 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.34 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.19 (s, 3H), 1.82-1.68 (m, 2H), 1.54-1.40 (m, 2H), 1.09 (s, 6H). MS: 487 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.95 (s, 1H), 8.58 (d, J=2.2 Hz, 1H), 8.48 (dd, J=4.8, 1.7 Hz, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.13-8.09 (m, 1H), 7.82-7.70 (m, 1H), 7.43-7.32 (m, 1H), 7.28-7.17 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H), 4.22 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.81-1.69 (m, 2H), 1.54-1.42 (m, 2H), 1.09 (s, 6H). MS: 487 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(pyridin-4-ylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.90 (s, 1H), 8.53 (d, J=5.0 Hz, 2H), 8.42 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 7.42-7.29 (m, 2H), 7.29-7.15 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.29-4.20 (m, 2H), 4.17 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.83-1.68 (m, 2H), 1.55-1.42 (m, 2H), 1.09 (s, 6H). MS: 487 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(cycloheptylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.85 (s, 1H), 8.42 (dd, J=5.0, 0.8 Hz, 1H), 8.13 (s, 1H), 7.33-7.15 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.17 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 2.69 (d, J=7.3 Hz, 2H), 2.19 (s, 3H), 2.07-1.91 (m, 1H), 1.82-1.70 (m, 2H), 1.70-1.30 (m, 12H), 1.30-1.15 (m, 2H), 1.09 (s, 6H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.83 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 7.29-7.16 (m, 2H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.82 (d, J=2.7 Hz, 1H), 4.09 (s, 1H), 3.98 (t, J=6.5 Hz, 2H), 2.79 (d, J=7.5 Hz, 2H), 2.37-2.22 (m, 1H), 2.19 (s, 3H), 1.82-1.65 (m, 4H), 1.65-1.57 (m, 2H), 1.57-1.47 (m, 2H), 1.47-1.32 (m, 4H), 1.30-1.17 (m, 2H), 1.06 (s, 6H). MS: 492 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.83 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.29-7.16 (m, 2H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.37 (t, J=5.1 Hz, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.51-3.36 (m, 2H), 2.79 (d, J=7.5 Hz, 2H), 2.37-2.22 (m, 1H), 2.19 (s, 3H), 1.79-1.66 (m, 4H), 1.66-1.56 (m, 2H), 1.56-1.36 (m, 6H), 1.30-1.15 (m, 2H). MS: 464 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 2-cycloheptyl-1-ethanol was used in place of 2-(tert-butoxy)ethan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.88 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.44-7.30 (m, 4H), 7.30-7.14 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.18 (s, 2H), 3.99 (t, J=6.3 Hz, 2H), 2.18 (s, 3H), 1.77-1.50 (m, 9H), 1.50-1.31 (m, 4H), 1.23-1.13 (m, 2H). MS: 510 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 15.08-14.30 (m, 1H), 9.88 (s, 1H), 8.48-8.32 (m, 1H), 8.11 (s, 1H), 7.48-7.29 (m, 2H), 7.29-7.09 (m, 4H), 6.93 (d, J=8.5 Hz, 1H), 6.82 (s, 1H), 4.21 (s, 2H), 4.01 (t, J=6.4 Hz, 2H), 3.92-3.67 (m, 2H), 3.30-3.14 (m, 2H), 2.18 (s, 3H), 1.80-1.48 (m, 5H), 1.33-1.08 (m, 2H). MS: 516 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 2-(2-bromoethyl)tetrahydro-2H-pyran was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.46-7.29 (m, 4H), 7.29-7.15 (m, 3H), 6.93 (dd, J=8.4, 2.8 Hz, 1H), 6.81 (d, J=2.8 Hz, 1H), 4.17 (s, 2H), 4.11-3.95 (m, 2H), 3.90-3.78 (m, 1H), 3.46-3.19 (m, 4H), 2.19 (s, 3H), 1.87-1.76 (m, 2H), 1.76-1.68 (m, 1H), 1.65-1.55 (m, 1H), 1.47-1.39 (m, 2H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, and 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.91 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.12 (s, 1H), 7.39-7.29 (m, 4H), 7.29-7.15 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.17 (s, 2H), 4.07 (t, J=5.9 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.42 (t, J=5.3 Hz, 4H), 2.19 (s, 3H), 1.55-1.41 (m, 4H), 1.41-1.27 (m, 2H). MS: 497 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.89 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.4 Hz, 1H), 7.36-7.11 (m, 6H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.33-4.24 (m, 2H), 4.21 (s, 2H), 4.11 (t, J=5.8 Hz, 2H), 2.75 (t, J=5.8 Hz, 2H), 2.19 (s, 3H), 1.56-1.43 (m, 4H), 1.43-1.32 (m, 2H), 1.31-1.23 (m, 2H). MS: 515 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2,4-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.52-7.40 (m, 1H), 7.31-7.16 (m, 3H), 7.13-7.04 (m, 1H), 6.94 (dd, J=8.4, 2.8 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 4.18 (s, 2H), 4.07 (t, J=5.9 Hz, 2H), 2.65 (t, J=5.9 Hz, 2H), 2.47-2.35 (m, 4H), 2.19 (s, 3H), 1.55-1.41 (m, 4H), 1.41-1.28 (m, 2H). MS: 533 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2,5-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.93 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.45-7.03 (m, 5H), 7.03-6.67 (m, 2H), 4.20 (s, 2H), 4.07 (t, J=5.9 Hz, 2H), 2.65 (t, J=5.9 Hz, 2H), 2.50-2.33 (m, 4H), 2.18 (s, 3H), 1.62-1.41 (m, 4H), 1.41-1.21 (m, 2H). MS: 533 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(3,5-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.99 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.14-8.06 (m, 1H), 7.28-7.05 (m, 5H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.22 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.9 Hz, 2H), 2.47-2.36 (m, 4H), 2.19 (s, 3H), 1.53-1.42 (m, 4H), 1.42-1.30 (m, 2H). MS: 533 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluoro-3-chlorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.93 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.57-7.48 (m, 1H), 7.43-7.36 (m, 1H), 7.28-7.17 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.26 (s, 2H), 4.08 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.8 Hz, 2H), 2.46-2.38 (m, 4H), 2.19 (s, 3H), 1.53-1.43 (m, 4H), 1.37 (t, J=6.2 Hz, 2H). MS: 549 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-(chloromethyl)-1-methylpiperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.11 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.44-7.30 (m, 2H), 7.28-7.14 (m, 4H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 4.19 (s, 2H), 3.97 (t, J=6.6 Hz, 1H), 3.86-3.79 (m, 1H), 2.82-2.66 (m, 2H), 2.27 (s, 1H), 2.18 (s, 3H), 2.16 (s, 3H), 2.01-1.83 (m, 2H), 1.79-1.67 (m, 2H), 1.47-1.26 (m, 2H). MS: 515 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-5-fluoro-4-methylphenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.11 (s, 1H), 7.39-7.30 (m, 4H), 7.24 (dd, J=20.1, 5.8 Hz, 2H), 6.91 (dd, J=11.7, 2.5 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 4.18 (d, J=5.4 Hz, 3H), 3.99 (t, J=6.6 Hz, 2H), 2.12-2.04 (m, 3H), 1.79-1.68 (m, 2H), 1.53-1.39 (m, 2H), 1.09 (s, 6H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-5-fluoro-4-methylphenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 9.92 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.09 (s, 1H), 7.52-7.29 (m, 2H), 7.29-7.14 (m, 3H), 6.90 (dd, J=11.7, 2.5 Hz, 1H), 6.70 (d, J=2.5 Hz, 1H), 4.21 (s, 2H), 4.17 (s, 1H), 3.99 (t, J=6.5 Hz, 2H), 2.07 (d, J=2.2 Hz, 3H), 1.81-1.70 (m, 2H), 1.51-1.37 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 5-bromo-2-fluoro-4-methylphenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.89 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.40-7.29 (m, 4H), 7.29-7.15 (m, 3H), 7.03 (d, J=8.7 Hz, 1H), 4.23-4.11 (m, 3H), 4.04 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.76 (dd, J=10.3, 6.0 Hz, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 10.06 (s, 1H), 8.54 (s, 1H), 8.05 (s, 1H), 7.44-7.30 (m, 2H), 7.28-7.16 (m, 3H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 4.21 (s, 2H), 4.16 (s, 1H), 3.95 (t, J=6.6 Hz, 2H), 2.01 (s, 3H), 1.80-1.67 (m, 2H), 1.51-1.41 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 10.06 (s, 1H), 8.55 (s, 1H), 8.08 (s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.4, 2.7 Hz, 1H), 6.75 (d, J=2.7 Hz, 1H), 4.17 (s, 1H), 3.95 (t, J=6.6 Hz, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.01 (s, 3H), 1.84-1.56 (m, 9H), 1.52-1.41 (m, 2H), 1.20-1.12 (m, 2H), 1.09 (s, 6H), 1.05-0.90 (m, 2H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 4-bromo-5-methylpyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.75 (s, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.44-7.29 (m, 2H), 7.29-7.14 (m, 3H), 6.90 (dd, J=8.4, 2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 4.17 (s, 1H), 3.94 (t, J=6.6 Hz, 2H), 1.99 (s, 3H), 1.94 (s, 3H), 1.79-1.68 (m, 2H), 1.52-1.39 (m, 2H), 1.08 (s, 6H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 4-bromo-5-methylpyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.74 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.4, 2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 4.18 (s, 1H), 3.94 (t, J=6.6 Hz, 2H), 2.66 (d, J=7.2 Hz, 2H), 2.00 (s, 3H), 1.95 (s, 3H), 1.82-1.57 (m, 8H), 1.52-1.40 (m, 2H), 1.24-1.13 (m, 3H), 1.08 (s, 6H), 1.05-0.90 (m, 2H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.08 (s, 1H), 8.47 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.45-7.30 (m, 2H), 7.30-7.14 (m, 3H), 6.97 (dd, J=8.5, 2.7 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 3.95 (t, J=6.5 Hz, 2H), 3.87 (s, 1H), 2.09 (s, 3H), 1.73-1.59 (m, 2H), 1.46-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 0.77 (t, J=7.4 Hz, 6H). MS: 550 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.02 (s, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.09 (d, J=5.6 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 3.96 (t, J=6.5 Hz, 2H), 3.87 (s, 1H), 2.66 (d, J=7.0 Hz, 2H), 2.10 (s, 3H), 1.81-1.55 (m, 8H), 1.46-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 1.26-1.06 (m, 3H), 1.03-0.90 (m, 2H), 0.77 (t, J=7.4 Hz, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 10.10 (s, 1H), 8.54 (s, 1H), 8.05 (s, 1H), 7.45-7.30 (m, 2H), 7.30-7.14 (m, 3H), 6.94 (dd, J=8.4, 2.7 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 3.95 (t, J=6.5 Hz, 2H), 3.86 (s, 1H), 2.00 (s, 3H), 1.73-1.60 (m, 2H), 1.46-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 0.77 (t, J=7.4 Hz, 6H). MS: 566 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 10.03 (s, 1H), 8.55 (s, 1H), 8.08 (s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.7 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 3.95 (t, J=6.6 Hz, 2H), 3.87 (s, 1H), 2.71-2.62 (m, 2H), 2.01 (s, 3H), 1.81-1.71 (m, 1H), 1.71-1.56 (m, 7H), 1.46-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 1.29-1.14 (m, 3H), 1.03-0.90 (m, 2H), 0.77 (t, J=7.5 Hz, 6H). MS: 554 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.33 (s, 1H), 9.74 (s, 1H), 8.31 (s, 1H), 7.90 (s, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.91 (dd, J=8.4, 2.7 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 3.94 (t, J=6.5 Hz, 2H), 3.87 (s, 1H), 2.71-2.61 (m, 2H), 2.00 (s, 3H), 1.95 (s, 3H), 1.83-1.55 (m, 8H), 1.44-1.37 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 1.23-1.09 (m, 3H), 1.04-0.91 (m, 2H), 0.77 (t, J=7.4 Hz, 6H). MS: 534 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.11 (s, 1H), 8.53 (s, 1H), 8.05 (s, 1H), 7.45-7.29 (m, 2H), 7.29-7.12 (m, 3H), 6.95 (d, J=9.0 Hz, 1H), 6.75 (d, J=2.7 Hz, 1H), 4.19 (s, 2H), 4.09 (s, 1H), 3.95 (t, J=6.5 Hz, 2H), 2.00 (s, 3H), 1.74-1.59 (m, 2H), 1.51-1.37 (m, 4H), 1.06 (s, 6H). MS: 552 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 10.04 (s, 1H), 8.55 (s, 1H), 8.08 (s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.96 (dd, J=8.4, 2.7 Hz, 1H), 6.76 (d, J=2.7 Hz, 1H), 4.09 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.66 (d, J=6.9 Hz, 2H), 2.01 (s, 3H), 1.65 (dd, J=13.9, 9.1 Hz, 8H), 1.49-1.35 (m, 4H), 1.22-1.10 (m, 3H), 1.06 (s, 6H), 1.04-0.94 (m, 2H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 10.05 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.47-7.29 (m, 2H), 7.29-7.11 (m, 3H), 6.96 (dd, J=8.5, 2.8 Hz, 1H), 6.76 (d, J=2.7 Hz, 1H), 4.23 (s, 2H), 3.92-3.78 (m, 4H), 3.32-3.26 (m, 2H), 2.01 (s, 3H), 1.99-1.92 (m, 1H), 1.73-1.59 (m, 2H), 1.37-1.26 (m, 2H). MS: 536 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 10.07 (s, 1H), 8.55 (s, 1H), 8.08 (s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.5, 2.7 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 3.92-3.77 (m, 4H), 2.66 (d, J=7.1 Hz, 2H), 2.02 (s, 3H), 1.97 (dd, J=9.5, 5.2 Hz, 1H), 1.82-1.56 (m, 8H), 1.39-1.13 (m, 7H), 1.04-0.91 (m, 2H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.12 (s, 1H), 8.54 (s, 1H), 8.05 (s, 1H), 7.44-7.29 (m, 2H), 7.28-7.15 (m, 3H), 6.96 (dd, J=8.4, 2.7 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 4.00 (t, J=6.3 Hz, 2H), 3.87-3.75 (m, 2H), 3.31-3.21 (m, 2H), 2.00 (s, 3H), 1.76-1.55 (m, 5H), 1.27-1.11 (m, 2H). MS: 550 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 10.06 (s, 1H), 8.55 (s, 1H), 8.08 (s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.96 (dd, J=8.4, 2.7 Hz, 1H), 6.77 (d, J=2.7 Hz, 1H), 4.01 (t, J=6.3 Hz, 2H), 3.86-3.76 (m, 2H), 3.30-3.20 (m, 2H), 2.71-2.61 (m, 2H), 2.01 (s, 3H), 1.82-1.55 (m, 11H), 1.29-1.08 (m, 5H), 1.05-0.89 (m, 2H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.76 (s, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.46-7.28 (m, 2H), 7.28-7.12 (m, 3H), 6.91 (dd, J=8.4, 2.7 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.86-3.75 (m, 2H), 3.30-3.19 (m, 2H), 1.99 (s, 3H), 1.94 (s, 3H), 1.72-1.54 (m, 5H), 1.25-1.17 (m, 2H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.74 (s, 1H), 8.31 (s, 1H), 7.91 (s, 1H), 7.24 (d, J=8.5 Hz, 1H), 6.92 (dd, J=8.5, 2.7 Hz, 1H), 6.69 (d, J=2.7 Hz, 1H), 4.00 (t, J=6.3 Hz, 2H), 3.81 (dd, J=11.8, 4.3 Hz, 2H), 3.26 (t, J=11.6 Hz, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.00 (s, 3H), 1.95 (s, 3H), 1.81-1.52 (m, 11H), 1.25-1.10 (m, 5H), 1.05-0.87 (m, 2H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.94 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.45-7.29 (m, 2H), 7.26-7.12 (m, 4H), 6.96 (d, J=2.6 Hz, 1H), 4.31-4.14 (m, 3H), 4.09 (t, J=6.6 Hz, 2H), 1.86-1.67 (m, 2H), 1.53-1.39 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 10.00 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.44-7.33 (m, 1H), 7.24-7.05 (m, 5H), 6.97 (d, J=2.5 Hz, 1H), 4.20 (d, J=6.3 Hz, 3H), 4.09 (t, J=6.6 Hz, 2H), 1.84-1.69 (m, 2H), 1.55-1.42 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.97 (s, 1H), 8.43 (dd, J=5.1, 0.8 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.43-7.32 (m, 2H), 7.23-7.11 (m, 4H), 6.97 (d, J=2.5 Hz, 1H), 4.31-4.13 (m, 3H), 4.09 (t, J=6.5 Hz, 2H), 1.86-1.69 (m, 2H), 1.54-1.41 