Patent Application
20240124486
The invention relates to a large ring TLR7 agonist, its preparation method, a pharmaceutical composition and its use.
Toll-like receptors (TLRs) are a class of structure-conserved proteins that form the first barrier in innate immune response. By recognizing a variety of conserved pathogen-associated molecular patterns (PAMPs), TLRs can recognize invasive microorganisms and endogenous molecules released after tissue injury or nonphysiological cell death, and activate signaling cascades, which leads to the production of proinflammatory cytokines. Inflammatory processes are essential for the initiation and progression of a variety of diseases, such as type I diabetes, sepsis, cancer, and viral infections. Therefore, strategies to manipulate inflammatory responses through small molecule TLR modulators to treat related diseases are promising.
Human TLR family consists of 10 known members, which are type I transmembrane proteins characterized by a leucine-rich extracellular domain and a cytosolic tail containing a conserved Toll/interleukin-1 receptor (TIR) domain. In this family, TLR3, TLR7, TLR8 and TLR9 are located in the intracellular endosomes (Vijay K., Int Immunopharmacol., 2018, 59, 391-412).
TLR7 recognizes single-stranded RNA (ssRNA) fragments. TLR7 is mainly expressed in plasmacytoid dendritic cells and B cells. Stimulation of TLR7 in those cells mainly induces the production of type I interferons, including interferon-α (IFN-α), and induces the transcription of interferon-stimulated genes (ISGs) (Gorden K B., J Immunol., 2005, 174, 1259-1268; Shah M., Expert Opin Investig Drugs, 2016, 25, 437-453). IFN-α is one of the major drugs for the treatment of chronic hepatitis B or C. Therefore, the development of TLR7 agonists for the treatment of viral infectious diseases is of great clinical significance.
Studies of treatment of cancer with TLR7 agonists were reported. Treatment of HER2-positive cancers with TLR7 agonist-anti-HER2 conjugates was reported in WO201772662. Yosuke Ota et al. reported that intravenous administration of the TLR7 agonist DSP-0509 and anti-PD-1 antibodies shown synergistical effects in antitumor immune responses (AACR 2018 Proceedings: Abstract 4726).
Currently there are several TLR7 agonist patent applications, but it is still necessary to continuously develop highly active, safer and highly therapeutic TLR7 agonists.
In view of the shortcomings of the existing TLR7 agonists which have a relatively homogeneous structure, the technical problem to be solved by the invention is to provide a large ring TLR7 agonist, its preparation method, pharmaceutical composition and its use, the compound structure of the present invention is novel, the activity and selectivity are better.
The present invention provides a compound as shown in Formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof (referring to the compound as shown in Formula I, a solvate thereof, a prodrug thereof, a metabolite thereof):
In scheme A or scheme B, R1-4 and R1-5 are independently OH, halogen, CN, C1-C6alkyl, R1-6 substituted C1-C6alkyl, C1-C6alkoxy, R1-9 substituted C1-C6alkoxy, —S(═O)2R1-7, —C(═O)R1-8, NR1-10R1-11, COOR1-12, SR1-13, C3-C7cycloalkyl, R1-19 substituted C3-C7cycloalkyl, “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, R1-20 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, R1-21 substituted “C1-C10 heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” or —Y—(CR1-14R1-15)u—COOR1-16; Y is O, S, S(═O)2 or NH; and u is 1, 2 or 3;
In some schemes, in the compound shown in formula I, its solvate, its prodrug, its metabolite, or their pharmaceutically acceptable salt, the definition of some groups may be as follows, and the definition of the remaining groups is as described in any of the above schemes (the content of this paragraph is hereinafter referred to as “in some embodiments”):
In some embodiments, when B is C2-C10alkylene, the C2-C10alkylene is C4-C6alkylene, preferably —(CH2)v—, and v is 4, 5 or 6.
In some embodiments, when B is C2-C10 unsaturated alkylene, the C2-C10 unsaturated alkylene is C4-C6 unsaturated alkylene, preferably
is Z configuration olefin
and/or E configuration olefin
p is 1, 2 or 3.
In some embodiments, when B is C2-C10alkylene substituted by R1-1, the C2-C10alkylene is C4-C6alkylene, preferably —(CH2)v—, and v is 4, 5 or 6.
In some aspects, when B is R1-1 substituted C2-C10alkylene, the number of the R1-1 is one or more, and when the number of the R1-1 is multiple, the R1-1 are the same or different; the multiple is 2 or 3.
In some embodiments, when B is R1-1 substituted C2-C10 unsaturated alkylene, the C2-C10 unsaturated alkylene is C4-C6 unsaturated alkylene, preferably
is Z configuration olefin
and/or E configuration olefin
p is 1, 2 or 3.
In some embodiments, when B is R1-1 substituted C2-C10 unsaturated hydrocarbylene, the number of R1-1 is one or more, when the number of R1-1 is multiple, each R1-1 are the same or different, the multiple is 2 or 3.
In some embodiments, when L5 is C3-C6cycloalkylene, the C3-C6cycloalkylene is C3-C5cyclopropylene, cyclobutylene, or cyclopentylene
or cyclopentylene
In some embodiments, when L5 is a halogenated C3 to C6cycloalkylene, the C3 to C6cycloalkylene is a C3 to C5cycloalkylene, such as cyclopropylene, cyclobutylene
or cyclopentylene
In some embodiments, when L5 is a halogenated C3-C6cycloalkylene, the number of the halogen is one or multiple, and the multiple can be 2 or 3.
In some embodiments, when L5 is “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S”, the heteroatom in the “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S” is O.
In some embodiments, when L5 is “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S”, the number of the heteroatoms in the “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when L5 is halogenated “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S”, the heteroatom in the “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S” is O.
In some embodiments, when L5 is halogenated “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S”, the number of the heteroatom in the “3-6 membered heterocycloalkylene having 1-3 hetero atoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when L5 is a halogenated “3-6 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the halogen is one or multiple, and the multiple can be 2 or 3.
in some embodiments, when Z1, Z2, Z3, Z4, Z6, Z7, Z8 and Z9 are independently C1-C6 alkylene, the C1-C6 alkylene is C1-C4 alkylene.
in some embodiments, when Z1, Z2, Z3, Z4, Z6, Z7, Z8, and Z9 are independently C1-C6 unsaturated hydrocarbylene, the C1-C6 unsaturated hydrocarbylene is C1-C4 unsaturated hydrocarbylene;
in some embodiments, when Z1, Z2, Z3, Z4, Z6, Z7, Z8 and Z9 are independently R1-2 substituted C1-C6 alkylene, the C1-C6alkylene is C1-C4alkylene.
In some embodiments, when Z1, Z2, Z3, Z4, Z6, Z7, Z8 and Z9 are independently R1-2 substituted C1-C6alkylene, the number of R1-2 is one or more, and when the number of R1-2 is multiple, the R1-2 are the same or different, and the multiple can be 2 or 3.
In some embodiments, when Z1, Z2, Z3, Z4, Z6, Z7, Z8, and Z9 are independently R1-2 substituted C1-C6 unsaturated hydrocarbylene, the C1-C6 unsaturated hydrocarbylene is C1-C4 unsaturated hydrocarbylene.
In some embodiments, when Z1, Z2, Z3, Z4, Z6, Z7, Z8 and Z9 are independently R1-2 substituted C1-C6 unsaturated hydrocarbylene, the number of R1-2 is one or more, when the number of R1-2 is multiple, the R1-2 are the same or different; the multiple can be 2 or 3.
In some embodiments, when Z5 is C2-C10 alkylene, the C2-C10 alkylene is C3-C5alkylene, preferably —(CH2)w—; w is 3, 4 or 5.
In some embodiments, when Z5 is C2-C10 unsaturated alkylene, the C2-C10 unsaturated alkylene is C3-C5 unsaturated alkylene, preferably
is Z configuration olefin
and/or E configuration olefin
s is 1 or 2.