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.26-7.13 (m, 2H), 6.97 (d, J=2.6 Hz, 1H), 4.20 (s, 1H), 4.09 (t, J=6.5 Hz, 2H), 2.78 (d, J=7.4 Hz, 2H), 2.37-2.19 (m, 1H), 1.85-1.66 (m, 4H), 1.66-1.56 (m, 2H), 1.56-1.41 (m, 4H), 1.26-1.20 (m, 2H), 1.09 (s, 6H). MS: 532 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.89 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.12 (m, 2H), 6.97 (d, J=2.6 Hz, 1H), 4.19 (s, 1H), 4.09 (t, J=6.6 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.82-1.55 (m, 8H), 1.52-1.43 (m, 2H), 1.27-1.13 (m, 3H), 1.10 (s, 6H), 1.05-0.88 (m, 2H). MS: 546 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.95 (s, 1H), 8.51-8.36 (m, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.43-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.22-7.11 (m, 2H), 6.96 (d, J=2.5 Hz, 1H), 4.17 (s, 2H), 4.08 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 1.78-1.63 (m, 2H), 1.49-1.38 (m, 2H), 1.34 (q, J=7.5 Hz, 4H), 0.77 (t, J=7.5 Hz, 6H). MS: 568 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.88 (d, J=46.2 Hz, 1H), 8.42 (dd, J=12.1, 5.2 Hz, 1H), 8.15 (s, 1H), 7.80 (dd, J=8.7, 4.7 Hz, 1H), 7.48-7.32 (m, 3H), 7.22-7.15 (m, 3H), 6.96 (d, J=2.6 Hz, 1H), 4.21 (s, 2H), 4.16-4.04 (m, 2H), 3.89 (s, 1H), 1.77-1.60 (m, 2H), 1.48-1.39 (m, 2H), 1.35 (q, J=7.5 Hz, 4H), 0.78 (t, J=7.4 Hz, 6H). MS: 586 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.89 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.26-7.11 (m, 2H), 6.97 (d, J=2.5 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.18 (m, 1H), 1.79-1.66 (m, 4H), 1.66-1.47 (m, 4H), 1.47-1.39 (m, 2H), 1.35 (q, J=7.5 Hz, 4H), 1.29-1.21 (m, 2H), 0.77 (t, J=7.4 Hz, 6H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.89 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.13 (m, 2H), 6.97 (d, J=2.6 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 2.67 (d, J=7.0 Hz, 2H), 1.83-1.56 (m, 8H), 1.51-1.39 (m, 2H), 1.35 (q, J=7.5 Hz, 4H), 1.27-1.09 (m, 3H), 1.06-0.89 (m, 2H), 0.77 (t, J=7.5 Hz, 6H). MS: 574 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and methyl bromoacetate was used in place of methyl 4-bromobutanoate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.96 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.41-7.29 (m, 4H), 7.29-7.13 (m, 3H), 6.99 (d, J=2.6 Hz, 1H), 4.69 (s, 1H), 4.17 (s, 2H), 3.85 (s, 2H), 1.20 (s, 6H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, methyl bromoacetate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.95 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.48-7.29 (m, 2H), 7.29-7.13 (m, 4H), 6.99 (d, J=2.6 Hz, 1H), 4.68 (s, 1H), 4.20 (s, 2H), 3.85 (s, 2H), 1.20 (s, 6H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, methyl bromoacetate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.27-7.14 (m, 2H), 7.00 (d, J=2.6 Hz, 1H), 4.69 (s, 1H), 3.85 (s, 2H), 2.77 (d, J=7.5 Hz, 2H), 2.34-2.20 (m, 1H), 1.79-1.66 (m, 2H), 1.66-1.56 (m, 2H), 1.56-1.43 (m, 2H), 1.23-1.14 (m, 8H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, methyl bromoacetate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.91 (s, 1H), 8.49-8.38 (m, 1H), 8.17 (d, J=1.4 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.29-7.11 (m, 2H), 7.00 (d, J=2.6 Hz, 1H), 4.69 (s, 1H), 3.85 (s, 2H), 2.66 (d, J=7.1 Hz, 2H), 1.85-1.52 (m, 6H), 1.30-1.07 (m, 9H), 1.07-0.90 (m, 2H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.95 (s, 1H), 8.43 (dd, J=5.1, 0.8 Hz, 1H), 8.16 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.44-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.22-7.10 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.17 (s, 2H), 4.14-4.00 (m, 3H), 1.71 (t, J=6.9 Hz, 2H), 1.51-1.32 (m, 4H), 1.06 (s, 6H). MS: 554 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.93 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.46-7.28 (m, 2H), 7.28-7.12 (m, 4H), 6.97 (d, J=2.5 Hz, 1H), 4.21 (s, 2H), 4.15-4.02 (m, 3H), 1.71 (t, J=7.0 Hz, 2H), 1.52-1.34 (m, 4H), 1.06 (s, 6H). MS: 572 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.90 (s, 1H), 8.44 (dd, J=5.1, 0.8 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.27-7.13 (m, 2H), 6.98 (d, J=2.5 Hz, 1H), 4.17-4.01 (m, 3H), 2.78 (d, J=7.4 Hz, 2H), 2.35-2.19 (m, 1H), 1.81-1.66 (m, 4H), 1.66-1.33 (m, 8H), 1.29-1.15 (m, 2H), 1.06 (s, 6H). MS: 546 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.90 (s, 1H), 8.43 (dd, J=5.1, 0.8 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.27-7.12 (m, 2H), 6.98 (d, J=2.5 Hz, 1H), 4.17-4.01 (m, 3H), 2.66 (d, J=7.1 Hz, 2H), 1.86-1.55 (m, 8H), 1.51-1.33 (m, 4H), 1.28-1.09 (m, 3H), 1.06 (s, 6H), 1.04-0.89 (m, 2H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.95 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.22 (m, 1H), 7.22-7.14 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.45 (t, J=5.1 Hz, 1H), 4.17 (s, 2H), 4.11 (t, J=6.5 Hz, 2H), 3.48-3.41 (m, 2H), 1.82-1.69 (m, 2H), 1.61-1.49 (m, 2H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.93 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.44-7.29 (m, 2H), 7.26-7.14 (m, 4H), 6.97 (d, J=2.5 Hz, 1H), 4.45 (t, J=5.1 Hz, 1H), 4.21 (s, 2H), 4.10 (t, J=6.5 Hz, 2H), 3.48-3.40 (m, 2H), 1.81-1.70 (m, 2H), 1.61-1.50 (m, 2H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.23-7.15 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.45 (t, J=5.2 Hz, 1H), 4.11 (t, J=6.6 Hz, 2H), 3.49-3.39 (m, 2H), 2.77 (d, J=7.5 Hz, 2H), 2.37-2.19 (m, 1H), 1.83-1.67 (m, 4H), 1.67-1.45 (m, 6H), 1.30-1.14 (m, 2H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.95 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.44-7.30 (m, 4H), 7.30-7.22 (m, 1H), 7.22-7.10 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.37 (t, J=5.1 Hz, 1H), 4.17 (s, 2H), 4.09 (t, J=6.5 Hz, 2H), 3.42-3.38 (m, 2H), 1.80-1.68 (m, 2H), 1.54-1.36 (m, 4H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 9.94 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.47-7.29 (m, 2H), 7.29-7.12 (m, 4H), 6.97 (d, J=2.6 Hz, 1H), 4.38 (d, J=5.5 Hz, 1H), 4.20 (s, 2H), 4.09 (t, J=6.5 Hz, 2H), 3.42-3.38 (m, 2H), 1.81-1.65 (m, 2H), 1.55-1.34 (m, 4H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.12 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.37 (t, J=5.1 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.45-3.36 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.21 (m, 1H), 1.81-1.66 (m, 4H), 1.66-1.38 (m, 8H), 1.28-1.15 (m, 2H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.89 (s, 1H), 8.44 (dd, J=5.1, 0.8 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.12 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.37 (t, J=5.1 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.45-3.36 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.83-1.53 (m, 8H), 1.53-1.36 (m, 4H), 1.26-1.15 (m, 3H), 1.03-0.90 (m, 2H). MS: 532 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.96 (s, 1H), 8.44 (dd, J=5.1, 0.8 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.48-7.29 (m, 4H), 7.29-7.13 (m, 3H), 7.01 (d, J=2.6 Hz, 1H), 4.28-4.20 (m, 2H), 4.17 (s, 2H), 3.73-3.62 (m, 2H), 3.30 (s, 3H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 9.95 (s, 1H), 8.43 (dd, J=5.1, 0.8 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.46-7.28 (m, 2H), 7.28-7.07 (m, 4H), 7.00 (d, J=2.5 Hz, 1H), 4.29-4.15 (m, 4H), 3.70-3.62 (m, 2H), 3.30 (s, 3H). MS: 516 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.91 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.32-7.12 (m, 2H), 7.01 (d, J=2.6 Hz, 1H), 4.31-4.17 (m, 2H), 3.72-3.62 (m, 2H), 3.30 (s, 3H), 2.77 (d, J=7.4 Hz, 2H), 2.37-2.18 (m, 1H), 1.79-1.66 (m, 2H), 1.66-1.44 (m, 4H), 1.29-1.12 (m, 2H). MS: 490 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.90 (s, 1H), 8.52-8.39 (m, 1H), 8.18 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.30-7.14 (m, 2H), 7.01 (d, J=2.6 Hz, 1H), 4.31-4.17 (m, 2H), 3.73-3.60 (m, 2H), 3.30 (s, 3H), 2.67 (d, J=7.0 Hz, 2H), 1.83-1.54 (m, 6H), 1.27-1.12 (m, 3H), 1.04-0.91 (m, 2H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.96 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.43-7.09 (m, 7H), 7.01 (d, J=2.6 Hz, 1H), 4.28-4.20 (m, 2H), 4.17 (s, 2H), 3.75-3.66 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.11 (t, J=7.0 Hz, 3H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 9.94 (s, 1H), 8.48-8.37 (m, 1H), 8.15 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.45-7.29 (m, 2H), 7.26-7.14 (m, 4H), 7.01 (d, J=2.6 Hz, 1H), 4.30-4.14 (m, 4H), 3.74-3.64 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.11 (t, J=7.0 Hz, 3H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.29-7.13 (m, 2H), 7.02 (d, J=2.6 Hz, 1H), 4.29-4.17 (m, 2H), 3.76-3.65 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.35-2.18 (m, 1H), 1.79-1.67 (m, 2H), 1.67-1.44 (m, 4H), 1.30-1.16 (m, 2H), 1.11 (t, J=7.0 Hz, 3H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.28-7.13 (m, 2H), 7.02 (d, J=2.6 Hz, 1H), 4.28-4.19 (m, 2H), 3.76-3.66 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 2.66 (d, J=7.0 Hz, 2H), 1.80-1.57 (m, 6H), 1.25-1.14 (m, 3H), 1.11 (t, J=7.0 Hz, 3H), 1.06-0.91 (m, 2H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.94 (s, 1H), 8.43 (dd, J=5.0, 0.8 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.41-7.11 (m, 7H), 7.01 (d, J=2.6 Hz, 1H), 4.25-4.12 (m, 4H), 3.74-3.67 (m, 2H), 3.62 (p, J=6.1 Hz, 1H), 1.09 (d, J=6.1 Hz, 6H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 9.94 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.48-7.28 (m, 2H), 7.28-7.11 (m, 4H), 7.01 (d, J=2.6 Hz, 1H), 4.29-4.13 (m, 4H), 3.76-3.66 (m, 2H), 3.61 (p, J=6.1 Hz, 1H), 1.09 (d, J=6.1 Hz, 6H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.33 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.11 (m, 2H), 7.01 (d, J=2.5 Hz, 1H), 4.26-4.15 (m, 2H), 3.75-3.67 (m, 2H), 3.62 (p, J=6.1 Hz, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.21 (m, 1H), 1.78-1.66 (m, 2H), 1.66-1.44 (m, 4H), 1.24-1.16 (m, 2H), 1.09 (d, J=6.1 Hz, 6H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.88 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.14 (m, 2H), 7.01 (d, J=2.6 Hz, 1H), 4.25-4.16 (m, 2H), 3.75-3.67 (m, 2H), 3.62 (p, J=6.1 Hz, 1H), 2.67 (d, J=6.9 Hz, 2H), 1.84-1.54 (m, 6H), 1.24-1.13 (m, 3H), 1.09 (d, J=6.1 Hz, 6H), 1.05-0.91 (m, 2H). MS: 532 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.53 (s, 1H), 9.95 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.40-7.11 (m, 7H), 7.00 (d, J=2.5 Hz, 1H), 4.22-4.10 (m, 4H), 3.69-3.59 (m, 2H), 1.14 (s, 9H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 9.94 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.51-7.27 (m, 2H), 7.27-7.10 (m, 4H), 7.00 (d, J=2.6 Hz, 1H), 4.28-4.09 (m, 4H), 3.65 (t, J=4.8 Hz, 2H), 1.14 (s, 9H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.88 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.11 (m, 2H), 7.01 (d, J=2.6 Hz, 1H), 4.24-4.11 (m, 2H), 3.71-3.60 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.28 (p, J=7.6 Hz, 1H), 1.79-1.66 (m, 2H), 1.66-1.43 (m, 4H), 1.25-1.20 (m, 2H), 1.15 (s, 9H). MS: 532 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.32 (s, 1H), 9.89 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.29-7.12 (m, 2H), 7.01 (d, J=2.6 Hz, 1H), 4.24-4.13 (m, 2H), 3.66 (dd, J=5.5, 4.0 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.83-1.56 (m, 6H), 1.23-1.16 (m, 3H), 1.15 (s, 9H), 1.05-0.93 (m, 2H). MS: 546 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.96 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.42-7.29 (m, 4H), 7.29-7.23 (m, 1H), 7.23-7.12 (m, 2H), 6.98 (d, J=2.6 Hz, 1H), 4.22-4.08 (m, 4H), 3.46 (t, J=6.2 Hz, 2H), 3.23 (s, 3H), 2.02-1.90 (m, 2H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.67 (s, 1H), 9.94 (s, 1H), 8.43 (dd, J=5.1, 0.8 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.46-7.28 (m, 2H), 7.28-7.12 (m, 4H), 6.98 (d, J=2.6 Hz, 1H), 4.21 (s, 2H), 4.14 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.2 Hz, 2H), 3.23 (s, 3H), 2.01-1.91 (m, 2H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.91 (s, 1H), 8.44 (dd, J=5.1, 0.8 Hz, 1H), 8.23-8.13 (m, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.28-7.12 (m, 2H), 6.99 (d, J=2.5 Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.2 Hz, 2H), 3.24 (s, 3H), 2.77 (d, J=7.5 Hz, 2H), 2.36-2.19 (m, 1H), 2.04-1.91 (m, 2H), 1.78-1.66 (m, 2H), 1.66-1.44 (m, 4H), 1.29-1.14 (m, 2H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.90 (s, 1H), 8.49-8.39 (m, 1H), 8.17 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.29-7.13 (m, 2H), 6.99 (d, J=2.6 Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 3.47 (t, J=6.2 Hz, 2H), 3.24 (s, 3H), 2.67 (d, J=7.0 Hz, 2H), 2.03-1.90 (m, 2H), 1.81-1.57 (m, 6H), 1.24-1.10 (m, 3H), 1.03-0.89 (m, 2H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, and 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.95 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.41-7.29 (m, 4H), 7.29-7.13 (m, 3H), 6.99 (d, J=2.6 Hz, 1H), 4.17 (s, 2H), 3.97 (d, J=6.5 Hz, 2H), 3.92-3.79 (m, 2H), 2.10-1.93 (m, 1H), 1.72-1.60 (m, 2H), 1.42-1.18 (m, 4H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.94 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.45-7.29 (m, 2H), 7.26-7.13 (m, 4H), 6.99 (d, J=2.6 Hz, 1H), 4.21 (s, 2H), 3.96 (d, J=6.5 Hz, 2H), 3.92-3.80 (m, 2H), 2.09-1.91 (m, 1H), 1.72-1.62 (m, 2H), 1.41-1.16 (m, 4H). MS: 556 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.99 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.44-7.32 (m, 1H), 7.26-7.13 (m, 4H), 7.13-7.04 (m, 1H), 6.99 (d, J=2.5 Hz, 1H), 4.21 (s, 2H), 3.96 (d, J=6.5 Hz, 2H), 3.91-3.80 (m, 2H), 3.35-3.29 (m, 2H), 2.07-1.95 (m, 1H), 1.73-1.60 (m, 2H), 1.41-1.25 (m, 2H). MS: 556 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.53 (s, 1H), 9.91 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.42-7.31 (m, 2H), 7.26-7.09 (m, 4H), 6.99 (d, J=2.5 Hz, 1H), 4.18 (s, 2H), 3.97 (d, J=6.5 Hz, 2H), 3.92-3.79 (m, 2H), 3.33-3.31 (m, 2H), 2.13-1.92 (m, 1H), 1.74-1.60 (m, 2H), 1.42-1.23 (m, 2H). MS: 556 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.89 (s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.25-7.14 (m, 2H), 6.99 (d, J=2.5 Hz, 1H), 3.97 (d, J=6.5 Hz, 2H), 3.91-3.81 (m, 2H), 3.33-3.26 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.35-2.18 (m, 1H), 2.11-1.93 (m, 1H), 1.79-1.42 (m, 8H), 1.41-1.27 (m, 2H), 1.27-1.18 (m, 2H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate.