In some embodiments, when Z5 is R1-3 substituted C2-C10alkylene, the C2-C10alkylene is C3-C5alkylene, preferably —(CH2)w—; w is 3, 4 or 5.
In some embodiments, when Z5 is R1-3 substituted C2-C10alkylene, the number of the R1-3 is one or more, when the number of the R1-3 is multiple, the R1-3 are the same or different; the multiple can be 2 or 3.
In some embodiments, when Z5 is R1-3 substituted C2-C10 unsaturated alkylene, the C2-C10 unsaturated alkylene is C3-C5 unsaturated alkylene, preferably
is Z configuration olefin
and/or E configuration olefin
s is 1 or 2.
In some embodiments, when Z5 is R1-3 substituted C2-C10 unsaturated hydrocarbylene, the number of R1-3 is one or more, when the number of R1-3 is multiple, each R1-3 are the same or different, the multiple can be 2 or 3.
In some embodiments, when R1-1, R1-2, and R1-3 are independently halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R1-1, R1-2, and R1-3 are independently C1-C6 alkyl, the C1-C6 alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-1, R1-2, and R1-3 are independently C1-C6alkoxy, the C1-C6alkoxy is C1-C3 alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R1-1-1 is C1-C3alkyl, the C1-C3 alkyl is methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R5 is halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R5 is C1-C6alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R10 and R12 are independently C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R10 and R12 are independently C1-C6 alkoxy-substituted C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R10 and R12 are independently C1-C6alkoxy substituted C1-C6alkyl, the C1-C6alkoxy are C1-C3alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy groups.
In some embodiments, when R11 is C1-C6alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R11 is R1-30 substituted C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R11 is R1-30 substituted C1-C6 alkyl, the number of the R1-30 is one or more, when the number of the R1-30 is multiple, the R1-30 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-30 is C1-C6alkoxy, the C1-C6alkoxy is C1-C3alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R10 and R11 together with the nitrogen atom to which they are attached form a “5-7 membered heterocycloalkyl having 1-2 heteroatoms, and the heteroatom is N”, the “5-7 membered heterocycloalkyl having 1-2 heteroatoms, and the heteroatom is N” is pyrrolidyl or piperidinyl;
In some embodiments, when R14, R15, R16, and R17 are independently C1-C6alkyl, the C1-C6 alkyl are C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl.
In some embodiments, when R14, R15, R16, and R17 are independently R13-1 substituted C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R14, R15, R16, and R17 are independently R13-1 substituted C1-C6alkyl, the number of R13-1 is one or more, and when the number of R13-1 is multiple, the R13-1 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R13-1 is C1-C6alkoxy, the C1-C6alkoxy is C1-C3alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, R13-2 is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-30-1 and R1-30-2 are independently C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-30-3 is C1-C6alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-30-4 is C1-C6alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-30-4 is C1-C6 alkoxy, the C1-C6alkoxy is C1-C3alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R1-30-5 is C1-C6 alkoxy, the C1-C6alkoxy is C1-C3alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R1-30-6 and R1-30-7 are independently C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-30-6 and R1-30-7 together with the nitrogen atom to which they are attached form a “5-7 membered heterocycloalkyl having 1-2 heteroatoms, and the heteroatom is N”, the “5-7 membered heterocycloalkyl having 1-2 heteroatoms, and the heteroatom is N” is pyrrolidyl or piperidinyl.
In some embodiments, when R5 is C1-C6alkoxy, the C1-C6alkoxy is C1-C3alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” are N and/or O.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the 4-7 membered heterocycloalkylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 5-6 membered heterocycloalkylene.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the methylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is not replaced, or one methylene group is replaced by a carbonyl group.
In some embodiments, when the R1, R2 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” together with the benzene ring bound to R1 and R2 is
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” are N and/or O.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form R1-4 substituted “heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-3 4-7 membered heterocycloalkyls”, the “heteroatoms are selected from one or more of N, O and S, 4-7 membered heterocycloalkyl with 1-3 heteroatoms”, the number of heteroatoms is 1 or 2.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the 4-7 membered heterocycloalkylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 5-6 membered heterocycloalkylene.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the methylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is not replaced, or one methylene is replaced by a carbonyl group.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the number of R1-4 is one or more, when the number of R1-4 is multiple, the R1-4 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” together with the benzene ring bound to R1 and R2 is
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” together with the benzene ring bound to R1 and R2 form
and the number of R1-4 is one or more, when the number of R1-4 is multiple, each R1-4 are the same or different.
In some embodiments, when R1, R2 and the carbon atom to which they are attached together form a C4-C7, the C4-C7cycloalkylene is C5-C6 cycloalkylene, such as a cyclopentylene
or a cyclohexylene
In some embodiments, when R1, R2 and the carbon atom to which they are attached together form a R1-5 substituted C4-C7cycloalkylene, the C4-C7cycloalkylene is C5-C6 cycloalkylene, such as cyclopentylene
or cyclohexylene
In some embodiments, when R1, R2 together with the carbon atoms to which they are attached form a R1-5-substituted C4-C7cycloalkylene, the number of R1-5 is one or more, and when the number of R1-5 is multiple, the R1-5 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1, R2 and their attached carbon atoms together form R1-5 substituted C4-C7 cycloalkylene, the R1-5 substituted C4-C7 cycloalkylene together with the benzene ring bonded to R1 and R2 form
and the number of R1-5 is 1 or 2, when the number of R1-5 is 2, the R1-5 are the same or different.
In some embodiments, in scheme A, when R3 is halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, in scheme A, when R3 is C1-C6 alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, in scheme A, when R3 is a halogenated C1-C6alkyl, the C1-C6 alkyl is a C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, in scheme A, when R3 is a halogenated C1-C6alkyl, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, in scheme A, when R3 is a halogenated C1-C6alkyl, the number of the halogens is one or multiple, and the multiple can be 2 or 3.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” are N and/or O.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the 4-7 membered heterocycloalkylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 5-6 membered heterocycloalkylene.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the methylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is not replaced, or one methylene group is replaced by a carbonyl group.
In some embodiments, when the R2, R3 together with the carbon atoms to which they are attached form a “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” together with the benzene ring bound to R2 and R3 from
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” are N and/or O.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form R′substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the number of heteroatom in “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form R′substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the 4-7 membered heterocycloalkylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is 5-6 membered heterocycloalkylene.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the methylene in the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” is not replaced, or one methylene is replaced by a carbonyl group.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the number of R1-4 is one or more, when the number of R1-4 is multiple, the R1-4 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form a R1-4 substituted “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S” together with the benzene ring bound to R1 and R2 from
and the number of R1-4 is one or more, when the number of R1-4 is multiple, the R1-4 are the same or different.
In some embodiments, when R2, R3 and the carbon atom to which they are attached together form a C4-C7 cycloalkylene, the C4-C7 cycloalkylene is C5-C6 cycloalkylene, such as a cyclopentylene or a cyclohexylene.
In some embodiments, when R2, R3 and the carbon atom to which they are attached together form a R1-5 substituted C4-C7cycloalkylene, the C4-C7cycloalkylene is C5-C6 cycloalkylene, such as cyclopentylene
or cyclohexylene
In some embodiments, when R2, R3 together with the carbon atoms to which they are attached form R1-5 substituted C4-C7cycloalkylene, the number of R1-5 is one or more, and when the number of R1-5 is multiple, the R1-5 are the same or different; the multiple can be 2 or 3.
In some embodiments, in scheme B, when R1 is halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, in scheme B, when R1 is C1-C6alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, in scheme B, when R1 is a halogenated C1-C6alkyl, the C1-C6 alkyl is a C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, in scheme B, when R1 is a halogenated C1-C6alkyl, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, in scheme B, when R1 is a halogenated C1-C6alkyl, the number of the halogens is one or multiple, and the multiple can be 2 or 3.
In some embodiments, when R1-4 and R1-5 are independently halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R1-4 and R1-5 are independently C1-C6alkyl, the C1-C6alkyl is C1-C4alkyl, such as methyl, ethyl, isopropyl or tertiary butyl.
In some embodiments, when R1-4 and R1-5 are independently R1-6 substituted C1-C6alkyl, the C1-C6alkyl is a C1-C4alkyl, such as methyl, ethyl, isopropyl or isobutyl.
In some embodiments, when R1-4 and R1-5 are independently R1-6 substituted C1-C6alkyl, the number of R1-6 is one or more, and when the number of R1-6 is multiple, the R1-6 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-4 and R1-5 are independently C1-C6alkoxy, the C1-C6alkoxy is C1-C3 alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R1-4 and R1-5 are independently R1-9 substituted C1-C6alkoxy, the C1-C6 alkoxy is C1-C3 alkoxy, such as methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, when R1-4 and R1-5 are independently R1-9 substituted C1-C6alkoxy, the number of R1-9 is one or more, and when the number of R1-9 is multiple, the R1-9 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-4 and R1-5 are independently C3-C7cycloalkyl, the C3-C7cycloalkyl is C3-C5cycloalkyl, such as cyclopropyl or cyclobutyl.
In some embodiments, when R1-4 and R1-5 are independently R1-19 substituted C3-C7cycloalkyl, the C3-C7cycloalkyl is a C3-C5cycloalkyl, such as cyclopropyl or cyclobutyl.
In some embodiments, when R1-4 and R1-5 are independently R1-19 substituted C3-C7cycloalkyl, the number of R1-19 is one or more, when the number of R1-19 is multiple, each R1-6 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-4 and R1-5 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatom in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is N or O.
In some embodiments, when R1-4 and R1-5 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is 1.
In some embodiments, when R1-4 and R1-5 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, 4-7 membered heterocycloalkyl of the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is a 5-6 membered heterocycloalkyl.
In some embodiments, when R1-4 and R1-5 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is piperidinyl
or tetrahydropyranyl
In some embodiments, when R1-4 and R1-5 are independently R1-20 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is N or O.
In some embodiments, when R1-4 and R1-5 are independently R1-20 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is 1.
In some embodiments, when R1-4 and R1-5 are independently R1-20 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, 4-7 membered heterocycloalkyl of the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is a 5-6 membered heterocycloalkyl.
In some embodiments, when R1-4 and R1-5 are independently R1-20 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is piperidinyl
or tetrahydropyran
In some embodiments, when R1-4 and R1-5 are independently R1-20 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of R1-20 is one or more, when the number of R1-20 is multiple, the R1-20 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-4 and R1-5 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is N and/or O.
In some embodiments, when R1-4 and R1-5 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1-4 and R1-5 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the C1-C10heteroaryl of the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is C3-C5heteroaryl.
In some embodiments, when R1-4 and R1-5 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is pyrimidinyl (for example,
pyridyl (for example,
or oxazolyl (for example,
In some embodiments, when R1-4 and R1-5 are independently R1-21 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the heteroatom in “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is N and/or O.
In some embodiments, when R1-4 and R1-5 are independently R1-21 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1-4 and R1-5 are independently R1-21 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the C1-C10heteroaryl of the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is C3-C5heteroaryl.
In some embodiments, when R1-4 and R1-5 are independently R1-21 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is pyrimidinyl (for example,
pyridyl (for example,
or oxazolyl (for example,
In some embodiments, when R1-4 and R1-5 are independently R1-21 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of R1-21 is one or more, when the number of R1-21 is multiple, each R1-21 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-6 and R1-9 are independently halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R1-6 and R1-9 are independently C1-C3alkoxy, the C1-C3alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy, such as methoxy.
In some embodiments, when R1-6 and R1-9 are independently C3-C7cycloalkyl, the C3-C7cycloalkyl is C3-C5cycloalkyl, such as cyclopropyl or cyclobutyl.
In some embodiments, when R1-6 and R1-9 are independently COOR1-18 substituted C3-C7cycloalkyl, the C3-C7cycloalkyl is a C3-C5cycloalkyl, such as cyclopropyl or cyclobutyl.
In some embodiments, when R1-6 and R1-9 are independently a COOR1-18 substituted C3-C7cycloalkyl, the number of the COOR1-18 is one or more, and when the number of the COOR1-18 is multiple, the COOR1-18 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-6 and R1-9 are independently “4-7 membered heterocycloalkylene having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatom is N.
In some embodiments, when R1-6 and R1-9 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is 1.
In some embodiments, when R1-6 and R1-9 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, 4-7 membered heterocycloalkyl of the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is a 5-6 membered heterocycloalkyl.
In some embodiments, when R1-6 and R1-9 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is tetrahydropyrrolyl
In some embodiments, when R1-6 and R1-9 are independently R1-22 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatom in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is N.
In some embodiments, when R1-6 and R1-9 are independently R1-22 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is 1.
In some embodiments, when R1-6 and R1-9 are independently R1-22 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, 4-7 membered heterocycloalkyl of the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is a 5-6 membered heterocycloalkyl.
In some embodiments, when R1-6 and R1-9 are independently R1-22 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is tetrahydropyrrolyl
In some embodiments, when R1-6 and R1-9 are independently R1-22 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of R1-22 is one or more, when the number of R1-22 is multiple, the R1-22 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-6 and R1-9 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is N.
In some embodiments, when R1-6 and R1-9 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is 1.
In some embodiments, when R1-6 and R1-9 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the C1-C10heteroaryl of the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is C3-C5heteroaryl.
In some embodiments, when R1-6 and R1-9 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is pyridinyl (such as
In some embodiments, when R1-6 and R1-9 are independently R1-23 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the heteroatom in “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is N.
In some embodiments, when R1-6 and R1-9 are independently R1-23 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is 1.
In some embodiments, when R1-6 and R1-9 are independently R1-23 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the C1-C10heteroaryl of the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is C3-C5heteroaryl.
In some embodiments, when R1-6 and R1-9 are independently R1-23 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is pyridinyl (such as
In some embodiments, when R1-6 and R1-9 are independently R1-23 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of R1-23 is one or more, when the number of R1-23 is multiple, each R1-23 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-7 and R1-8 are independently C1-C3alkyl, the C1-C3 alkyl is methyl, ethyl, n-propyl or isopropyl, for example methyl.
In some embodiments, when R1-7 and R1-8 are independently C3-C7cycloalkyl, the C3-C7cycloalkyl is C3-C5cycloalkyl, such as cyclopropyl or cyclobutyl.
In some embodiments, when R1-7 and R1-8 are independently R1-24 substituted C3-C7cycloalkyl, the C3-C7cycloalkyl is a C3-C5cycloalkyl, such as cyclopropyl or cyclobutyl.
In some embodiments, when R1-7 and R1-8 are independently R1-24 substituted C3-C7 cycloalkyl, the number of R1-24 is one or more, when the number of R1-24 is multiple, each R1-24 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-7 and R1-8 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatom in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is N or O.
In some embodiments, when R1-7 and R1-8 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1-7 and R1-8 are independently “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, 4-7 membered heterocycloalkyl of the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is a 5-6 membered heterocycloalkyl.
In some embodiments, when R1-7 and R1-8 are independently R1-25 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the heteroatom in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is N and/or O.
In some embodiments, when R1-7 and R1-8 are independently R1-25 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of the heteroatoms in the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1-7 and R1-8 are independently R1-25 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, 4-7 membered heterocycloalkyl of the “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S” is a 5-6 membered heterocycloalkyl.