1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.29-7.13 (m, 2H), 7.00 (d, J=2.6 Hz, 1H), 3.97 (d, J=6.4 Hz, 2H), 3.92-3.79 (m, 2H), 3.37-3.33 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.10-1.92 (m, 1H), 1.81-1.72 (m, 1H), 1.70-1.62 (m, 6H), 1.40-1.11 (m, 6H), 1.05-0.89 (m, 2H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, and in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.95 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.42-7.29 (m, 4H), 7.29-7.23 (m, 1H), 7.23-7.13 (m, 2H), 6.99 (d, J=2.6 Hz, 1H), 4.25-4.06 (m, 4H), 3.89-3.71 (m, 2H), 3.29-3.16 (m, 2H), 1.77-1.65 (m, 3H), 1.65-1.53 (m, 2H), 1.29-1.18 (m, 2H). MS: 552 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.94 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.48-7.28 (m, 2H), 7.28-7.12 (m, 4H), 6.99 (d, J=2.6 Hz, 1H), 4.21 (s, 2H), 4.14 (t, J=6.1 Hz, 2H), 3.89-3.76 (m, 2H), 3.31-3.20 (m, 2H), 1.77-1.55 (m, 5H), 1.31-1.12 (m, 2H). MS: 570 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 4, ethyl 5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.97 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.15 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.45-7.32 (m, 1H), 7.23-7.13 (m, 4H), 7.13-7.05 (m, 1H), 7.00 (d, J=2.6 Hz, 1H), 4.21 (s, 2H), 4.14 (t, J=6.1 Hz, 2H), 3.93-3.72 (m, 2H), 3.32-3.21 (m, 2H), 1.75-1.57 (m, 5H), 1.29-1.13 (m, 2H). MS: 570 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 4, ethyl 5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.96 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.44-7.31 (m, 2H), 7.27-7.10 (m, 4H), 7.00 (d, J=2.6 Hz, 1H), 4.23-4.10 (m, 4H), 3.87-3.77 (m, 2H), 3.31-3.20 (m, 2H), 1.79-1.57 (m, 5H), 1.30-1.14 (m, 2H). MS: 570 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.17 (d, J=1.4 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.25-7.14 (m, 2H), 7.00 (d, J=2.5 Hz, 1H), 4.14 (t, J=6.1 Hz, 2H), 3.93-3.69 (m, 2H), 3.30-3.23 (m, 2H), 2.77 (d, J=7.5 Hz, 2H), 2.36-2.19 (m, 1H), 1.78-1.42 (m, 11H), 1.31-1.13 (m, 4H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 2-bromo-3-methylphenol, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.90 (s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.17 (s, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.25-7.14 (m, 2H), 7.00 (d, J=2.5 Hz, 1H), 4.15 (t, J=6.1 Hz, 2H), 3.88-3.76 (m, 2H), 3.30-3.21 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.82-1.52 (m, 10H), 1.31-1.07 (m, 6H), 1.07-0.91 (m, 2H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-bromo-4-ethynylphenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.87 (s, 1H), 8.43 (d, J=5.3 Hz, 1H), 8.37 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.42-7.29 (m, 5H), 7.26 (s, 1H), 7.10-6.97 (m, 2H), 4.18 (s, 2H), 4.16-4.09 (m, 2H), 4.05 (s, 1H), 3.65 (t, J=4.8 Hz, 2H), 1.15 (s, 9H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.38-7.29 (m, 5H), 7.29-7.19 (m, 1H), 7.16-6.99 (m, 2H), 4.24-4.11 (m, 3H), 4.01 (t, J=6.5 Hz, 2H), 1.84-1.69 (m, 2H), 1.55-1.43 (m, 2H), 1.10 (s, 6H). MS: 490 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.92 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.48-7.26 (m, 4H), 7.26-7.15 (m, 2H), 7.15-6.99 (m, 2H), 4.26-4.14 (m, 3H), 4.01 (t, J=6.5 Hz, 2H), 1.84-1.68 (m, 2H), 1.56-1.41 (m, 2H), 1.10 (s, 6H). MS: 508 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.21 (s, 1H), 9.91 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.48-7.26 (m, 4H), 7.26-7.14 (m, 2H), 7.14-6.97 (m, 2H), 4.21 (s, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.91-3.88 (m, 1H), 1.77-1.57 (m, 2H), 1.48-1.39 (m, 2H), 1.35 (q, J=7.5 Hz, 4H), 0.78 (t, J=7.6 Hz, 6H). MS: 536 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.89 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 7.48-7.26 (m, 4H), 7.26-7.15 (m, 2H), 7.15-7.02 (m, 2H), 4.21 (s, 2H), 3.95-3.81 (m, 4H), 3.40-3.33 (m, 2H), 2.07-1.93 (m, 1H), 1.75-1.60 (m, 2H), 1.41-1.25 (m, 2H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, OH), 9.89 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 7.46-7.26 (m, 4H), 7.26-7.16 (m, 2H), 7.13 (dd, J=6.3, 3.1 Hz, 1H), 7.11-7.04 (m, 1H), 4.21 (s, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.87-3.77 (m, 2H), 3.27 (dd, J=11.6, 2.1 Hz, 2H), 2.09-1.90 (m, 1H), 1.70-1.59 (m, 4H), 1.23-1.12 (m, 2H). MS: 520 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 9.85 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.32 (dd, J=10.4, 9.0 Hz, 1H), 7.13 (dd, J=6.3, 3.1 Hz, 1H), 7.11-7.04 (m, 1H), 4.08 (t, J=6.3 Hz, 2H), 3.88-3.76 (m, 2H), 3.30-3.20 (m, 2H), 2.68 (d, J=7.1 Hz, 2H), 1.77-1.60 (m, 10H), 1.29-1.14 (m, 6H), 1.06-0.90 (m, 2H). MS: 508 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.07 (s, 1H), 8.51 (d, J=1.4 Hz, 1H), 8.20 (d, J=5.4 Hz, 1H), 7.44-7.29 (m, 3H), 7.26-7.16 (m, 2H), 7.15-7.04 (m, 2H), 4.21 (s, 2H), 4.17 (s, 1H), 4.00 (t, J=6.5 Hz, 2H), 1.82-1.68 (m, 2H), 1.54-1.42 (m, 2H), 1.10 (s, 6H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 10.04 (s, 1H), 8.52 (d, J=1.4 Hz, 1H), 8.23 (d, J=5.5 Hz, 1H), 7.40-7.26 (m, 1H), 7.17-7.03 (m, 2H), 4.18 (s, 1H), 4.00 (t, J=6.5 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.84-1.71 (m, 3H), 1.71-1.61 (m, 4H), 1.55-1.44 (m, 2H), 1.29-1.12 (m, 4H), 1.10 (s, 6H), 1.05-0.92 (m, 2H). MS: 514 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.10 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H), 7.51-7.14 (m, 5H), 7.14-7.04 (m, 1H), 6.99 (dd, J=5.9, 3.1 Hz, 1H), 4.26-4.14 (m, 3H), 3.98 (t, J=6.6 Hz, 2H), 1.83-1.67 (m, 2H), 1.54-1.39 (m, 2H), 1.09 (s, 6H).
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.08 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.37-7.26 (m, 1H), 7.14-7.06 (m, 1H), 7.00 (dd, J=5.9, 3.1 Hz, 1H), 4.18 (s, 1H), 3.99 (t, J=6.5 Hz, 2H), 2.72-2.61 (m, 2H), 1.83-1.71 (m, 3H), 1.71-1.62 (m, 4H), 1.51-1.43 (m, 2H), 1.28-1.11 (m, 4H), 1.10 (s, 6H), 1.06-0.90 (m, 2H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.83 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.49-7.12 (m, 5H), 7.12-6.97 (m, 1H), 6.90 (dd, J=6.0, 3.1 Hz, 1H), 4.27-4.13 (m, 3H), 3.98 (t, J=6.6 Hz, 2H), 2.12 (s, 3H), 1.83-1.67 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.14 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.46-7.25 (m, 3H), 7.25-7.15 (m, 2H), 7.14-7.05 (m, 1H), 6.99 (dd, J=5.9, 3.1 Hz, 1H), 4.21 (s, 2H), 3.98 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 1.75-1.61 (m, 2H), 1.48-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 0.77 (t, J=7.4 Hz, 6H). MS: 570 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.08 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.39-7.23 (m, 1H), 7.15-7.04 (m, 1H), 6.99 (dd, J=5.8, 3.1 Hz, 1H), 3.99 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 2.67 (d, J=6.9 Hz, 2H), 1.82-1.57 (m, 8H), 1.49-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 1.28-1.09 (m, 3H), 1.06-0.91 (m, 2H), 0.77 (t, J=7.5 Hz, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.16 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.45-7.26 (m, 3H), 7.26-7.15 (m, 2H), 7.15-7.04 (m, 1H), 7.00 (dd, J=5.8, 3.1 Hz, 1H), 4.21 (s, 2H), 4.10 (s, 1H), 3.99 (t, J=6.4 Hz, 2H), 1.74-1.63 (m, 2H), 1.51-1.34 (m, 4H), 1.06 (s, 6H). MS: 556 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 10.10 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.37-7.26 (m, 1H), 7.16-7.06 (m, 1H), 7.01 (dd, J=5.8, 3.1 Hz, 1H), 4.10 (s, 1H), 4.00 (t, J=6.5 Hz, 2H), 2.70-2.61 (m, 2H), 1.81-1.56 (m, 8H), 1.51-1.34 (m, 4H), 1.28-1.14 (m, 3H), 1.07 (s, 6H), 1.04-0.89 (m, 2H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 10.05 (s, 1H), 8.51 (s, 1H), 8.25-8.09 (m, 1H), 7.45-7.07 (m, 6H), 6.53 (s, 1H), 4.23 (s, 2H), 3.93-3.82 (m, 4H), 3.35 (d, J=2.1 Hz, 2H), 2.05-1.92 (m, 1H), 1.72-1.61 (m, 2H), 1.39-1.24 (m, 2H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 10.03 (s, 1H), 8.55-8.49 (m, 1H), 8.24 (d, J=5.4 Hz, 1H), 7.37-7.30 (m, 1H), 7.18-7.06 (m, 2H), 3.93-3.82 (m, 4H), 3.41-3.33 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.05-1.90 (m, 1H), 1.83-1.55 (m, 8H), 1.40-1.26 (m, 2H), 1.26-1.06 (m, 3H), 1.06-0.91 (m, 2H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 10.12 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.46-7.26 (m, 3H), 7.26-7.15 (m, 2H), 7.15-7.06 (m, 1H), 7.01 (dd, J=5.9, 3.1 Hz, 1H), 4.21 (s, 2H), 3.92-3.76 (m, 4H), 3.33-3.25 (m, 2H), 2.04-1.91 (m, 1H), 1.72-1.59 (m, 2H), 1.41-1.25 (m, 2H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.09 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.37-7.26 (m, 1H), 7.16-7.07 (m, 1H), 7.02 (dd, J=5.9, 3.1 Hz, 1H), 3.93-3.82 (m, 4H), 3.34-3.27 (m, 2H), 2.71-2.63 (m, 2H), 2.06-1.92 (m, 1H), 1.85-1.52 (m, 8H), 1.39-1.14 (m, 5H), 1.06-0.90 (m, 2H). MS: 528 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.83 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.46-7.14 (m, 5H), 7.10-7.01 (m, 1H), 6.92 (dd, J=5.9, 3.1 Hz, 1H), 4.20 (s, 2H), 3.95-3.76 (m, 4H), 3.32-3.24 (m, 2H), 2.12 (s, 3H), 2.05-1.92 (m, 1H), 1.74-1.61 (m, 2H), 1.39-1.24 (m, 2H). MS: 520 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 9.80 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.34-7.24 (m, 1H), 7.11-7.02 (m, 1H), 6.92 (dd, J=6.0, 3.1 Hz, 1H), 3.93-3.79 (m, 4H), 3.33-3.27 (m, 2H), 2.70-2.62 (m, 2H), 2.13 (s, 3H), 2.05-1.93 (m, 1H), 1.82-1.55 (m, 8H), 1.40-1.14 (m, 5H), 1.05-0.90 (m, 2H). MS: 508 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.11 (s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 7.50-7.27 (m, 3H), 7.27-7.15 (m, 2H), 7.15-7.06 (m, 1H), 7.02 (dd, J=5.9, 3.1 Hz, 1H), 4.22 (s, 2H), 4.04 (t, J=6.3 Hz, 2H), 3.86-3.78 (m, 2H), 3.32-3.23 (m, 2H), 1.78-1.56 (m, 5H), 1.29-1.12 (m, 2H). MS: 554 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.08 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.36-7.25 (m, 1H), 7.16-7.06 (m, 1H), 7.02 (dd, J=5.9, 3.1 Hz, 1H), 4.05 (t, J=6.2 Hz, 2H), 3.87-3.78 (m, 2H), 3.31-3.24 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.81-1.56 (m, 11H), 1.28-1.13 (m, 5H), 1.04-0.90 (m, 2H). MS: 542 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.86 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.45-7.14 (m, 5H), 7.11-7.01 (m, 1H), 6.92 (dd, J=6.0, 3.1 Hz, 1H), 4.20 (s, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.86-3.78 (m, 2H), 3.30-3.24 (m, 2H), 2.12 (s, 3H), 1.77-1.54 (m, 5H), 1.30-1.08 (m, 2H). MS: 534 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-methyl-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 9.79 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.35-7.22 (m, 1H), 7.11-7.02 (m, 1H), 6.93 (dd, J=6.0, 3.1 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H), 3.87-3.77 (m, 2H), 3.32-3.22 (m, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.13 (s, 3H), 1.81-1.55 (m, 11H), 1.30-1.11 (m, 5H), 1.05-0.89 (m, 2H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.93 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.43-7.18 (m, 6H), 7.13-6.93 (m, 2H), 4.26-4.09 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.83-1.69 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.95 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.45-7.14 (m, 5H), 7.06 (dd, J=8.7, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.27-4.16 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.83-1.69 (m, 2H), 1.53-1.39 (m, 2H), 1.09 (s, 6H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3,4-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.99 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.48-7.36 (m, 2H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.22-7.14 (m, 1H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.26-4.13 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.83-1.69 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 542 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(5-chloro-2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.94 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.21 (s, 1H), 7.60-7.46 (m, 2H), 7.46-7.36 (m, 1H), 7.36-7.22 (m, 2H), 7.13-6.95 (m, 2H), 4.27-4.15 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.82-1.69 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3-chloro-5-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.02 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.43-7.33 (m, 1H), 7.33-7.26 (m, 2H), 7.26-7.16 (m, 1H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.23 (s, 2H), 4.19 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.82-1.69 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3-chloro-4-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.98 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.59 (dd, J=7.2, 2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.43-7.32 (m, 2H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.28-4.14 (m, 3H), 4.01 (t, J=6.5 Hz, 2H), 1.82-1.70 (m, 2H), 1.52-1.42 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(4-fluoro-3-methoxybenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 9.92 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.31-7.25 (m, 1H), 7.20-7.12 (m, 2H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 6.89-6.83 (m, 1H), 4.24-4.11 (m, 3H), 4.01 (t, J=6.5 Hz, 2H), 3.83 (s, 3H), 1.83-1.69 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 554 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3-fluoro-5-methylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.96 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.11-6.85 (m, 5H), 4.23-4.09 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 2.30 (s, 3H), 1.82-1.70 (m, 2H), 1.55-1.39 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(4-fluoro-3-methylbenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.52 (s, 1H), 9.91 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.36-6.94 (m, 6H), 4.18 (s, 1H), 4.13 (s, 2H), 4.01 (t, J=6.6 Hz, 2H), 2.21 (d, J=2.0 Hz, 3H), 1.83-1.69 (m, 2H), 1.54-1.41 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluoro-3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.76 (s, 1H), 9.98 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 7.86-7.65 (m, 2H), 7.57-7.34 (m, 2H), 7.28 (d, J=5.1 Hz, 1H), 7.11-6.91 (m, 2H), 4.32 (s, 2H), 4.18 (s, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.83-1.66 (m, 2H), 1.55-1.39 (m, 2H), 1.09 (s, 6H). MS: 592 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluoro-5-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.92 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.21 (s, 1H), 7.90 (d, J=6.