In some embodiments, when R1-7 and R1-8 are independently R1-25 substituted “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, the number of R1-25 is one or more, when the number of R1-25 is multiple, the R1-25 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-7 and R1-8 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is N and/or O.
In some embodiments, when R1-7 and R1-8 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1-7 and R1-8 are independently “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the C1-C10heteroaryl of the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is C3-C5heteroaryl.
In some embodiments, when R1-7 and R1-8 are independently R1-26 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the heteroatom in “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is N and/or O.
In some embodiments, when R1-7 and R1-8 are independently R1-26 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the number of heteroatoms in the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is 1 or 2.
In some embodiments, when R1-7 and R1-8 are independently R1-26 substituted “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”, the C1-C10heteroaryl of the “C1-C10heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” is C3-C5heteroaryl.
In some embodiments, when R1-7 and R1-8 are independently C6-C10aryl, the C6-C10aryl is phenyl.
In some embodiments, when R1-7 and R1-8 are independently R1-27 substituted C6-C10aryl, the C6-C10aryl is phenyl.
In some embodiments, when R1-7 and R1-8 are independently R1-27 substituted C6-C10aryl, the number of R1-27 is one or more, when the number of R1-27 is multiple, each R1-27 are the same or different; the multiple can be 2 or 3.
In some embodiments, when R1-10, R1-11, R1-12, R1-16, R1-17, R1-18, R1-28 and R1-29 are independently C1-C3alkyl, the C1-C3alkyl is methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-13 is C1-C6alkyl, the C1-C6 alkyl is C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-13 is halogenated C1-C6alkyl, the C1-C6 alkyl is a C1-C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-13 is halogenated C1-C6alkyl, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R1-13 is halogenated C1-C6alkyl, the number of the halogens is one or multiple, and the multiple can be 2 or 3.
In some embodiments, when R1-14 and R1-15 are independently C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-14 and R1-15 are independently halogenated C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, such as methyl, ethyl, n-propyl or isopropyl.
In some embodiments, when R1-14 and R1-15 are independently halogenated C1-C6alkyl, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R1-14 and R1-15 are independently halogenated C1-C6alkyl, wherein the number of the halogen is one or multiple, and the multiple can be 2 or 3.
In some embodiments, when R1-19, R1-20, R1-21, R1-22, R1-23, and R1-24 are independently halogen, the halogen is fluorine, chlorine, bromine or iodine.
In some embodiments, when R1-19, R1-20, R1-21, R1-22, R1-23 and R1-24 are independently C1-C6alkyl, the C1-C6alkyl is C1-C3alkyl, for example, methyl, ethyl, n-propyl or isopropyl.
In some embodiments, X is N.
In some embodiments, A is O, S, S(═O)2, NH or NCH3.
In some embodiments, A is O, S or S(═O)2.
In some embodiments, A is O or S(═O)2.
In some embodiments, n and r are 1.
In some embodiments, L5 is C3-C6 cycloalkylene.
In some embodiments, L2 and L4 are independently O.
In some embodiments, Z5 is C2-C10alkylene or C2-C10 unsaturated alkylene.
In some embodiments, B is C2-C10alkylene, C2-C10 unsaturated alkylene, —Z5-L2- or —(CH2)n-L5-(CH2)r-L4-.
In some embodiments, B is C4-C6alkylene, C4-C6 unsaturated alkylene, —Z5-L2- or —(CH2)n-L5-(CH2)r-L4-, Z5 is C3-C5alkylene or C3-C5 unsaturated alkylene.
In some embodiments, B is
—(CH2)v—,
—(CH2)w—O— or —CH2-L5-CH2—O—; p is 1, 2 or 3; v is 4, 5 or 6; s is 1 or 2; w is 3, 4 or 5; L5 is C3-C5cycloalkylene.
In some embodiments, p is 2; v is 5; s is 1; w is 4; L5 is cyclopropylene or cyclobutylene.
In some embodiments, R1-4 is C1-C6alkyl, R1-6 substituted C1-C6alkyl, —S(═O)2R1-7, —C(═O)R1-8, COOR1-12, C3-C7cycloalkyl, “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”, “C1-C10 heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S” or R1-21 substituted “C1-C10 heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”.
In some embodiments, R1-6 is halogen, OH, COOR1-17, S(═O)2R1-31, C1-C3alkoxy, “4-7 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S”
or “C1-C10 heteroaryl having 1-4 heteroatoms selected from one or more of N, O and S”
In some embodiments, R1-7 and R1-8 are independently C1-C3alkyl (e. g. methyl) or C6-C10aryl (e. g. phenyl).
In some embodiments, R1-7 and R1-8 are independently C1-C3alkyl (e. g. methyl).
In some embodiments, R1-21 is C1-C3alkyl.
In some embodiments, R1-5 is C1-C4alkyl or COOH.
In some embodiments, where R1-4 is COOH, C1-C4alkyl, R1-6 substituted C1-C4alkyl, —C(═O)R1-8, —S(═O)2R1-7,
or cyclobutyl; R1-6 is COOR1-17, C1-C3alkoxy,
R1-7 is methyl; and R1-8 is methyl.
In some embodiments, in scheme A, R3 is H.
In some embodiments, in scheme A, R1, R2 together with the carbon atoms to which they are attached form a “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O”, R1-4 substituted “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O”, C5-C6cycloalkylene or R1-5 substituted C5-C6cycloalkylene; wherein the methylene in the “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O” and R′substituted “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O” is not replaced, or one methylene is replaced by a carbonyl group.
In some embodiments, in scheme B, R1 is H.
In some embodiments, in scheme B, R2, R3 together with the carbon atoms to which they are attached form a “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O”, R1-4 substituted “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O”; wherein the methylene in the “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O” and R′substituted “5-6 membered heterocycloalkylene having 1-2 heteroatoms selected from one or more of N and/or O” is not replaced.
In some embodiments, R5 is H.
In some embodiments, R10 is C1-C6alkyl, and R11 is C1-C6alkyl.
In some embodiments, R12 is C1-C6alkyl.
In some embodiments, R9 is H.
In some embodiments, R13 is H or COOR17.
In some embodiments, R17 is C1-C6alkyl.
In some embodiments, R13 is H.
In some embodiments, -A-B— is
—O—(CH2)v—,
—S—(CH2)v—,
—S(═O)2—(CH2)v—,
NH—(CH2)v—,
—N(CH3)—(CH2)v—,
—O—(CH2)w—O— or —O—CH2-L5-CH2—O— (e. g.
m is 1, 2 or 3); p is 1, 2 or 3; v is 4, 5 or 6; s is 1 or 2; w is 3, 4 or 5; L5 is C3-C5 cycloalkylene.
In some embodiments, -A-B— is
—O—(CH2)v—,
—S—(CH2)v—,
—S(═O)2—(CH2)v—,
—O—(CH2)w—O—,
p is 1, 2 or 3; v is 4, 5 or 6; s is 1 or 2; w is 3 or 4.
In some embodiments,
is
the number of R1-4 is 1 or more, when number of R1-4 is multiple, the R1-4 are the same or different; the number of R1-5 is 1 or 2, and when the number of R1-5 is 2, the R1-5 are the same or different.
In some embodiments, the compound as shown in formula I is any one of the following compounds:
The invention also provides a compound as shown in formula II:
wherein, RA and RB are independently H or amino protecting groups, and RA and RB cannot simultaneously be H; X, A, B, R2, R3 and R5 are defined as described above.
In formula II, the amino protecting group may be a common amino protecting group in the art, such as p-methoxybenzyl (PMB).