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.56-7.41 (m, 2H), 7.28 (dd, J=5.2, 1.6 Hz, 1H), 7.11-6.93 (m, 2H), 4.32 (s, 2H), 4.18 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.83-1.68 (m, 2H), 1.54-1.40 (m, 2H), 1.09 (s, 6H). MS: 592 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 4, ethyl 5-(3-fluoro-5-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.02 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.68-7.45 (m, 4H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.12-6.94 (m, 2H), 4.34 (s, 2H), 4.19 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.84-1.69 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 592 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(4-fluoro-3-(trifluoromethyl)benzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.53 (s, 1H), 9.91 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.20 (d, J=20.8 Hz, 1H), 7.88-7.64 (m, 2H), 7.57-7.44 (m, 2H), 7.33-7.21 (m, 1H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.32 (s, 2H), 4.17 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.82-1.70 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 592 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(5-ethyl-2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.88 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.35-6.93 (m, 6H), 4.25-4.09 (m, 3H), 4.09-3.93 (m, 2H), 2.58 (q, J=7.6 Hz, 2H), 1.82-1.68 (m, 2H), 1.55-1.38 (m, 2H), 1.16 (t, J=7.6 Hz, 3H), 1.09 (s, 6H). MS: 552 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2,3,4-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.89 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.41-7.21 (m, 3H), 7.12-6.95 (m, 2H), 4.28 (s, 2H), 4.17 (s, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.84-1.69 (m, 2H), 1.53-1.39 (m, 2H), 1.09 (s, 6H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2,3,5-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.75 (s, 1H), 10.01 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.28-8.13 (m, 1H), 7.56-7.41 (m, 2H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.25-7.14 (m, 1H), 7.10-6.95 (m, 2H), 4.28 (s, 2H), 4.17 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.82-1.69 (m, 2H), 1.54-1.39 (m, 2H), 1.09 (s, 6H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2,3,6-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 9.95 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 7.58-7.42 (m, 2H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.25-7.14 (m, 1H), 7.10-6.93 (m, 2H), 4.26 (s, 2H), 4.19 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.84-1.69 (m, 2H), 1.53-1.39 (m, 2H), 1.10 (s, 6H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3,4,5-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.04 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.23 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.41-7.23 (m, 3H), 7.08-6.97 (m, 2H), 4.26-4.15 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.82-1.70 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (s, 6H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2,4,5-trifluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.92 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.72-7.44 (m, 3H), 7.29 (d, J=4.8 Hz, 1H), 7.12-6.94 (m, 2H), 4.28-4.07 (m, 3H), 4.01 (t, J=6.5 Hz, 2H), 1.83-1.66 (m, 2H), 1.55-1.39 (m, 2H), 1.09 (s, 6H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.12-6.96 (m, 2H), 4.19 (s, 1H), 4.02 (t, J=6.5 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.20 (m, 1H), 1.82-1.66 (m, 4H), 1.66-1.57 (m, 2H), 1.57-1.43 (m, 4H), 1.24-1.20 (m, 2H), 1.09 (s, 6H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.92 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.30-8.18 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.13-6.94 (m, 2H), 4.21 (s, 1H), 4.01 (t, J=6.5 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.87-1.55 (m, 8H), 1.51-1.41 (m, 2H), 1.21-1.12 (m, 3H), 1.09 (s, 6H), 1.05-0.89 (m, 2H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(pyrrolidin-1-ylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 9.95 (s, 1H), 8.52-8.40 (m, 1H), 8.29-8.19 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.27 (dd, J=5.1, 1.6 Hz, 1H), 7.13-6.94 (m, 2H), 4.18 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 3.82 (s, 2H), 2.60-2.53 (m, 4H), 1.85-1.63 (m, 6H), 1.55-1.42 (m, 2H), 1.09 (s, 6H). MS: 499 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 9.96 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.30-8.17 (m, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.44-7.18 (m, 6H), 7.13-6.92 (m, 2H), 4.18 (s, 2H), 4.00 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 1.78-1.59 (m, 2H), 1.51-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 0.77 (t, J=7.4 Hz, 6H). MS: 534 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.47-7.30 (m, 2H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.25-7.16 (m, 2H), 7.05 (dd, J=8.8, 3.0 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 4.21 (s, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 1.76-1.62 (m, 2H), 1.47-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 0.77 (t, J=7.5 Hz, 6H). MS: 552 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.90 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.32-8.18 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.12-6.94 (m, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.19 (m, 1H), 1.80-1.64 (m, 4H), 1.64-1.47 (m, 4H), 1.47-1.29 (m, 6H), 1.29-1.14 (m, 2H), 0.77 (t, J=7.4 Hz, 6H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.4 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.16-6.95 (m, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.89 (s, 1H), 2.67 (d, J=7.1 Hz, 2H), 1.86-1.56 (m, 8H), 1.48-1.39 (m, 2H), 1.35 (q, J=7.5 Hz, 4H), 1.25-1.12 (m, 3H), 1.05-0.92 (m, 2H), 0.78 (t, J=7.5 Hz, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and methyl bromoacetate was used in place of methyl 4-bromobutanoate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.96 (s, 1H), 8.55-8.39 (m, 1H), 8.29-8.16 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.41-7.19 (m, 6H), 7.13-6.99 (m, 2H), 4.66 (s, 1H), 4.18 (s, 2H), 3.77 (s, 2H), 1.19 (s, 6H). MS: 478 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl bromoacetate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.31-8.12 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.47-7.26 (m, 3H), 7.26-7.13 (m, 2H), 7.13-6.96 (m, 2H), 4.66 (s, 1H), 4.21 (s, 2H), 3.77 (s, 2H), 1.19 (s, 6H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl bromoacetate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.91 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.34-8.19 (m, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.15-6.93 (m, 2H), 4.66 (s, 1H), 3.78 (s, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.37-2.19 (m, 1H), 1.82-1.66 (m, 2H), 1.66-1.44 (m, 4H), 1.30-1.12 (m, 8H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl bromoacetate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.16-6.95 (m, 2H), 4.66 (s, 1H), 3.78 (s, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.83-1.71 (m, 1H), 1.71-1.53 (m, 5H), 1.29-1.06 (m, 9H), 1.06-0.89 (m, 2H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.96 (s, 1H), 8.45 (dd, J=5.1, 0.8 Hz, 1H), 8.23 (dd, J=1.5, 0.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.45-7.20 (m, 6H), 7.13-6.97 (m, 2H), 4.18 (s, 2H), 4.10 (s, 1H), 4.02 (t, J=6.5 Hz, 2H), 1.75-1.62 (m, 2H), 1.51-1.32 (m, 4H), 1.06 (s, 6H). MS: 520 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 9.94 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.31-8.13 (m, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.45-7.30 (m, 2H), 7.27 (dd, J=5.1, 1.6 Hz, 1H), 7.25-7.15 (m, 2H), 7.09-6.98 (m, 2H), 4.21 (s, 2H), 4.11 (s, 1H), 4.01 (t, J=6.4 Hz, 2H), 1.69 (t, J=7.0 Hz, 2H), 1.49-1.33 (m, 4H), 1.06 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.90 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.25 (dd, J=1.6, 0.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.11-6.96 (m, 2H), 4.10 (s, 1H), 4.02 (t, J=6.5 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.19 (m, 1H), 1.79-1.65 (m, 4H), 1.65-1.33 (m, 8H), 1.30-1.15 (m, 2H), 1.06 (s, 6H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.13-6.97 (m, 2H), 4.10 (s, 1H), 4.03 (t, J=6.4 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.84-1.58 (m, 7H), 1.52-1.35 (m, 4H), 1.31-1.10 (m, 4H), 1.06 (s, 6H), 1.02-0.92 (m, 2H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.92 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.40-7.30 (m, 4H), 7.30-7.21 (m, 2H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 4.45 (t, J=5.1 Hz, 1H), 4.18 (s, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.47-3.41 (m, 2H), 1.81-1.69 (m, 2H), 1.61-1.50 (m, 2H). MS: 478 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.91 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.21 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.46-7.31 (m, 2H), 7.28 (d, J=5.2 Hz, 1H), 7.26-7.15 (m, 2H), 7.11-6.98 (m, 2H), 4.45 (t, J=5.2 Hz, 1H), 4.21 (s, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.46-3.42 (m, 2H), 1.80-1.67 (m, 2H), 1.62-1.49 (m, 2H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.88 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.29 (d, J=5.0 Hz, 1H), 7.12-6.99 (m, 2H), 4.45 (t, J=5.2 Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.46-3.43 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.31-2.23 (m, 1H), 1.78-1.68 (m, 4H), 1.65-1.48 (m, 6H), 1.25-1.22 (m, 2H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 4-bromo-1-butanol was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 9.89 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.24 (d, J=1.1 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.13-6.98 (m, 2H), 4.45 (t, J=5.2 Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.47-3.41 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.81-1.52 (m, 10H), 1.22-0.90 (m, 5H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.95 (s, 1H), 8.45 (d, J=5.0 Hz, 1H), 8.22 (d, J=1.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.39-7.30 (m, 4H), 7.30-7.19 (m, 2H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 4.44-4.30 (m, 1H), 4.18 (s, 2H), 4.02 (t, J=6.5 Hz, 2H), 3.44-3.37 (m, 2H), 1.78-1.64 (m, 2H), 1.53-1.35 (m, 4H). MS: 492 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.45-7.31 (m, 2H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.26-7.13 (m, 2H), 7.11-6.99 (m, 2H), 4.38 (s, 1H), 4.21 (s, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.45-3.37 (m, 2H), 1.79-1.66 (m, 2H), 1.52-1.37 (m, 4H). MS: 510 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.89 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.14-6.96 (m, 2H), 4.38 (t, J=5.2 Hz, 1H), 4.02 (t, J=6.5 Hz, 2H), 3.46-3.35 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.20 (m, 1H), 1.80-1.67 (m, 4H), 1.67-1.38 (m, 8H), 1.30-1.15 (m, 2H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 5-bromo-1-pentanol was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 9.89 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.07 (dd, J=8.8, 3.1 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 4.38 (t, J=5.2 Hz, 1H), 4.02 (t, J=6.5 Hz, 2H), 3.45-3.37 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.84-1.54 (m, 8H), 1.52-1.36 (m, 4H), 1.27-1.11 (m, 3H), 1.04-0.91 (m, 2H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.96 (s, 1H), 8.45 (dd, J=5.1, 0.8 Hz, 1H), 8.24 (dd, J=1.6, 0.8 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.43-7.30 (m, 4H), 7.30-7.20 (m, 2H), 7.15-6.98 (m, 2H), 4.25-4.10 (m, 4H), 3.71-3.59 (m, 2H), 3.30 (s, 3H). MS: 464 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.94 (s, 1H), 8.56-8.38 (m, 1H), 8.31-8.14 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.46-7.14 (m, 5H), 7.14-6.94 (m, 2H), 4.21 (s, 2H), 4.18-4.11 (m, 2H), 3.73-3.60 (m, 2H), 3.30 (s, 3H). MS: 482 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.25 (t, J=1.