The compound shown in Formula II is any of the following compounds:
The invention also provides the preparation method of the compound as shown in formula I, which comprises the following method I. method II or method III:
The method I comprises the following steps: performing the following deprotection reaction on the compound as shown in formula II to obtain the compound as shown in formula I;
In method I, R9 and R13 are H, RA, RB, A, B, R1, R2, R3 and R5 are defined as above;
The method II comprises the following steps: performing an acylation reaction of the compound of formula I-A and the compound of formula III-A to obtain the compound of formula I;
In method II, R9 is CONR10R11 or C(═O)R12, R10, R11, R12, A, B, R1, R2, R3, R5 and R13 are defined as above;
The method III comprises the following steps: performing an acylation reaction of the compound of formula I-B and the compound of formula III-B to obtain the compound of formula I;
In method III, R13 is CONR14R15, C(═O)R16 or COOR17, R14, R15, R16, R17, A, B, R1, R2, R3, R5 and R9 are defined as above.
In method I, the procedure and conditions of the deprotection reaction can be conventional in the art, such as heating in trifluoroacetic acid.
In method II or method III, the procedure and conditions of the acylation reaction can be conventional in the art, for example, in the presence of a base (such as pyridine and triethylamine, pyridine and DIPEA, DMAP and triethylamine or DMAP and DIPEA).
The preparation method of the compound as shown in formula I may further include the following steps: the compound as shown in formula IV performs the following intra-molecular ring forming reaction to obtain the compound as shown in formula II;
RC is C1-C3alkyl, and RA, RB, A, B, R1, R2, R3, R5 and R9 are defined as above.
The procedures and conditions for the intramolecular cyclisation reaction may be conventional in the art, for example in the presence of acetic acid and a metal (e. g. zinc and/or iron).
The present invention also provides a pharmaceutical composition comprising the compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
The present invention also provides a use of the compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a medicament. The medicament is for treating or preventing a tumor or an infection caused by a virus, preferably one or more of HBV, HCV, HIV and influenza virus.
The present invention also provides a use of the compound of formula I, a solvate thereof, a prodrug thereof, a metabolite thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a TLR7 agonist.
In the application, the TLR7 agonist can be used in mammalian organisms; it can also be used in vitro, mainly as experimental use, for example: as a standard sample or control to provide comparison, or according to the conventional method in the art to prepare a kit, to provide rapid detection of TLR7 inhibitory effect.
Unless otherwise specified, the terms used in the present invention have the following meanings:
Herein, the ethylenically linked “” means that the olefin is in the Z configuration, the E configuration, or a mixture of the two, for example
is a Z configuration olefin
and/or an E configuration olefin
As used herein, the term may be preceded and/or followed by a single dash “-”, or a double dash “=”, indicating the bond order of the bond between the named substituent and the parent moiety; a single dash indicating a single bond and a double dash indicating a double bond. In the absence of a single or double dash, a single bond may be considered to be formed between a substituent and its parent moiety; furthermore, unless otherwise indicated, substituents are read as “left to right” or “top to bottom”. For example, “—Z5-L2-” means that Z5 is connected to A, and L2 is connected to B;
means “(CH2)p” is connected to A.
The term “pharmaceutically acceptable” means that the salts, solvents, excipients, and the like are generally non-toxic, safe, and suitable for patient use. The “patient” is preferably a mammal, more preferably a human.
The term “mammal” includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, most preferably humans.
The term “pharmaceutically acceptable salt” refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acid, and the inorganic acid includes but is not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid and the like. The pharmaceutically acceptable acid includes an organic acid, and the organic acid includes, but is not limited: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, oleic acid, tannic acid, pantothenic acid, ascorbic acid, 4′-methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e. g., glutamic acid, arginine), etc. When the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. See Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
The term “solvate” refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. The solvent includes, but is not limited to, water, methanol, ethanol and the like.
The term “prodrug” refers to a derivative of a compound of the invention which is converted to a compound of the invention (drug) when the derivative is administered to a warm-blooded animal (e. g., a human). Typical examples of prodrugs include compounds having a biologically labile protecting group on a functional portion of the active compound. Prodrugs include compounds that can produce an active compound by oxidation, reduction, amination, deamination, hydroxylation, dehydroxylation, hydrolysis, dehydration, alkylation, dealkylation, acylation, deacylation, phosphorylation, dephosphorylation.
The term “metabolite” refers to a degradation product of a compound of the invention by one or more metabolic processes, which exerts a desired biological activity.
The terms “compound”, “solvate”, “prodrug”, “metabolite” and “pharmaceutically acceptable salt” may exist in crystalline or amorphous form. The term “crystal form” means that the ions or molecules therein are arranged strictly periodically in three-dimensional space in a certain manner, and have a regular pattern of periodic repetition at intervals of a certain distance; due to the different periodic arrangements, there may be multiple crystal forms, that is, polymorphic phenomena. The term “amorphous” means that the ions or molecules therein present a disordered distribution state, that is, the ions and molecules do not have periodic arrangement rules.
The terms “compounds”, “solvates”, “prodrugs”, “metabolites” and “pharmaceutically acceptable salts”, if stereoisomers exist, may exist as individual stereoisomers or as mixtures thereof (e. g., racemates). The term “stereoisomer” refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution by bonding (chemical combination, etc.) or salt formation (physical combination, etc.). The term “single stereoisomer” means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
The terms “compound”, “solvate”, “prodrug”, “metabolite” and “pharmaceutically acceptable salt”, if tautomers exist, may exist in the form of a single tautomer or a mixture thereof, preferably in the form of the more stable tautomer. For example,
are tautomers.
The atoms in the terms “compound”, “solvate”, “prodrug”, “metabolite”, and “pharmaceutically acceptable salt” may be present in their natural or non-natural abundance. In the case of a hydrogen atom, its natural abundance form refers to about 99.985% of it being protium and about 0.015% of it being deuterium; its non-natural abundance form refers to about 95% of it being deuterium. That is, one or more of the atoms in the terms “compound,” “pharmaceutically acceptable salt,” “solvate,” and “solvate of a pharmaceutically acceptable salt” may be an atom present in a form that is not present in natural abundance.
When any variable (for example, R1-1) appears multiple times in the definition of a compound, the definition of each position of the variable has nothing to do with the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted by 1, 2 or 3 R1-1 groups, that is, the group may be substituted by up to 3 R1-1, the position R1-1 The definition is independent of the definition of the other positions R1-1. In addition, combinations of substituents and/or variables are permissible only if the combination results in a stable compound.
The term “halogen” refers to fluorine, chlorine, bromine or iodine.
The term “alkyl” refers to a linear or branched saturated aliphatic hydrocarbon group having a specified number of carbon atoms, and generally refers to a saturated alkyl. Examples of alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyls.
The term “alkylene” refers to a divalent group of a linear or branched saturated aliphatic hydrocarbon group having a specified number of carbon atoms. The two valents can be concentrated on the same atom, such as methylene (—CH2—), ethylene (—CHCH3—), and the two valents can also be connected to two atoms respectively, such as 1, 2-ethylene (—CH2CH2—).
the term “unsaturated” alkylene” refers to an alkyl having the specified number of carbon atoms, comprising one or more units of unsaturation of straight-chain or branched-chain of aliphatic hydrocarbon radical of one to a divalent radical of for example —CH2CH2CH ═CHCH2—.
The term “alkoxy” refers to the group-O—RX, where RX is an alkyl as defined above.
The term “cycloalkyl” refers to a monovalent saturated cyclic alkyl, examples of which are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The term “cycloalkylene” refers to a divalent group of a saturated cyclic alkylene, such as cycloalkylene
cyclobutylene
cyclopentylene
or cyclohexylene
etc.
The term “heterocycloalkyl” refers to a saturated monocyclic group having a heteroatom. Examples of heterocycloalkyls are: tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyridyl, tetrahydropyrrolyl, azacyclobutane, thiazolidinyl, azolyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azacycloheptanyl, diazacycloheptanyl, oxazacycloheptanyl, etc.