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.16-6.98 (m, 2H), 4.25-4.09 (m, 2H), 3.75-3.61 (m, 2H), 3.30 (s, 3H), 2.78 (d, J=7.5 Hz, 2H), 2.37-2.18 (m, 1H), 1.81-1.67 (m, 2H), 1.67-1.44 (m, 4H), 1.32-1.13 (m, 2H). MS: 456 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-methoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.25 (d, J=1.5 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.16-7.00 (m, 2H), 4.23-4.10 (m, 2H), 3.72-3.61 (m, 2H), 3.30 (s, 3H), 2.67 (d, J=7.1 Hz, 2H), 1.85-1.53 (m, 6H), 1.28-1.11 (m, 3H), 1.03-0.90 (m, 2H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.94 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.23 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.43-7.30 (m, 4H), 7.30-7.22 (m, 2H), 7.18-6.97 (m, 2H), 4.22-4.11 (m, 4H), 3.73-3.66 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.12 (t, J=7.0 Hz, 3H). MS: 478 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.28-8.16 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.46-7.13 (m, 5H), 7.13-6.97 (m, 2H), 4.21 (s, 2H), 4.18-4.09 (m, 2H), 3.75-3.63 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 1.11 (t, J=7.0 Hz, 3H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.90 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.25 (t, J=1.1 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.17-6.96 (m, 2H), 4.23-4.09 (m, 2H), 3.75-3.65 (m, 2H), 3.49 (q, J=7.0 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.18 (m, 1H), 1.80-1.67 (m, 2H), 1.67-1.57 (m, 2H), 1.57-1.44 (m, 2H), 1.25-1.16 (m, 2H), 1.12 (t, J=7.0 Hz, 3H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-ethoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.7 Hz, 1H), 7.20-7.00 (m, 2H), 4.16 (dd, J=5.6, 3.5 Hz, 2H), 3.70 (dd, J=5.6, 3.4 Hz, 2H), 3.50 (q, J=7.0 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.83-1.53 (m, 6H), 1.25-1.14 (m, 3H), 1.12 (t, J=7.0 Hz, 3H), 1.06-0.88 (m, 2H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.96 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.29-8.16 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.44-7.18 (m, 6H), 7.18-6.96 (m, 2H), 4.18 (s, 2H), 4.15-4.05 (m, 2H), 3.75-3.66 (m, 2H), 3.61 (p, J=6.1 Hz, 1H), 1.09 (d, J=6.0 Hz, 6H). MS: 492 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 9.94 (s, 1H), 8.45 (dd, J=5.1, 0.8 Hz, 1H), 8.30-8.14 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.46-7.25 (m, 3H), 7.25-7.13 (m, 2H), 7.13-6.97 (m, 2H), 4.21 (s, 2H), 4.17-4.06 (m, 2H), 3.74-3.65 (m, 2H), 3.61 (p, J=6.1 Hz, 1H), 1.09 (d, J=6.1 Hz, 6H). MS: 510 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.90 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.25 (d, J=1.4 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.19-6.99 (m, 2H), 4.22-4.05 (m, 2H), 3.75-3.66 (m, 2H), 3.62 (p, J=6.1 Hz, 1H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.20 (m, 1H), 1.84-1.66 (m, 2H), 1.66-1.46 (m, 4H), 1.26-1.18 (m, 2H), 1.10 (d, J=6.1 Hz, 6H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-2-isopropoxyethane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.15-6.96 (m, 2H), 4.18-4.09 (m, 2H), 3.74-3.65 (m, 2H), 3.62 (p, J=6.1 Hz, 1H), 2.67 (d, J=7.1 Hz, 2H), 1.85-1.56 (m, 6H), 1.26-1.17 (m, 3H), 1.10 (d, J=6.1 Hz, 6H), 1.05-0.91 (m, 2H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.93 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.23 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.43-7.18 (m, 6H), 7.14-6.97 (m, 2H), 4.18 (s, 2H), 4.13-4.00 (m, 2H), 3.64 (t, J=4.8 Hz, 2H), 1.15 (s, 9H). MS: 506 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 9.90 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.45-7.31 (m, 2H), 7.28 (dd, J=5.2, 1.6 Hz, 1H), 7.26-7.15 (m, 2H), 7.12-7.01 (m, 2H), 4.21 (s, 2H), 4.14-4.03 (m, 2H), 3.69-3.58 (m, 2H), 1.15 (s, 9H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.87 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.34-7.24 (m, 1H), 7.16-6.96 (m, 2H), 4.16-4.03 (m, 2H), 3.70-3.56 (m, 2H), 2.79 (d, J=7.5 Hz, 2H), 2.37-2.22 (m, 1H), 1.80-1.66 (m, 2H), 1.66-1.57 (m, 2H), 1.57-1.41 (m, 2H), 1.29-1.18 (m, 2H), 1.15 (s, 9H). MS: 498 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.88 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.25 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 7.13-7.00 (m, 2H), 4.17-4.03 (m, 2H), 3.70-3.60 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.84-1.57 (m, 6H), 1.28-1.13 (m, 12H), 1.03-0.91 (m, 2H). MS: 512 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, and 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.96 (s, 1H), 8.45 (dd, J=5.1, 0.8 Hz, 1H), 8.22 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.40-7.23 (m, 6H), 7.13-6.95 (m, 2H), 4.18 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.2 Hz, 2H), 3.24 (s, 3H), 2.00-1.89 (m, 2H). MS: 478 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.69 (s, 1H), 9.94 (s, 1H), 8.45 (dd, J=5.1, 0.8 Hz, 1H), 8.28-8.13 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.44-7.31 (m, 2H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.26-7.16 (m, 2H), 7.10-6.95 (m, 2H), 4.21 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.2 Hz, 2H), 3.23 (s, 3H), 2.03-1.89 (m, 2H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.91 (s, 1H), 8.46 (dd, J=5.1, 0.8 Hz, 1H), 8.24 (dd, J=1.5, 0.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.13-6.99 (m, 2H), 4.08 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.18 (m, 1H), 2.00-1.89 (m, 2H), 1.79-1.67 (m, 2H), 1.67-1.44 (m, 4H), 1.30-1.15 (m, 2H). MS: 470 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-bromo-3-methoxypropane was used in place of iodomethane, 3-bromo-4-chlorophenol was used in place of 2-bromo-3-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.40 (s, 1H), 9.90 (s, 1H), 8.52-8.40 (m, 1H), 8.24 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.14-6.96 (m, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.46 (t, J=6.3 Hz, 2H), 3.24 (s, 3H), 2.67 (d, J=7.1 Hz, 2H), 2.02-1.87 (m, 2H), 1.82-1.58 (m, 6H), 1.28-1.11 (m, 3H), 1.05-0.89 (m, 2H). MS: 484 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, and 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 9.95 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.42-7.30 (m, 4H), 7.30-7.19 (m, 2H), 7.14-6.97 (m, 2H), 4.18 (s, 2H), 3.96-3.80 (m, 4H), 3.35-3.26 (m, 2H), 2.05-1.94 (m, 1H), 1.73-1.61 (m, 2H), 1.40-1.24 (m, 2H). MS: 504 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 9.94 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.21 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.47-7.12 (m, 5H), 7.12-6.95 (m, 2H), 4.21 (s, 2H), 3.95-3.79 (m, 4H), 3.33-3.26 (m, 2H), 2.06-1.92 (m, 1H), 1.75-1.62 (m, 2H), 1.41-1.19 (m, 2H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.91 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.30-8.19 (m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.15-6.97 (m, 2H), 3.94-3.81 (m, 4H), 3.32-3.22 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.17 (m, 1H), 2.06-1.93 (m, 1H), 1.79-1.46 (m, 8H), 1.39-1.14 (m, 4H). MS: 496 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.91 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.6 Hz, 1H), 7.61-7.44 (m, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.18-6.96 (m, 2H), 4.00-3.80 (m, 4H), 3.33-3.23 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.10-1.91 (m, 1H), 1.83-1.54 (m, 8H), 1.38-1.09 (m, 5H), 1.04-0.90 (m, 2H). MS: 510 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, and in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 9.96 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.23 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.41-7.21 (m, 6H), 7.12-7.00 (m, 2H), 4.18 (s, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.88-3.76 (m, 2H), 3.31-3.22 (m, 2H), 1.76-1.55 (m, 5H), 1.23-1.14 (m, 2H). MS: 518 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.95 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.28-8.14 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.46-7.30 (m, 2H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.26-7.12 (m, 2H), 7.12-7.00 (m, 2H), 4.20 (s, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.88-3.76 (m, 2H), 3.30-3.24 (m, 2H), 1.79-1.56 (m, 5H), 1.22-1.13 (m, 2H). MS: 536 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.91 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.14-6.99 (m, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.88-3.75 (m, 2H), 3.31-3.21 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.19 (m, 1H), 1.78-1.55 (m, 9H), 1.55-1.46 (m, 2H), 1.26-1.19 (m, 4H). MS: 510 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.91 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.33-8.17 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.28 (dd, J=5.1, 1.6 Hz, 1H), 7.14-6.98 (m, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.87-3.76 (m, 2H), 3.30-3.21 (m, 2H), 2.67 (d, J=7.1 Hz, 2H), 1.83-1.51 (m, 11H), 1.27-1.12 (m, 5H), 1.05-0.89 (m, 2H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chloro-5-fluorophenol was used in place of 3-bromo-4-methylphenol. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 9.91 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.46-7.26 (m, 4H), 7.26-7.15 (m, 2H), 7.15-7.02 (m, 2H), 4.21 (s, 2H), 4.10 (s, 1H), 4.02 (t, J=6.4 Hz, 2H), 1.77-1.64 (m, 2H), 1.52-1.42 (m, 2H), 1.07 (s, 6H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chloro-5-fluorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 9.98 (s, 1H), 8.47 (d, J=5.2 Hz, 1H), 8.40 (d, J=1.7 Hz, 1H), 7.58 (dd, J=5.2, 1.7 Hz, 1H), 7.41 (dd, J=9.8, 1.8 Hz, 1H), 7.35-7.31 (m, 4H), 7.29-7.23 (m, 1H), 4.29-4.20 (m, 3H), 4.18 (s, 2H), 1.89-1.77 (m, 2H), 1.58-1.47 (m, 2H), 1.12 (s, 6H). MS: 542 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 10.13 (s, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.43-7.29 (m, 2H), 7.26-7.14 (m, 2H), 7.14-7.03 (m, 2H), 4.20 (s, 2H), 4.17 (s, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.83-1.69 (m, 2H), 1.52-1.42 (m, 2H), 1.09 (s, 6H). MS: 542 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 10.06 (s, 1H), 8.52 (d, J=1.2 Hz, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.15-7.04 (m, 2H), 4.17 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.82-1.56 (m, 8H), 1.52-1.41 (m, 2H), 1.28-1.12 (m, 3H), 1.09 (s, 6H), 1.05-0.90 (m, 2H). MS: 530 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 10.14 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.44-7.29 (m, 2H), 7.26-7.15 (m, 2H), 7.08 (dd, J=8.9, 3.0 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 4.25-4.14 (m, 3H), 3.99 (t, J=6.6 Hz, 2H), 1.81-1.69 (m, 2H), 1.52-1.40 (m, 2H), 1.09 (s, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.09 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.09 (dd, J=8.9, 3.0 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 4.18 (s, 1H), 4.00 (t, J=6.6 Hz, 2H), 2.67 (d, J=6.9 Hz, 2H), 1.82-1.55 (m, 8H), 1.52-1.42 (m, 2H), 1.28-1.12 (m, 3H), 1.09 (s, 6H), 1.05-0.87 (m, 2H). MS: 546 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-methylpyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.80 (s, 1H), 8.32 (s, 1H), 7.93 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.45-7.28 (m, 2H), 7.28-7.14 (m, 2H), 7.05 (dd, J=8.9, 3.0 Hz, 1H), 6.90 (d, J=3.0 Hz, 1H), 4.26-4.12 (m, 3H), 3.99 (t, J=6.6 Hz, 2H), 2.05 (s, 3H), 1.82-1.66 (m, 2H), 1.51-1.41 (m, 2H), 1.08 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-methylpyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.79 (s, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.05 (dd, J=8.9, 3.0 Hz, 1H), 6.91 (d, J=3.0 Hz, 1H), 4.18 (s, 1H), 3.99 (t, J=6.6 Hz, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.05 (s, 3H), 1.82-1.56 (m, 8H), 1.52-1.41 (m, 2H), 1.30-1.12 (m, 3H), 1.09 (s, 6H), 1.04-0.90 (m, 2H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.13 (s, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.45-7.29 (m, 2H), 7.26-7.15 (m, 2H), 7.14-7.04 (m, 2H), 4.20 (s, 2H), 4.00 (t, J=6.5 Hz, 2H), 3.87 (s, 1H), 1.76-1.61 (m, 2H), 1.47-1.38 (m, 2H), 1.34 (q, J=7.5 Hz, 4H), 0.77 (t, J=7.4 Hz, 6H). MS: 570 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 10.07 (s, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.13-7.04 (m, 2H), 4.01 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 2.66 (d, J=7.1 Hz, 2H), 1.82-1.55 (m, 8H), 1.46-1.39 (m, 2H), 1.34 (q, J=7.5 Hz, 4H), 1.28-1.09 (m, 3H), 1.05-0.91 (m, 2H), 0.77 (t, J=7.5 Hz, 6H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (s, 1H), 10.13 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.46-7.29 (m, 2H), 7.26-7.15 (m, 2H), 7.08 (dd, J=8.9, 3.0 Hz, 1H), 6.99 (d, J=3.0 Hz, 1H), 4.21 (s, 2H), 3.99 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 1.74-1.61 (m, 2H), 1.45-1.37 (m, 2H), 1.34 (q, J=7.5 Hz, 4H), 0.77 (t, J=7.5 Hz, 6H). MS: 586 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, ethylmagnesium bromide was used in place of methylmagnesium bromide, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.09 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.09 (dd, J=8.9, 3.0 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 4.00 (t, J=6.5 Hz, 2H), 3.88 (s, 1H), 2.67 (d, J=6.8 Hz, 2H), 1.82-1.56 (m, 8H), 1.48-1.38 (m, 2H), 1.34 (q, J=7.4 Hz, 4H), 1.27-1.09 (m, 3H), 1.05-0.89 (m, 2H), 0.77 (t, J=7.4 Hz, 6H). MS: 574 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 10.05 (s, 1H), 8.52 (d, J=15.7 Hz, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.44-7.07 (m, 6H), 4.23 (s, 2H), 4.08 (s, 1H), 4.01 (t, J=6.4 Hz, 2H), 1.76-1.63 (m, 2H), 1.50-1.33 (m, 4H), 1.06 (s, 6H). MS: 556 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 10.11 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.46-7.27 (m, 2H), 7.27-7.13 (m, 2H), 7.09 (dd, J=8.9, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.23 (s, 2H), 4.11 (s, 1H), 4.00 (t, J=6.7 Hz, 2H), 1.74-1.62 (m, 2H), 1.48-1.29 (m, 4H), 1.06 (s, 6H). MS: 572 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 10.12 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.10 (dd, J=8.9, 3.0 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 4.10 (s, 1H), 4.01 (t, J=6.7 Hz, 2H), 2.66 (d, J=7.0 Hz, 2H), 1.83-1.40 (m, 11H), 1.30-1.08 (m, 4H), 1.06 (s, 6H), 1.03-0.88 (m, 2H). MS: 560 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.13 (s, 1H), 8.51 (d, J=1.2 Hz, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.43-7.29 (m, 2H), 7.25-7.16 (m, 2H), 7.14-7.09 (m, 2H), 4.21 (s, 2H), 3.92-3.80 (m, 4H), 3.38-3.32 (m, 2H), 2.05-1.92 (m, 1H), 1.72-1.58 (m, 2H), 1.41-1.23 (m, 2H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 10.07 (s, 1H), 8.52 (s, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.17-7.07 (m, 2H), 3.94-3.82 (m, 4H), 3.37-3.30 (m, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.06-1.92 (m, 1H), 1.82-1.56 (m, 8H), 1.39-1.25 (m, 2H), 1.25-1.10 (m, 3H), 1.05-0.90 (m, 2H). MS: 528 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.63 (s, 1H), 10.14 (s, 1H), 8.57 (s, 1H), 8.11 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.45-7.29 (m, 2H), 7.26-7.14 (m, 2H), 7.10 (dd, J=8.9, 3.0 Hz, 1H), 7.02 (d, J=3.0 Hz, 1H), 4.21 (s, 2H), 3.96-3.75 (m, 4H), 3.34-3.23 (m, 2H), 2.06-1.90 (m, 1H), 1.73-1.60 (m, 2H), 1.40-1.24 (m, 2H). MS: 556 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 5-chloro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.10 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.11 (dd, J=8.9, 3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 3.95-3.81 (m, 4H), 3.34-3.26 (m, 2H), 2.66 (d, J=7.0 Hz, 2H), 2.07-1.92 (m, 1H), 1.83-1.55 (m, 8H), 1.39-1.07 (m, 5H), 1.07-0.89 (m, 2H). MS: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 4-bromo-5-methylpyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.81 (s, 1H), 8.32 (s, 1H), 7.93 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.46-7.29 (m, 2H), 7.26-7.15 (m, 2H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 6.92 (d, J=3.0 Hz, 1H), 4.20 (s, 2H), 3.95-3.78 (m, 4H), 3.38-3.30 (m, 2H), 2.05 (s, 3H), 2.02-1.92 (m, 1H), 1.66 (dd, J=12.8, 3.1 Hz, 2H), 1.39-1.24 (m, 2H). MS: 536 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 4-bromo-5-methylpyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 9.79 (s, 1H), 8.33 (s, 1H), 7.96 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.07 (dd, J=8.9, 3.0 Hz, 1H), 6.93 (d, J=3.0 Hz, 1H), 3.92-3.81 (m, 4H), 3.38-3.33 (m, 2H), 2.70-2.62 (m, 2H), 2.05 (s, 3H), 2.04-1.92 (m, 1H), 1.82-1.58 (m, 8H), 1.38-1.12 (m, 5H), 1.05-0.89 (m, 2H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.14 (s, 1H), 8.51 (d, J=1.1 Hz, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.56-7.49 (m, 1H), 7.45-7.29 (m, 2H), 7.25-7.15 (m, 2H), 7.15-7.06 (m, 2H), 4.20 (s, 2H), 4.06 (t, J=6.2 Hz, 2H), 3.87-3.76 (m, 2H), 3.35-3.28 (m, 2H), 1.77-1.55 (m, 5H), 1.29-1.12 (m, 2H). MS: 554 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.07 (s, 1H), 8.52 (d, J=1.2 Hz, 1H), 8.15 (d, J=5.5 Hz, 1H), 7.57-7.48 (m, 1H), 7.17-7.08 (m, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.88-3.75 (m, 2H), 3.31-3.21 (m, 2H), 2.66 (d, J=7.0 Hz, 2H), 1.83-1.55 (m, 12H), 1.30-1.12 (m, 4H), 1.05-0.90 (m, 2H). MS: 542 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.64 (s, 1H), 10.15 (s, 1H), 8.57 (s, 1H), 8.10 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.45-7.29 (m, 2H), 7.26-7.14 (m, 2H), 7.10 (dd, J=8.9, 3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 4.21 (s, 2H), 4.05 (t, J=6.3 Hz, 2H), 3.86-3.74 (m, 2H), 3.31-3.19 (m, 2H), 1.76-1.54 (m, 5H), 1.27-1.13 (m, 2H). MS: 570 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 4-bromo-5-chloropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.38 (s, 1H), 10.09 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.10 (dd, J=8.9, 3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H), 4.05 (t, J=6.4 Hz, 2H), 3.86-3.75 (m, 2H), 3.31-3.20 (m, 2H), 2.67 (d, J=6.8 Hz, 2H), 1.82-1.54 (m, 11H), 1.28-1.13 (m, 5H), 1.05-0.89 (m, 2H). MS: 558 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 10.35 (s, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.48-7.16 (m, 6H), 7.09-6.90 (m, 2H), 4.26-4.12 (m, 3H), 3.98 (t, J=6.6 Hz, 2H), 2.31 (s, 3H), 1.86-1.66 (m, 2H), 1.56-1.40 (m, 2H), 1.09 (s, 6H). MS: 487 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 10.33 (s, 1H), 9.01 (d, J=1.2 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 7.51-7.29 (m, 2H), 7.29-7.13 (m, 3H), 7.08-6.91 (m, 2H), 4.22 (s, 2H), 4.18 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 2.31 (s, 3H), 1.83-1.68 (m, 2H), 1.54-1.42 (m, 2H), 1.09 (s, 6H). MS: 505 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(3-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 10.39 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.24 (d, J=1.2 Hz, 1H), 7.46-7.31 (m, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.23-7.14 (m, 2H), 7.14-7.06 (m, 1H), 7.03 (d, J=2.7 Hz, 1H), 6.98 (dd, J=8.3, 2.8 Hz, 1H), 4.22 (s, 2H), 4.18 (s, 1H), 3.98 (t, J=6.6 Hz, 2H), 2.31 (s, 3H), 1.83-1.69 (m, 2H), 1.54-1.43 (m, 2H), 1.09 (s, 6H). MS: 505 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2,4-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.72 (s, 1H), 10.35 (s, 1H), 9.01 (d, J=1.2 Hz, 1H), 8.23 (d, J=1.2 Hz, 1H), 7.56-7.40 (m, 1H), 7.27 (dd, J=10.8, 7.8 Hz, 2H), 7.16-7.06 (m, 1H), 7.06-6.91 (m, 2H), 4.25-4.13 (m, 3H), 3.97 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 1.82-1.67 (m, 2H), 1.53-1.42 (m, 2H), 1.09 (s, 6H). MS: 523 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2,5-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.51 (s, 1H), 10.33 (s, 1H), 9.00 (d, J=1.2 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.39-7.11 (m, 4H), 7.08-6.90 (m, 2H), 4.24-4.12 (m, 3H), 3.98 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 1.82-1.69 (m, 2H), 1.53-1.42 (m, 2H), 1.10 (s, 6H). MS: 523 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(3,5-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 10.44 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.24 (d, J=1.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.22-7.06 (m, 3H), 7.03 (d, J=2.7 Hz, 1H), 6.98 (dd, J=8.4, 2.8 Hz, 1H), 4.24 (s, 2H), 4.18 (s, 1H), 3.98 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 1.82-1.68 (m, 2H), 1.53-1.43 (m, 2H), 1.09 (s, 6H). MS: 523 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(3-chloro-2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 10.31 (s, 1H), 9.01 (d, J=1.2 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 7.60-7.45 (m, 1H), 7.45-7.33 (m, 1H), 7.33-7.15 (m, 2H), 7.08-6.91 (m, 2H), 4.27 (s, 2H), 4.18 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 1.83-1.69 (m, 2H), 1.54-1.40 (m, 2H), 1.09 (s, 6H). MS: 539 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.27 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.09-6.90 (m, 2H), 4.18 (s, 1H), 3.98 (t, J=6.5 Hz, 2H), 2.79 (d, J=7.5 Hz, 2H), 2.32 (s, 3H), 2.30-2.18 (m, 1H), 1.82-1.67 (m, 4H), 1.67-1.56 (m, 2H), 1.56-1.43 (m, 4H), 1.25-1.21 (m, 2H), 1.10 (s, 6H). MS: 479 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 10.28 (s, 1H), 9.02 (s, 1H), 8.26 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.03 (d, J=2.7 Hz, 1H), 6.99 (dd, J=8.3, 2.8 Hz, 1H), 4.18 (s, 1H), 3.98 (t, J=6.6 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.32 (s, 3H), 1.83-1.55 (m, 8H), 1.52-1.42 (m, 2H), 1.25-1.14 (m, 3H), 1.10 (s, 6H), 1.04-0.89 (m, 2H). MS: 493 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, and in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 10.34 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.22 (m, 2H), 7.04 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.3, 2.8 Hz, 1H), 4.19 (s, 2H), 3.92-3.80 (m, 4H), 3.33-3.28 (m, 2H), 2.31 (s, 3H), 2.05-1.93 (m, 1H), 1.76-1.62 (m, 2H), 1.39-1.26 (m, 2H). MS: 485 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.75 (s, 1H), 10.34 (s, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 7.46-7.30 (m, 2H), 7.30-7.16 (m, 3H), 7.04 (d, J=2.8 Hz, 1H), 6.99 (dd, J=8.4, 2.8 Hz, 1H), 4.22 (s, 2H), 3.92-3.79 (m, 4H), 3.32-3.25 (m, 2H), 2.31 (s, 3H), 2.05-1.92 (m, 1H), 1.73-1.62 (m, 2H), 1.40-1.26 (m, 2H). MS: 503 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.48 (s, 1H), 10.27 (s, 1H), 9.03 (d, J=1.3 Hz, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 7.00 (dd, J=8.3, 2.8 Hz, 1H), 3.93-3.81 (m, 4H), 3.33-3.29 (m, 2H), 2.79 (d, J=7.5 Hz, 2H), 2.32 (s, 3H), 2.31-2.21 (m, 1H), 2.08-1.93 (m, 1H), 1.79-1.45 (m, 8H), 1.38-1.27 (m, 2H), 1.27-1.17 (m, 2H). MS: 477 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.26 (s, 1H), 9.02 (d, J=1.3 Hz, 1H), 8.25 (d, J=1.3 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.4, 2.8 Hz, 1H), 3.92-3.81 (m, 4H), 3.37-3.32 (m, 2H), 2.67 (d, J=7.1 Hz, 2H), 2.31 (s, 3H), 2.06-1.93 (m, 1H), 1.82-1.53 (m, 8H), 1.42-1.25 (m, 2H), 1.25-1.06 (m, 3H), 1.06-0.91 (m, 2H). MS: 491 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, and in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 10.35 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.45-7.17 (m, 6H), 7.17-6.86 (m, 2H), 4.19 (s, 2H), 4.04 (t, J=6.3 Hz, 2H), 3.93-3.66 (m, 2H), 3.30-3.20 (m, 2H), 2.31 (s, 3H), 1.82-1.56 (m, 5H), 1.28-1.17 (m, 2H). MS: 499 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 10.34 (s, 1H), 9.01 (d, J=1.2 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 7.47-7.29 (m, 2H), 7.29-7.15 (m, 3H), 7.08-6.93 (m, 2H), 4.22 (s, 2H), 4.03 (t, J=6.3 Hz, 2H), 3.91-3.74 (m, 2H), 3.30-3.18 (m, 2H), 2.30 (s, 3H), 1.83-1.53 (m, 5H), 1.24-1.13 (m, 2H). MS: 517 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.49 (s, 1H), 10.27 (s, 1H), 9.02 (d, J=1.3 Hz, 1H), 8.25 (d, J=1.3 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.12-6.83 (m, 2H), 4.04 (t, J=6.3 Hz, 2H), 3.93-3.66 (m, 2H), 3.30-3.17 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.31 (s, 3H), 2.29-2.14 (m, 1H), 1.80-1.43 (m, 11H), 1.26-1.14 (m, 4H). MS: 491 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 10.26 (s, 1H), 9.01 (s, 1H), 8.25 (s, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 7.00 (dd, J=8.4, 2.8 Hz, 1H), 4.04 (t, J=6.3 Hz, 2H), 3.82 (dd, J=11.2, 4.3 Hz, 2H), 3.28-3.22 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.31 (s, 3H), 1.83-1.55 (m, 12H), 1.25-1.17 (m, 4H), 1.04-0.89 (m, 2H). MS: 505 [M+H]+.
The preparation was carried out in a similar manner to Example 92, except that in step 1, 1-(2-chloroethyl)piperidine hydrochloride was used in place of iodomethane, 3-bromo-4-methylphenol was used in place of 2-bromo-3-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.57 (s, 1H), 10.33 (s, 1H), 9.01 (d, J=1.2 Hz, 1H), 8.23 (d, J=1.3 Hz, 1H), 7.46-7.29 (m, 2H), 7.29-7.16 (m, 3H), 7.05 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.4, 2.8 Hz, 1H), 4.21 (s, 2H), 4.09 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.9 Hz, 2H), 2.47-2.39 (m, 4H), 2.31 (s, 3H), 1.54-1.44 (m, 4H), 1.41-1.31 (m, 2H). MS: 516 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.68 (s, 1H), 10.45 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.25 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.38-7.29 (m, 4H), 7.29-7.20 (m, 2H), 7.11 (d, J=2.6 Hz, 1H), 4.24-4.15 (m, 3H), 4.10 (t, J=6.6 Hz, 2H), 1.84-1.69 (m, 2H), 1.54-1.41 (m, 2H), 1.10 (s, 6H). MS: 541 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.75 (s, 1H), 10.46 (s, 1H), 9.02 (d, J=1.3 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.45-7.30 (m, 2H), 7.27-7.16 (m, 3H), 7.11 (d, J=2.6 Hz, 1H), 4.27-4.16 (m, 3H), 4.10 (t, J=6.6 Hz, 2H), 1.86-1.71 (m, 2H), 1.55-1.42 (m, 2H), 1.10 (s, 6H). MS: 559 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 10.39 (s, 1H), 9.03 (d, J=1.3 Hz, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.24 (dd, J=8.7, 2.6 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.20 (s, 1H), 4.10 (t, J=6.5 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.17 (m, 1H), 1.86-1.66 (m, 4H), 1.66-1.43 (m, 6H), 1.25-1.18 (m, 2H), 1.10 (s, 6H). MS: 533 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.37 (s, 1H), 9.03 (d, J=1.2 Hz, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.24 (dd, J=8.9, 2.6 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.20 (s, 1H), 4.10 (t, J=6.6 Hz, 2H), 2.67 (d, J=7.1 Hz, 2H), 1.85-1.54 (m, 8H), 1.54-1.41 (m, 2H), 1.23-1.16 (m, 3H), 1.10 (s, 6H), 1.05-0.89 (m, 2H). MS: 547 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.65 (s, 1H), 10.45 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.25 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.13 (d, J=2.6 Hz, 1H), 4.19 (s, 2H), 3.98 (d, J=6.5 Hz, 2H), 3.92-3.81 (m, 2H), 3.37-3.32 (m, 2H), 2.07-1.94 (m, 1H), 1.74-1.60 (m, 2H), 1.40-1.26 (m, 2H). MS: 539 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 10.46 (s, 1H), 9.02 (d, J=1.3 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.49-7.28 (m, 2H), 7.28-7.07 (m, 4H), 4.22 (s, 2H), 3.97 (d, J=6.5 Hz, 2H), 3.93-3.82 (m, 2H), 3.36-3.30 (m, 2H), 2.09-1.95 (m, 1H), 1.74-1.62 (m, 2H), 1.42-1.24 (m, 2H). MS: 557 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.38 (s, 1H), 9.03 (d, J=1.2 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.26 (dd, J=8.8, 2.6 Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 3.98 (d, J=6.4 Hz, 2H), 3.93-3.83 (m, 2H), 3.43-3.36 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.36-2.21 (m, 1H), 2.08-1.95 (m, 1H), 1.75-1.64 (m, 4H), 1.64-1.56 (m, 2H), 1.56-1.46 (m, 2H), 1.39-1.28 (m, 2H), 1.23-1.14 (m, 2H). MS: 531 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.38 (s, 1H), 9.03 (d, J=1.3 Hz, 1H), 8.26 (d, J=1.3 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.26 (dd, J=8.7, 2.6 Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 3.98 (d, J=6.5 Hz, 2H), 3.93-3.81 (m, 2H), 3.35-3.30 (m, 2H), 2.67 (d, J=7.1 Hz, 2H), 2.11-1.96 (m, 1H), 1.83-1.57 (m, 8H), 1.42-1.26 (m, 2H), 1.26-1.07 (m, 3H), 1.07-0.91 (m, 2H). MS: 545 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, and in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.47 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.25 (d, J=1.2 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.18 (m, 2H), 7.13 (d, J=2.6 Hz, 1H), 4.25-4.10 (m, 4H), 3.88-3.76 (m, 2H), 3.27-3.23 (m, 2H), 1.77-1.65 (m, 3H), 1.65-1.56 (m, 2H), 1.26-1.19 (m, 2H). MS: 553 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 10.47 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.24 (d, J=1.2 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.50-7.30 (m, 2H), 7.30-7.06 (m, 4H), 4.21 (s, 2H), 4.15 (t, J=6.1 Hz, 2H), 3.88-3.76 (m, 2H), 3.29-3.18 (m, 2H), 1.71-1.56 (m, 4H), 1.30-1.13 (m, 3H). MS: 571 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.40 (s, 1H), 9.03 (s, 1H), 8.26 (s, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.26 (dd, J=8.8, 2.6 Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.82 (dd, J=10.8, 4.3 Hz, 2H), 3.29-3.21 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.37-2.18 (m, 1H), 1.82-1.66 (m, 5H), 1.66-1.57 (m, 4H), 1.57-1.46 (m, 2H), 1.25-1.14 (m, 4H). MS: 545 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-chloro-4-(trifluoromethyl)phenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 10.40 (s, 1H), 9.03 (d, J=1.2 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.26 (dd, J=8.7, 2.6 Hz, 1H), 7.14 (d, J=2.6 Hz, 1H), 4.16 (t, J=6.1 Hz, 2H), 3.90-3.73 (m, 2H), 3.31-3.20 (m, 2H), 2.67 (d, J=7.1 Hz, 2H), 1.83-1.54 (m, 