The term “heterocycloalkyl” refers to a divalent group of a saturated monocyclic group having a heteroatom. Examples of heterocycloalkyl are: sub-tetrahydrofuryl
sub-tetrahydropyrrol
sub-tetrahydrothienyl
sub-tetrahydropyridyl
sub-tetrahydropyrrolyl
etc.
The term “aryl” refers to a C6-C10aryl, such as phenyl or naphthyl.
The term “heteroaryl” refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 5-6-membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur. When it is a bicyclic ring, at least one ring is aromatic, for example, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, iso-azolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, quinolyl, isoquinolyl, etc.
The term “heteroarylene” refers to a divalent group containing a heteroatom aromatic group, preferably containing 1, 2 or 3 aromatic 5-6-membered monocyclic or 9-10 membered bicyclic divalent groups independently selected from nitrogen, oxygen and sulfur. When it is a bicyclic ring, at least one ring has aromaticity, for example, sub-furyl (for example
sub-pyridyl (for example
sub-pyridazinyl (for example
sub-pyrimidinyl (for example
sub-pyrazinyl-based (for example
sub-thienyl (for example
The term “pharmaceutical excipients” refers to excipients and additives used in the production of pharmaceutical products and the formulation of prescriptions, and is all substances contained in pharmaceutical preparations except active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)
The term “therapy” refers to therapeutic therapy. When a specific condition is involved, treatment means: (1) to alleviate one or more biological manifestations of the disease or condition, (2) to interfere with (a) one or more points in the biological cascade that causes or causes the disease or (B) One or more biological manifestations of the disease, (3) to improve one or more symptoms, effects or side effects related to the disease, or one or more symptoms, effects, or side effects associated with the condition or treatment thereof, or (4) slowing the development of one or more biological manifestations of the condition or condition.
The term “prevention” refers to a reduction in the risk of acquiring or developing a disease or disorder.
On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, that is, each preferred example of the present invention can be obtained.
The reagents and raw materials used in the invention are commercially available.
The positive progress of the present invention is that the present invention provides a series of macrocyclic compounds with good TLR7 agonistic activity, which can be used to treat or prevent tumors or virus-caused infections.
Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited to the scope of the described examples. The following embodiments do not indicate the specific conditions of the experimental method, in accordance with the conventional methods and conditions, or in accordance with the commodity instructions.
The compound of the invention is prepared by the following process:
In scheme 1, the initial compound A-1 is nitrated to obtain compound A-2; A-2 is halogenated to obtain compound A-3; A-3 is ammoniated to obtain A-4; A-4 is acylated to obtain A-5; A-5 is aminated to obtain A-6; A-6 is oxidized to obtain A-7 or A-7′; A-9 is obtained by substitution reaction with A-8; A-9 undergoes substitution reaction with A-10 to form A-11; A-11 undergoes olefin metathesis reaction to obtain macrocyclic compound A-12; A-12 is closed in one step through nitro reduction to obtain A-13; A-13 is deprotecting group to obtain A-14; A-14 is catalytically hydrogenated to obtain A-15.
In scheme 2, the initial compound A-7 or A-7 and B-1 are substituted to obtain the compound B-2; B-2 and B-3 are substituted to obtain the compound B-4; B-4 is subjected to olefin metathesis to obtain the macrocyclic compound B-5; B-5 is ring-closed by nitro reduction to obtain B-6; B-6 is deprotected to obtain B-7; B-7 is catalytic hydrogenated to obtain B-8.
In scheme 3, the initial compound C-1 is aminated to obtain compound C-2; C-2 and A-8 are substituted to obtain compound C-3; C-3 and A-10 are substituted to obtain compound C-4; C-4 is subjected to olefin metathesis to obtain macrocyclic compound B-5; C-5 is subjected to one-step nitro reduction to obtain C-6; C-6 is deprotected to obtain C-7; C-7 is catalytic hydrogenated to obtain C-8.
In scheme 4, the initial compound D-1 and compound D-2 are substituted to obtain compound D-3; D-3 and A-6 are substituted to obtain compound D-4; D-4 is oxidized to obtain compound D-5; D-5 is deprotected to obtain compound D-6; D-6 undergoes substitution reaction to close the A-15 ring to obtain D-7. D-7 closes the ring in one step through nitro reduction to obtain D-8; D-9 is obtained by catalytic hydrogenation of D-8.
In scheme 5, the initial compound D-1 is substituted to obtain compound E-1; E-1 and A-6 are substituted to obtain compound E-2; E-2 is oxidized to obtain compound E-3; Compound E-4 is obtained by deprotecting E-3; E-4 undergoes substitution reaction to close the ring to obtain E-5; E-5 undergoes nitro reduction to close the ring to obtain E-6; E-6 undergoes catalytic hydrogenation to obtain E-7.
In scheme 6, compound A-15 undergoes acylation reaction to generate compound G-1 (the R9 is CONR10R11 or C(═O)R12); G-1 continue to undergo acylation reaction to generate compound G-2 (R9 is CONR10R11 or C(═O)R12, R13 is CONR14R15, C(═O)R16 or COOR17).
In the above schemes 1 to 6, LG is-OH, halogen, —OS(O)2(C1-C4alkyl), and the definitions of each substituent in each compound are as described in the preceding items.
In the following examples, the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10−6 (ppm). The NMR was determined by Bruker AVANCE-400 NMR. The solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).
SHIMADZU LC system (column: Xselect®: CSH™ Prep-C18, 19*150 mm, liquid processor LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution).
LC/MS spectra of the compounds were obtained using LC/MS (Agilent Technologies 1200 Series). The LC/MS conditions were as follows (10 min run time):
Unless otherwise specified, in the following examples, the intermediates and final compounds were purified using silica gel column chromatography, or using a Xselect®-CSH™ Prep-C18 (5 μm, OBD™ 19*150 mm) column or using a XBridge™ Prep Phenyl(5 μm, OBD™ 30*100 mm) on a reversed-phase chromatographic column by preparative HPLC.
Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
The Combiflash Rf200 (TELEDYNE ISCO) was used CombiFlash a rapid preparator.
Thin layer chromatography (TLC) silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications of silica gel plate used for thin layer chromatography detection products are 0.15 mm-0.2 mm, and the specifications of thin layer chromatography separation and purification products are 0.4 mm-0.5 mm.
The known starting materials of the present invention can be synthesized using or following methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darry Chemicals and other companies.
Ac2O: Acetic anhydride; AIBN: 2,2′-azobis(2-methylpropionitrile); BH3: Borane; Boc2O: tert-butyldicarbonate; CBr4: Carbon tetrabromide; CH3I (MeI): Iodomethane; con. H2SO4: con. sulfuric acid; con. HNO3: con. nitric acid; Cs2CO3: Caesium carbonate; DCM: dichloromethane; DIAD: diisopropyl azodiformate; DIBAL-H: diisobutyl aluminium hydride; DIEA: N,N-diisopropylethylamine; DMAP: 4-Dimethylaminopyridine; N,N-dimethylformamide; DMSO: dimethyl sulfoxide; H2SO4: sulfuric acid; HOAc; Acetic Acid; K2CO3: Potassium carbonate; K3PO4: Tripotassium Orthophosphate; LiAlH4: Lithium Aluminum Hydride; LiHMDS: Lithium bis(trimethylsilyl)amide; LiOH: Lithium hydroxide; mCPBA: 3-Chloroperbenzoic acid; MeOH: methanol; NaCNBH3: Sodium cyanoborohydride; NaH: Sodium hydride; NaHCO3: sodium bicarbonate; NBS: N-Bromosuccinimide; NIS: N-iodosuccinimide; PCy3: tricyclohexylphosphane; Pd(dppf)Cl2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(OAc)2: Palladium(II)acetate; Pd/C: Palladium 10% on Carbon; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium; POCl3: phosphorus oxychloride; PPh3: triphenylphosphine; SOCl2: thienyl chloride; TBAF: Tetrabutylammonium fluoride; TBDPSCl: tort-Butyldiphenylchlorosilane; TBSCl: t-Butyldimethylchlorosilane; t-BuOK: potassium t-butoxide; TEA: triethylamine; TES: Triethylsilane; TFA: trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; TfOH: Trifluoromethanesulfonic acid; THF: Tetrahydrofuran.; TLC: thin layer chromatography; TMP: Trimethyl phosphate; XantPhos: 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene; Zn: Zinc; ZnCl2: Zinc chloride.