11H), 1.24-1.06 (m, 5H), 1.06-0.89 (m, 2H). MS: 559 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.61 (s, 1H), 10.42 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.45 (d, J=1.3 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.38-7.30 (m, 4H), 7.30-7.22 (m, 1H), 7.20 (d, J=3.0 Hz, 1H), 7.11 (dd, J=8.8, 3.1 Hz, 1H), 4.27-4.13 (m, 3H), 4.01 (t, J=6.5 Hz, 2H), 1.84-1.70 (m, 2H), 1.53-1.43 (m, 2H), 1.09 (s, 6H). MS: 507 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 10.42 (s, 1H), 9.05 (d, J=1.2 Hz, 1H), 8.44 (d, J=1.2 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.46-7.30 (m, 2H), 7.27-7.15 (m, 3H), 7.11 (dd, J=8.8, 3.1 Hz, 1H), 4.31-4.14 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.84-1.68 (m, 2H), 1.55-1.41 (m, 2H), 1.09 (s, 6H). MS: 525 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.32 (s, 1H), 10.34 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.46 (d, J=1.2 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.21 (d, J=3.1 Hz, 1H), 7.11 (dd, J=8.8, 3.1 Hz, 1H), 4.19 (s, 1H), 4.02 (t, J=6.5 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.37-2.20 (m, 1H), 1.85-1.66 (m, 4H), 1.66-1.42 (m, 6H), 1.25-1.16 (m, 2H), 1.10 (s, 6H). MS: 499 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 10.35 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 7.11 (dd, J=8.9, 3.1 Hz, 1H), 4.19 (s, 1H), 4.02 (t, J=6.5 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H), 1.84-1.55 (m, 8H), 1.55-1.41 (m, 2H), 1.26-1.14 (m, 3H), 1.10 (s, 6H), 1.05-0.91 (m, 2H). MS: 513 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.42 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.45 (d, J=1.3 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.41-7.29 (m, 4H), 7.29-7.19 (m, 2H), 7.12 (dd, J=8.9, 3.1 Hz, 1H), 4.18 (s, 2H), 3.97-3.82 (m, 4H), 3.30-3.28 (m, 2H), 2.05-1.93 (m, 1H), 1.75-1.60 (m, 2H), 1.40-1.25 (m, 2H). MS: 505 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.41 (s, 1H), 9.05 (d, J=1.2 Hz, 1H), 8.44 (d, J=1.3 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.46-7.30 (m, 2H), 7.28-7.16 (m, 3H), 7.12 (dd, J=8.9, 3.1 Hz, 1H), 4.21 (s, 2H), 3.94-3.81 (m, 4H), 3.31-3.29 (m, 2H), 2.09-1.92 (m, 1H), 1.73-1.60 (m, 2H), 1.40-1.25 (m, 2H). MS: 523 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.50 (s, 1H), 10.35 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.46 (d, J=1.3 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.23 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.8, 3.1 Hz, 1H), 3.95-3.81 (m, 4H), 3.31-3.28 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.37-2.19 (m, 1H), 2.09-1.94 (m, 1H), 1.80-1.44 (m, 8H), 1.39-1.27 (m, 2H), 1.27-1.22 (m, 2H). MS: 497 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 2, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 10.35 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.46 (d, J=1.2 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.23 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.9, 3.1 Hz, 1H), 3.98-3.82 (m, 4H), 3.31-3.28 (m, 2H), 2.67 (d, J=7.0 Hz, 2H), 2.11-1.92 (m, 1H), 1.83-1.56 (m, 8H), 1.41-1.26 (m, 2H), 1.26-1.10 (m, 3H), 1.07-0.92 (m, 2H). MS: 511 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine. 1H NMR (400 MHz, DMSO-d6) δ 14.71 (s, 1H), 10.43 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.44 (d, J=1.3 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 7.37-7.30 (m, 4H), 7.29-7.21 (m, 2H), 7.12 (dd, J=8.9, 3.1 Hz, 1H), 4.18 (s, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.90-3.73 (m, 2H), 3.28-3.20 (m, 2H), 1.77-1.56 (m, 5H), 1.30-1.15 (m, 2H). MS: 519 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 10.58 (s, 1H), 9.04 (d, J=1.3 Hz, 1H), 8.44 (d, J=1.3 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.43-7.28 (m, 2H), 7.25-7.15 (m, 3H), 7.12 (dd, J=8.8, 3.1 Hz, 1H), 4.19 (s, 2H), 4.07 (t, J=6.2 Hz, 2H), 3.86-3.78 (m, 2H), 3.29-3.27 (m, 2H), 1.74-1.57 (m, 5H), 1.28-1.19 (m, 2H). MS: 537 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.39 (s, 1H), 10.33 (s, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.46 (d, J=1.3 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.23 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.9, 3.1 Hz, 1H), 4.08 (t, J=6.2 Hz, 2H), 3.89-3.77 (m, 2H), 3.28-3.23 (m, 2H), 2.82-2.75 (m, 2H), 2.36-2.21 (m, 1H), 1.77-1.56 (m, 10H), 1.56-1.46 (m, 2H), 1.24-1.16 (m, 3H). MS: 511 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 2, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, in step 3, 6-chloropyrimidin-4-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 10.36 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.23 (d, J=3.1 Hz, 1H), 7.12 (dd, J=8.8, 3.1 Hz, 1H), 4.08 (t, J=6.2 Hz, 2H), 3.86-3.78 (m, 2H), 3.28-3.23 (m, 2H), 2.67 (d, J=7.1 Hz, 2H), 1.79-1.72 (m, 1H), 1.72-1.55 (m, 10H), 1.24-1.08 (m, 5H), 1.05-0.92 (m, 2H). MS: 525 [M+H]+.
Steps 1 to 2 were carried out in a similar manner to Steps 1 to 2 of Example 160, except that 3-bromo-4-methylbenzenethiol was used in place of 3-bromo-4-methylphenol.
Step 3: 5-((3-bromo-4-methylphenyl)thio)-2-methylpentan-2-ol (606 mg, 2 mmol) was dissolved in dichloromethane (6 mL), m-chloroperoxybenzoic acid (520 mg, 3 mmol) was added in batches at 0° C., and reacted at 25° C. for 1.5 hours. The reaction solution was diluted with dichloromethane, washed with saturated aqueous solution of sodium carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, purified by column chromatography to afford 600 mg of 5-((3-bromo-4-methylphenyl)sulfonyl)-2-methylpentan-2-ol.
Steps 4 to 5 were carried out in a similar manner to Steps 3 to 4 of Example 160, except that 5-((3-bromo-4-methylphenyl)sulfonyl)-2-methylpentan-2-ol was used in place of 5-(3-bromo-4-methylphenoxy)-2-methylpentan-2-ol.
1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.00 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.15 (d, J=1.5 Hz, 1H), 7.88 (dd, J=8.1, 2.0 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.40-7.20 (m, 6H), 4.20 (s, 1H), 4.18 (s, 2H), 3.32-3.23 (m, 2H), 2.38 (s, 3H), 1.71-1.55 (m, 2H), 1.44-1.32 (m, 2H), 1.02 (s, 6H). MS: 534 [M+H]+.
The preparation was carried out in a similar manner to Example 474, except that in step 5, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (s, 1H), 9.94 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.25-8.10 (m, 1H), 7.88 (dd, J=8.0, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.29 (dd, J=5.1, 1.6 Hz, 1H), 4.20 (s, 1H), 3.39-3.34 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.39 (s, 3H), 2.35-2.18 (m, 1H), 1.81-1.67 (m, 2H), 1.67-1.56 (m, 4H), 1.56-1.45 (m, 2H), 1.44-1.33 (m, 2H), 1.26-1.18 (m, 2H), 1.03 (s, 6H). MS: 526 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-((2-fluorophenyl)(hydroxyl)methyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.89 (s, 1H), 9.87 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.20 (d, J=1.5 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.43-7.34 (m, 1H), 7.32-7.16 (m, 3H), 7.05 (dd, J=8.8, 3.0 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 6.77 (s, 1H), 6.15 (d, J=4.9 Hz, 1H), 4.19 (s, 1H), 4.00 (t, J=6.6 Hz, 2H), 1.82-1.70 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 540 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl (R)-5-(hydroxyl(phenyl)methyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 9.86 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.54-7.44 (m, 3H), 7.44-7.34 (m, 2H), 7.34-7.23 (m, 2H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 6.71 (d, J=4.3 Hz, 1H), 5.96 (d, J=4.3 Hz, 1H), 4.18 (s, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.82-1.68 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl (S)-5-(hydroxyl(phenyl)methyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.78 (s, 1H), 9.88 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.21 (s, 1H), 7.54-7.44 (m, 3H), 7.38 (t, J=7.5 Hz, 2H), 7.34-7.24 (m, 2H), 7.06 (dd, J=8.8, 3.0 Hz, 1H), 7.00 (d, J=3.1 Hz, 1H), 6.71 (s, 1H), 5.95 (s, 1H), 4.19 (s, 1H), 4.01 (t, J=6.6 Hz, 2H), 1.82-1.69 (m, 2H), 1.51-1.40 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
Steps 1 to 2 were carried out in a similar manner to Steps 1 to 2 of Example 47, except that (3,6-dihydro-2H-pyran-4-yl)boronic acid was used in place of cyclopent-1-en-1-ylboronic acid, and 5-bromo-2-methylphenol was used in place of 4-bromopyridin-2-amine.
Steps 3 to 5 were carried out in a similar manner to Example 43, except that 2-methyl-5-(tetrahydro-2H-pyran)-4-yl)phenol was used in place of 5,6,7,8-tetrahydronaphthalen-1-ol. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.5 Hz, 1H), 7.45-7.29 (m, 4H), 7.29-7.13 (m, 5H), 4.18 (s, 2H), 4.01-3.91 (m, 2H), 3.50-3.41 (m, 2H), 2.85-2.71 (m, 1H), 2.28 (s, 3H), 1.81-1.64 (m, 4H). MS: 454 [M+H]+.
Step 1 was carried out in a similar manner to Step 2 of Example 78, except that 3-bromo-4-methylbenzaldehyde was used in place of 2-bromo-4-(2-(tert-butoxy)ethoxy)benzaldehyde, and trimethyl phosphonoacetate was used in place of methyltriphenylphosphonium bromide.
Steps 2 to 3 were carried out in a similar manner to Example 33, except that methyl 3-(3-bromo-4-methylphenyl)acrylate was used in place of 2-bromo-4-fluoro-1-methylbenzene. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 9.93 (s, 1H), 8.44 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.77-7.62 (m, 3H), 7.42 (d, J=8.0 Hz, 1H), 7.38-7.30 (m, 4H), 7.30-7.18 (m, 2H), 6.69 (d, J=16.0 Hz, 1H), 4.18 (s, 2H), 3.72 (s, 3H), 2.29 (s, 3H). MS: 454 [M+H]+.
It was carried out in a similar manner to steps 2 to 3 of Example 47, except that methyl (E)-3-(3-(2-aminopyridin-4-yl)-4-methylphenyl)acrylate (see Example 480 for the synthetic method) was used in place of 4-(cyclopent-1-en-1-yl)pyridin-2-amine, and ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate.
1H NMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.13 (d, J=1.4 Hz, 1H), 7.35-7.17 (m, 3H), 7.14 (d, J=1.8 Hz, 1H), 3.58 (s, 3H), 2.87 (t, J=7.6 Hz, 2H), 2.82-2.72 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 2.35-2.25 (m, 1H), 2.24 (s, 3H), 1.79-1.67 (m, 2H), 1.67-1.56 (m, 2H), 1.56-1.48 (m, 2H), 1.26-1.21 (m, 2H). MS: 448 [M+H]+.
Step 1: The preparation was carried out in a similar manner to step 2 of Example 160, except that methyl 3-(3-(2-aminopyridin-4-yl)-4-methylphenyl)propionate was used in place of methyl 4-(3-bromo-4-methylphenoxy)butanoate.
Step 2: The preparation was carried out in a similar manner to step 3 of Example 100, except that 4-(3-(2-aminopyridin-4-yl)-4-methylphenyl)-2-methylbutan-2-ol was used in place of 4-(2-methyl-5-(octyloxy)phenyl)pyridin-2-amine.
1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.4 Hz, 1H), 7.39-7.30 (m, 4H), 7.29-7.23 (m, 2H), 7.23-7.16 (m, 2H), 7.09 (d, J=1.8 Hz, 1H), 4.24 (s, 1H), 4.18 (s, 2H), 2.70-2.59 (m, 2H), 2.24 (s, 3H), 1.71-1.60 (m, 2H), 1.13 (s, 6H). MS: 456 [M+H]+.
Step 1: Synthesis of 3-(3-(2-aminopyridin-4-yl)-4-methylphenyl)propanol
Methyl 3-(3-(2-aminopyridin-4-yl)-4-methylphenyl)propionate (270 mg, 1 mmol) was placed in anhydrous tetrahydrofuran (3 mL), and lithium aluminum hydride (115 mg, 3 mmol) was added in batches under argon protection at 0° C. After reacting at 50° C. for 2 hours, the reaction solution was quenched with saturated ammonium chloride, diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to afford 150 mg of product.
Step 2: It was carried out in a similar manner to step 2 of Example 1, except that 3-(3-(2-aminopyridin-4-yl)-4-methylphenyl)propanol was used in place of 4-phenylpyridin-2-amine.
1H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 9.90 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 8.15-8.08 (m, 1H), 7.40-7.30 (m, 4H), 7.30-7.23 (m, 2H), 7.23-7.13 (m, 2H), 7.09 (d, J=1.8 Hz, 1H), 4.67-4.34 (m, 1H), 4.17 (s, 2H), 3.41 (t, J=6.4 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 2.24 (s, 3H), 1.80-1.66 (m, 2H). MS: 428 [M+H]+.
It was carried out in a similar manner to steps 2 to 4 of Example 160, except that 3-bromo-4-methylbenzaldehyde was used in place of methyl 4-(3-bromo-4-methylphenoxy)butanoate, and (3-methoxypropyl)magnesium bromide was used in place of methylmagnesium bromide. 1H NMR (400 MHz, DMSO-d6) δ 14.48 (s, 1H), 9.90 (s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.12 (s, 1H), 7.38-7.22 (m, 7H), 7.22-7.17 (m, 2H), 5.19 (d, J=4.5 Hz, 1H), 4.67-4.43 (m, 1H), 4.18 (s, 2H), 3.29 (t, J=6.3 Hz, 2H), 3.18 (s, 3H), 2.26 (s, 3H), 1.69-1.52 (m, 3H), 1.52-1.39 (m, 1H). MS: 472 [M+H]+.
Step 1: Synthesis of 1-(3-methoxy-4-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one
4-Bromo-2-methoxy-1-methylbenzene (500 mg, 2.5 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and n-butyl lithium (2.5M, 1 mL, 2.5 mmol) was added dropwise at −78° C. under argon protection. After reacting at this temperature for 30 minutes, N-methoxy-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide (505 mg, 2.7 mmol) in anhydrous tetrahydrofuran (1 mL) was added, warmed slowly, and reacted at room temperature for 2 hours. The reaction solution was quenched with saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to afford 500 mg of product.
Step 2: Synthesis of 1-(3-hydroxyl-4-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one
1-(3-Methoxy-4-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one (500 mg, 2.0 mmol) was dissolved in anhydrous dichloromethane (5 mL), a solution of boron tribromide in dichloromethane (1M, 3 mL, 3 mmol) was added dropwise at 0° C. under argon protection, and the reaction was slowly warmed to room temperature and reacted for 2 hours. The reaction solution was quenched with saturated aqueous solution of ammonium chloride, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and purified by column chromatography to afford 350 mg of product.
Steps 3 to 5 were carried out in a similar manner to Example 43, except that 1-(3-hydroxyl-4-methylphenyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one was used in place of 5,6,7,8-tetrahydronaphthalen-1-ol.