Intermediate 1
Step 1: Preparation of Compound 2
To a stirred solution of fuming nitric acid (70 mL) was added compound 1 (25 g, 0.16 mol) at 0° C., then the resulting mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into ice-water and filtered, washed with water, ether and dried to afford compound 2 (22 g, 68%) as a light brown solid. MS: 204.0 (M+H)+.
Step 2: Preparation of Compound 3
To a stirred suspension of compound 2 (22 g, 0.11 mol) in POCl3 (80 mL) was added N,N-diethylaniline (26 mL) at 0° C., then the resulting mixture was stirred at 110° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 3 (15 g, 58%) as a yellow oil.
Step 3: Preparation of Compound 4
To a stirred mixture solution of compound 3 (15 g, 63 mmol) in THF (180 mL) was added TEA (19.8 mL, 0.14 mol) and 7.0 M NH 3 solution in Methanol (9.9 mL, 69.3 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to afford compound 4 (13 g). MS: 221.0 (M+H)+.
Step 4: Preparation of Compound 5
To a stirred mixture solution of compound 4 (13 g, 590 mmol) and TEA (12 g, 0.12 mol) in DCM (130 mL) was added Ethyl chloroformate (7.6 g, 71 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 6 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 5 (15 g, 58%) as a yellow solid. MS: 293.2 (M+H)+. 1HNMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 4.16 (q, J=8 Hz, 2H), 2.57 (s, 3H), 1.22 (t, J=8 Hz, 3H).
Step 5: Preparation of Compound 6
To a stirred mixture solution of compound 5 (1 g, 3.42 mmol) in DCM (30 mL) was added TEA (0.69 g, 6.83 mmol) and bis (4-methoxybenzyl) amine (1.32 g, 5.12 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with sodium thiosulfate solution, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 6 (1.5 g, 91%) as a yellow oil. MS: 514.2 (M+H)+.
Step 6: Preparation of Compound 7
To a stirred mixture solution of compound 6 (1.5 g, 2.92 mmol) in DCM (30 mL) was added mCPBA (0.75 g, 4.38 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 7 (1.3 g, 82%) as a yellow oil. MS: 530.2 (M+H)+.
Step 7: Preparation of Intermediate 1
To a stirred mixture solution of compound 7 (700 mg, 1.28 mmol) in 3-butene-1-ol (5 mL) was added TEA (390 mg, 3.85 mmol) at 20° C., then the resulting mixture was stirred at 80° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 1 (500 mg, 74.4%) as a colorless oil. MS: 538.2 (M+H)+.
Intermediate 2
To a stirred mixture solution of 2,6-dichloro-3-nitropyridine-4-amine (10.0 g, 48.1 mmol) and TEA (7.30 g, 72.1 mmol) in THF (30 mL) was added ethyl chloroformate (6.26 g, 57.7 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 4 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 2 (10 g, 75%) as a yellow solid. MS: 280.1 (M+H)+.
Intermediate 3
To a stirred mixture solution of compound 7 (1.48 g, 2.8 mmol) in pent-4-en-1-ol (3 mL) was added TEA (565 mg, 5.6 mmol) at 20° C., then the resulting mixture was stirred at 80° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 3 (1.25 g, 81%) as a yellow oil. MS: 552.4 (M+H)+.
Intermediate 4
Step 1: Preparation of Compound 9
To a stirred mixture solution of compound 8 (10 g, 43.7 mmol) in CCl4 (250 mL) was added NB S (8.55 g, 48.0 mmol) and AIBN (1.43 g, 8.73 mmol) at 20° C., then the resulting mixture was stirred at 80° C. for 14 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 9 (7.5 g, 55.8%) as a white solid.
Step 2: Preparation of Compound 10
A mixture solution of compound 9 (10 g, 32.5 mmol), 2-methylpropan-2-amine (4.75 g, 64.9 mmol) and K2CO3 (13.46 g, 97 mmol) in THF (100 mL) was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 10 (6.6 g, 67.7%) as a yellow oil. MS: 300.1 (M+H)+.
Step 3: Preparation of Compound 11
To a stirred mixture solution of compound 10 (0.70 g, 2.33 mmol) in DCM (15 mL) was added triphosgene (0.692 g, 2.33 mmol) and TEA (0.71 g, 7.00 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in ACN (15 mL) and potassium ethylxanthate (0.37 g, 2.33 mmol), then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 11 (0.35 g, 33.5%) as a yellow solid.
Step 4: Preparation of Compound 12
A mixture solution of compound 11 (2.7 g, 6.02 mmol) and dilauroyl peroxide (2.88 g, 7.23 mmol) in DCM (100 mL) was stirred at 50° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 12 (1.20 g, 61.1%) as a yellow solid. MS: 326.1 (M+H)+.
Step 5: Preparation of Compound 13
A mixture solution of compound 12 (1.0 g, 3.1 mmol) in CF3SO3H (5.0 g, 33.3 mmol) was stirred at 50° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 13 (0.54 g, 62.2%) as a white solid. MS: 270.1 (M+H)+.
Step 6: Preparation of Compound 14
To a stirred mixture solution of compound 13 (1.20 g, 4.44 mmol) in THF (10 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (1.76 mL, 4.4 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 14 (0.7 g, 74.7%) as a white solid. MS: 242.1 (M+H)+.
Step 7: Preparation of Compound 15
To a stirred mixture solution of compound 14 (1.70 g, 7.02 mmol) in DMF (20 mL) was added imidazole (1.43 g, 7.02 mmol) and TBSCl (2.12 g, 14.05 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 15 (1.9 g, 76%) as a white solid. MS: 356.1 (M+H)+.
Step 8: Preparation of Compound 16
A mixture solution of compound 15 (1.90 g, 5.33 mmol), ethyl 2-bromoacetate (1.34 g, 8.00 mmol) and K2CO3 (2.2 g, 16.0 mmol) in ACN (25 mL) was stirred at 50° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 16 (2.2 g, 93%) as a yellow solid. MS: 442.2 (M+H)+.
Step 9: Preparation of Compound 17
A mixture solution of compound 16 (0.6 g, 1.36 mmol), water (3 mL), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (0.68 g, 4.07 mmol), (dppf)Cl2Pd (0.099 g, 0.14 mmol) and potassium phosphate (0.86 g, 4.07 mmol) in Dioxane (15 mL) was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 17 (0.4 g, 73.1%) as a white solid. MS: 404.3 (M+H)+.
Step 10: Preparation of Intermediate 4
A mixture solution of compound 17 (0.42 g, 1.04 mmol) and 1.0 M TBAF THF solution (1.04 mL, 1.04 mmol) in THF (10 mL) was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 4 (0.22 g, 73.1%) as a white solid. MS: 290.2 (M+H)+.
Intermediate 5
Step 1: Preparation of Compound 18
To a stirred mixture solution of compound 15 (0.30 g, 1.11 mmol) in DMF (10 mL) was added t-BuOK (0.19 g, 1.67 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. Then CH3I (0.32 g, 2.22 mmol) was added to the above mixture solution and the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 18 (0.28 g, 89%) as a white solid. MS: 370.1 (M+H)+.