1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.96 (s, 1H), 8.46 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.96 (d, J=1.7 Hz, 1H), 7.91 (dd, J=7.9, 1.8 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.21 (m, 2H), 4.18 (s, 2H), 3.88-3.75 (m, 2H), 3.32-3.25 (m, 2H), 3.00 (d, J=6.7 Hz, 2H), 2.35 (s, 3H), 2.20-2.05 (m, 1H), 1.66-1.54 (m, 2H), 1.34-1.22 (m, 2H). MS: 496 [M+H]+.
It was carried out in a similar manner to Example 485, except that in step 5, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.42 (s, 1H), 9.91 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 8.16 (d, J=1.4 Hz, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.92 (dd, J=8.0, 1.8 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H), 3.89-3.76 (m, 2H), 3.32-3.24 (m, 2H), 3.00 (d, J=6.7 Hz, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.35 (s, 3H), 2.31-2.22 (m, 1H), 2.18-2.05 (m, 1H), 1.80-1.67 (m, 2H), 1.67-1.56 (m, 4H), 1.56-1.44 (m, 2H), 1.32-1.21 (m, 4H). MS: 488 [M+H]+.
Step 1: Synthesis of methyl 3-(3-bromo-4-methylbenzamido)propionate
3-Bromo-4-methylbenzoic acid (430 mg, 2 mmol), methyl 3-aminopropionate hydrochloride (280 mg, 2 mmol), T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide) (950 mg, 50%, 3 mmol) and DIEA (780 mg, 6 mmol) were dissolved in dichloromethane (6 mL), and reacted at 25° C. for 2 hours. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness, purified by column chromatography to afford 540 mg of product.
Steps 2 to 4 were carried out in a similar manner to steps 2 to 4 of Example 160, except that methyl 3-(3-bromo-4-methylbenzamido)propionate was used in place of methyl 4-(3-bromo-4-methylphenoxy)butanoate.
1H NMR (400 MHz, DMSO-d6) δ 14.54 (s, 1H), 9.94 (s, 1H), 8.50-8.38 (m, 2H), 8.14 (s, 1H), 7.82 (dd, J=8.0, 1.9 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.39-7.29 (m, 4H), 7.29-7.17 (m, 2H), 4.33 (s, 1H), 4.18 (s, 2H), 3.38-3.34 (m, 2H), 2.32 (s, 3H), 1.71-1.58 (m, 2H), 1.12 (s, 6H). MS: 499 [M+H]+.
The preparation was carried out in a similar manner to Example 487, except that in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.89 (s, 1H), 8.55-8.34 (m, 2H), 8.16 (s, 1H), 7.82 (dd, J=8.0, 1.9 Hz, 1H), 7.75 (d, J=1.9 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.26 (dd, J=5.1, 1.6 Hz, 1H), 4.33 (s, 1H), 3.38-3.35 (m, 2H), 2.78 (d, J=7.5 Hz, 2H), 2.32 (s, 3H), 2.30-2.19 (m, 1H), 1.83-1.68 (m, 2H), 1.68-1.56 (m, 4H), 1.56-1.41 (m, 2H), 1.26-1.20 (m, 2H), 1.13 (s, 6H). MS: 491 [M+H]+.
The preparation was carried out in a similar manner to Example 487, except that in step 1, monomethyl succinate was used in place of 3-bromo-4-methylbenzoic acid, and 3-bromo-4-methylaniline was used in place of methyl 3-aminopropionate hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.97 (s, 1H), 9.86 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 8.12 (s, 1H), 7.56 (d, J=8.1 Hz, 2H), 7.40-7.30 (m, 4H), 7.30-7.22 (m, 2H), 7.22-7.15 (m, 1H), 4.25 (s, 1H), 4.19 (s, 2H), 2.41-2.30 (m, 2H), 2.21 (s, 3H), 1.73-1.61 (m, 2H), 1.10 (s, 6H). MS: 499 [M+H]+.
The preparation was carried out in a similar manner to Example 487, except that in step 1, monomethyl succinate was used in place of 3-bromo-4-methyl benzoic acid, 3-bromo-4-methylaniline was used in place of methyl 3-aminopropionate hydrochloride, and in step 4, ethyl 5-(cyclopentylmethyl)-4H-1,2,4-triazole-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.37 (s, 1H), 9.98 (s, 1H), 9.83 (s, 1H), 8.42 (d, J=5.2 Hz, 1H), 8.14 (s, 1H), 7.63-7.51 (m, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.19 (d, J=5.2 Hz, 1H), 4.25 (s, 1H), 2.79 (d, J=7.5 Hz, 2H), 2.41-2.32 (m, 2H), 2.32-2.24 (m, 1H), 2.22 (s, 3H), 1.79-1.44 (m, 8H), 1.25-1.19 (m, 2H), 1.10 (s, 6H). MS: 491 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 4, ethyl 5-(3-chloro-2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.73 (s, 1H), 9.92 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 8.10 (s, 1H), 7.57-7.48 (m, 1H), 7.43-7.35 (m, 1H), 7.28-7.18 (m, 3H), 6.93 (dd, J=8.4, 2.7 Hz, 1H), 6.80 (d, J=2.7 Hz, 1H), 4.26 (s, 2H), 4.17 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.19 (s, 3H), 1.82-1.65 (m, 2H), 1.54-1.42 (m, 2H), 1.09 (s, 6H). MS: 538 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 10.09 (s, 1H), 8.47 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.46-7.30 (m, 2H), 7.30-7.14 (m, 3H), 6.97 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 4.17 (s, 1H), 3.95 (t, J=6.6 Hz, 2H), 2.09 (s, 3H), 1.81-1.67 (m, 2H), 1.52-1.41 (m, 2H), 1.09 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.36 (s, 1H), 10.00 (s, 1H), 8.48 (s, 1H), 8.09 (d, J=5.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.4, 2.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 4.17 (s, 1H), 3.96 (t, J=6.6 Hz, 2H), 2.66 (d, J=7.0 Hz, 2H), 2.10 (s, 3H), 1.82-1.57 (m, 8H), 1.52-1.41 (m, 2H), 1.24-1.13 (m, 3H), 1.09 (s, 6H), 1.04-0.91 (m, 2H). MS: 510 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (s, 1H), 10.02 (s, 1H), 8.47 (s, 1H), 8.06 (d, J=5.5 Hz, 1H), 7.46-7.30 (m, 2H), 7.30-7.15 (m, 3H), 6.97 (dd, J=8.5, 2.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 4.21 (s, 2H), 4.09 (s, 1H), 3.96 (t, J=6.5 Hz, 2H), 2.09 (s, 3H), 1.68 (t, J=6.8 Hz, 2H), 1.52-1.30 (m, 4H), 1.06 (s, 6H). MS: 536 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.99 (s, 1H), 8.48 (s, 1H), 8.09 (d, J=5.5 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.98 (dd, J=8.4, 2.7 Hz, 1H), 6.85 (d, J=2.7 Hz, 1H), 4.09 (s, 1H), 3.97 (t, J=6.5 Hz, 2H), 2.67 (d, J=6.9 Hz, 2H), 2.10 (s, 3H), 1.79-1.57 (m, 8H), 1.47-1.39 (m, 3H), 1.24-1.10 (m, 4H), 1.06 (s, 6H), 1.02-0.90 (m, 2H). MS: 524 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.59 (s, 1H), 10.02 (s, 1H), 8.47 (s, 1H), 8.06 (d, J=5.4 Hz, 1H), 7.44-7.29 (m, 2H), 7.29-7.14 (m, 3H), 6.98 (dd, J=8.4, 2.7 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 4.21 (s, 2H), 3.91-3.79 (m, 4H), 3.33-3.23 (m, 2H), 2.09 (s, 3H), 2.04-1.90 (m, 1H), 1.72-1.61 (m, 2H), 1.39-1.24 (m, 2H). MS: 520 [M+H]+.
The preparation was carried out in a similar manner to Example 64, except that in step 1, (tetrahydro-2H-pyran-4-yl)methanol was used in place of 2-(tert-butoxy)ethan-1-ol, in step 2, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 3, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 10.00 (s, 1H), 8.48 (s, 1H), 8.09 (d, J=5.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 6.99 (dd, J=8.4, 2.7 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 3.92-3.78 (m, 4H), 3.32-3.24 (m, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.10 (s, 3H), 2.04-1.91 (m, 1H), 1.81-1.55 (m, 8H), 1.36-1.15 (m, 5H), 1.04-0.93 (m, 2H). MS: 508 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.66 (s, 1H), 10.09 (s, 1H), 8.47 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.46-7.30 (m, 2H), 7.30-7.14 (m, 3H), 6.98 (dd, J=8.5, 2.7 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 4.20 (s, 2H), 4.01 (t, J=6.3 Hz, 2H), 3.81 (dd, J=11.6, 4.2 Hz, 2H), 3.29-3.21 (m, 2H), 2.09 (s, 3H), 1.76-1.52 (m, 5H), 1.25-1.12 (m, 2H). MS: 534 [M+H]+.
The preparation was carried out in a similar manner to Example 85, except that in step 1, 2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol was used in place of 2-(2-methoxyethoxy)ethan-1-ol, in step 3, 5-fluoro-4-bromopyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 9.99 (s, 1H), 8.47 (s, 1H), 8.09 (d, J=5.6 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.98 (dd, J=8.4, 2.7 Hz, 1H), 6.87 (d, J=2.7 Hz, 1H), 4.02 (t, J=6.3 Hz, 2H), 3.89-3.76 (m, 2H), 3.30-3.20 (m, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.10 (s, 3H), 1.80-1.55 (m, 11H), 1.30-1.13 (m, 5H), 1.04-0.92 (m, 2H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-fluorophenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, and in step 4, ethyl 5-(2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.60 (s, 1H), 9.85 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.35 (s, 1H), 7.51-7.15 (m, 6H), 7.15-7.00 (m, 2H), 4.23 (s, 2H), 4.11 (s, 1H), 4.02 (t, J=6.4 Hz, 2H), 1.75-1.64 (m, 2H), 1.52-1.37 (m, 4H), 1.07 (s, 6H). MS: 522 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(3-chloro-2,4-difluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.72 (s, 1H), 9.98 (s, 1H), 8.45 (d, J=5.1 Hz, 1H), 8.21 (s, 1H), 7.57-7.44 (m, 2H), 7.38-7.25 (m, 2H), 7.06 (dd, J=8.9, 3.0 Hz, 1H), 7.01 (d, J=3.0 Hz, 1H), 4.26 (s, 2H), 4.18 (s, 1H), 4.01 (t, J=6.5 Hz, 2H), 1.82-1.69 (m, 2H), 1.53-1.40 (m, 2H), 1.09 (s, 6H). MS: 576 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, methyl 5-bromopentanoate was used in place of methyl 4-bromobutanoate, in step 3, 4-bromo-5-fluoropyridin-2-amine was used in place of 4-bromopyridin-2-amine, and in step 4, ethyl 5-(cyclohexylmethyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (s, 1H), 10.04 (s, 1H), 8.52 (d, J=1.2 Hz, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.17-7.05 (m, 2H), 4.09 (s, 1H), 4.02 (t, J=6.5 Hz, 2H), 2.67 (d, J=7.1 Hz, 2H), 1.82-1.57 (m, 8H), 1.51-1.33 (m, 4H), 1.28-1.10 (m, 3H), 1.06 (s, 6H), 1.04-0.88 (m, 2H). Ms: 544 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-(5-cyclopropyl-2-fluorobenzyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.56 (s, 1H), 9.89 (s, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.22 (s, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.28 (d, J=5.2 Hz, 1H), 7.17-6.95 (m, 5H), 4.22-4.11 (m, 3H), 4.01 (t, J=6.6 Hz, 2H), 1.95-1.85 (m, 1H), 1.82-1.69 (m, 2H), 1.53-1.41 (m, 2H), 1.09 (s, 6H), 0.97-0.88 (m, 2H), 0.68-0.57 (m, 2H). MS: 564 [M+H]+.
The preparation was carried out in a similar manner to Example 160, except that in step 1, 3-bromo-4-chlorophenol was used in place of 3-bromo-4-methylphenol, and in step 4, ethyl 5-((4-fluoro-[1,1′-biphenyl]-3-yl)methyl)-4H-1,2,4-triazol-3-carboxylate was used in place of ethyl 5-benzyl-4H-1,2,4-triazol-3-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 14.70 (s, 1H), 9.94 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 7.82-7.68 (m, 1H), 7.68-7.56 (m, 3H), 7.56-7.41 (m, 3H), 7.41-7.22 (m, 3H), 7.14-6.89 (m, 2H), 4.29 (s, 2H), 4.17 (s, 1H), 4.00 (t, J=6.6 Hz, 2H), 1.82-1.68 (m, 2H), 1.54-1.39 (m, 2H), 1.09 (s, 6H). MS: 600 [M+H]+.
Western blot was used to determine the effect of the test compounds on the phosphorylation of intracellular RIPK1 during the induction of programmed necrosis of HT29 cells, verifying the effect of compounds on RIPK1 phosphorylation, and initially estimating the IC50 range of compounds for RIPK1 phosphorylation.
I. Main Assay Reagents/Instruments
II. Experiment Procedure
III. Typical Assay Results and Analysis
The inhibition rate of compounds on protein phosphorylation was calculated according to the fluorescence intensity value, and the calculation method is as follows:
Inhibition rate (%)=(1−AB)×100%
A: Fluorescence intensity value after treatment with IL-2 and compound
B: Fluorescence intensity value after treatment with IL-2
The compound of Example 2 was tested by the above method, and the results were shown in
In this assay example 2, under the condition of inducing programmed cell necrosis, different concentrations of the test compounds were added to test the IC50 of the rescue effect of the test compounds on the programmed necrosis.
I. Main Assay Reagents, Instruments and Materials
Compounds: Dissolved in DMSO to make a 10 mM solution;
TNF-α: The initial concentration was 100 μg/mL;
Z-VAD-FMK: Dissolved in DMSO to make a 10 mM solution;
AT-406: Dissolved in DMSO to make a 10 mM solution.
II. Experimental Steps
Table 4 lists the determination results of some compounds of the present disclosure in inhibiting HT29 cell necrosis, wherein A represents IC50 is less than or equal to 100 nM, B represents IC50 is greater than 100 nM but less than or equal to 1000 nM, C represents IC50 is greater than 1000 nM but less than or equal to 10000 nM, D represents IC50 is greater than 10000 nM.
The biological data provided by the present disclosure shows that the compounds of the present disclosure are beneficial for the treatment or prevention of diseases caused by abnormal RIP1 kinase. Therefore, the compounds of the present disclosure are beneficial to the treatment of diseases related to RIP1 including ocular fundus disease, xerophthalmia, psoriasis, leucoderma, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary cancer and sarcoma, cholangiocarcinoma, inflammatory bowel disease, ulcerative colitis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, spondyloarthritis, gout, SoJIA, Sjogren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behçet's disease, interleukin-1 converzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor related periodic syndrome and periodontitis. The compounds of the present disclosure can be used as monotherapy or combination therapy, and can be used in combination with multiple compounds of the present disclosure or in combination with other drugs that are not included in the present disclosure.
The above descriptions are only the preferred embodiments of the present disclosure and are not intended to limit the present disclosure. Any modification, equivalent replacement and improvement made within the spirit and principle of the present disclosure shall be included in the protection scope of the present disclosure.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201910071476.7 | Jan 2019 | CN | national |
| 202010027582.8 | Jan 2020 | CN | national |
The present application is a national application of PCT/CN2020/072738 filed on Jan. 17, 2020, which claims the priority of the Chinese Patent Application No. 201910071476.7 filed on Jan. 25, 2019, and the Chinese Patent Application No. 202010027582.8 filed on Jan. 10, 2020. The Chinese Patent Application No. 201910071476.7 and the Chinese Patent Application No. 202010027582.8 are incorporated herein by reference as part of the disclosure of the present application.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2020/072738 | 1/17/2020 | WO |