Step 2: Preparation of Compound 19
A mixture solution of compound 18 (0.28 g, 0.76 mmol), water (1 mL), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (0.38 g, 2.27 mmol), (dppf)Cl2Pd (0.055 g, 0.076 mmol) and potassium phosphate (0.48 g, 2.27 mmol) in Dioxane (5 mL) was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 19 (0.22 g, 88%) as a yellow solid. MS: 332.2 (M+H)+.
Step 3: Preparation of Intermediate 5
A mixture solution of compound 19 (0.22 g, 0.66 mmol) and 1.0 M TBAF THF solution (0.66 mL, 0.66 mmol) in THF (10 mL) was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 5 (0.130 g, 90%) as a yellow solid. MS: 218.2 (M+H)+.
Intermediate 6
Step 1: Preparation of Compound 20
To a stirred mixture solution of compound 15 (0.65 g, 1.82 mmol) in DMF (15 mL) was added t-BuOK (0.31 g, 2.74 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. Then 1-(2-bromoethyl)pyrrolidine (0.59 g, 2.74 mmol) was added to the above mixture solution and the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 20 (0.25 g, 30.2%) as a yellow solid. MS: 453.2 (M+H)+.
Step 2: Preparation of Compound 21
A mixture solution of compound 20 (0.21 g, 0.46 mmol), water (2 mL), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (233 mg, 1.39 mmol), (dppf)Cl2Pd (33.9 mg, 0.046 mmol) and potassium phosphate (295 mg, 1.39 mmol) in Dioxane (10 mL) was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 21 (0.13 g, 67.7%) as a yellow solid. MS: 415.3 (M+H)+.
Step 3: Preparation of Intermediate 6
A mixture solution of compound 21 (200 mg, 0.48 mmol) and 1.0 M TBAF THF solution (0.48 mL, 0.48 mmol) in THF (5 mL) was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 6 (0.081 g, 55.2%) as a yellow solid. MS: 301.2 (M+H)+.
Intermediate 7
Step 1: Preparation of Compound 23
To a stirred mixture solution of compound 22 (3.30 g, 14.49 mmol) in DCM (15 mL) was added TFAA (6.09 g, 29.0 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 23 (4.0 g, 96%) as a colorless oil. MS: 288.1 (M+H)+.
Step 2: Preparation of Compound 24
To a stirred mixture solution of compound 23 (5.01 g, 17.41 mmol) in TFA (40 mL) was added NIS (7.8 g, 34.8 mmol) and H2SO4 (0.368 g, 3.75 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 24 (3.7 g, 51%) as a white solid. MS: 414.5 (M+H)+.
Step 3: Preparation of Compound 25
To a stirred suspension of compound 24 (1.70 g, 4.11 mmol) in MeOH (20 mL) was added K2CO3 (1.37 g) and H2O (2.5 mL) at 0° C., then the resulting mixture was stirred at 20° C. for 3 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford compound 25.
Step 4: Preparation of Compound 26
To a stirred mixture solution of compound 25 (1.3 g, 4.11 mmol) in EA (20 mL) and H2O (20 mL) was added a solution of Boc2O (1.08 g, 4.93 mmol) and NaHCO3 (464 mg, 5.1 mmol) in EA (20 mL) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 26 (1.5 g, 87%) as a colorless oil.
Step 5: Preparation of Compound 27
A mixture solution of compound 26 (1.0 g, 2.4 mmol)), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (4.03 g, 23.97 mmol), tris(dibenzylideneacetone)dipalladium (0.44 g, 0.48 mmol), tricyclohexylphosphane (0.13 g, 0.48 mmol) and potassium metaphosphate (1.5 g, 7.3 mmol) in DMF (10 mL) was stirred at 80° C. for 2 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 27 (700 mg, 88%) as a yellow oil.
Step 6: Preparation of Intermediate 7
To a stirred mixture solution of compound 27 (600 mg, 1.81 mmol) in THF (15 mL) was added 1.5 M DIBAL-H solution in toluene (3.62 mL, 5.43 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding MeOH and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 7 (130 mg, 23.6%) as a yellow oil.
Intermediate 8
Step 1: Preparation of Compound 29
To a stirred mixture solution of compound 28 (5.0 g, 22 mmol) in DCM (120 mL) was added TFAA (6.1 mL, 43.9 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 29 (5.9 g, 93%) as a white solid. MS: 288.1 (M+H)+. 1H-NMR (CDCl3, 400 MHz): δ 7.91-7.86 (m, 2H), 7.24-7.19 (m, 1H), 4.82 (d, J=20 Hz, 2H), 3.92 (s, 3H), 3.87 (t, J=6.0 Hz, 2H), 3.03-2.99 (m, 2H).
Step 2: Preparation of Compound 30
To a stirred mixture solution of compound 29 (5.89 g, 20.51 mmol) in TFA (40 mL) was added NIS (7.8 g, 34.8 mmol) and H2SO4 (4 mL) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 30 (7 g, 83%) as a white solid. 1H-NMR (CDCl3, 400 MHz): δ 8.39 (s, 1H), 7.83 (s, 1H), 4.69-4.68 (m, 2H), 3.92 (s, 3H), 3.90-3.82 (m, 2H), 3.01-2.95 (m, 2H).
Step 3: Preparation of Compound 31
To a stirred suspension of compound 30 (7.0 g, 16.9 mmol) in MeOH (20 mL) was added K2CO3 (4.7 g) and H2O (10 mL) at 0° C., then the resulting mixture was stirred at 20° C. for 3 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford compound 31. MS: 318.1
Step 4: Preparation of Compound 32
To a stirred mixture solution of compound 31 (5.4 g, 16.9 mmol) in EA (60 mL) and H2O (60 mL) was added a solution of Boc2O (4.5 g, 20.3 mmol) and NaHCO3 (1.7 g, 20 mmol) in EA (20 mL) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 32 (5.8 g, 82%) as a colorless oil. MS: 403.1 (M−55+41)+. 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H) 7.79 (s, 1H), 4.47 (s, 2H), 3.91 (s, 3H), 3.63 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.6 Hz, 2H), 1.50 (s, 9H).
Step 5: Preparation of Compound 33
A mixture solution of compound 32 (1.0 g, 2.4 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (4.0 g, 24 mmol), tris(dibenzylideneacetone)dipalladium (0.44 g, 0.48 mmol), tricyclohexylphosphane (0.13 g, 0.48 mmol) and potassium metaphosphate (1.5 g, 7.3 mmol) in DMF (15 mL) was stirred at 80° C. for 2 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 33 (608 mg, 77%) as a yellow oil. MS: 317.2 (M−55+41)+.
Step 6: Preparation of Intermediate 8
To a stirred mixture solution of compound 33 (1.1 g, 3.2 mmol) in THF (40 mL) was added 1.5 M DIBAL-H solution in toluene (6.4 mL, 9.6 mmol) at −10° C., then the resulting mixture was stirred at −10° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding a solution of NH4Cl and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 8 (480 mg, 49%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.03 (s, 2H), 5.97-5.87 (m, 1H), 5.11-5.03 (m, 2H), 4.63 (s, 2H), 4.53 (s, 2H), 3.61 (t, J=5.6 Hz, 2H), 3.33 (d, J=5.6 Hz, 2H), 2.84 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).
Intermediate 9
Step 1: Preparation of Compound 35
To a stirred mixture solution of compound 34 (5.0 g, 28.1 mmol) in AcOH (100 mL) was added benzyltrimethylammonium dichloroiodate (11.72 g, 33.7 mmol) and ZnCl2 (4.59 g, 33.7 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 15 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 35 (5.8 g) as a yellow solid. MS: 303.0 (M−H)−.
Step 2: Preparation of Compound 36
To a stirred mixture solution of compound 35 (5.8 g, 19.07 mmol) in MeOH (50 mL) was added SOCl2 (4.54 g, 38.1 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 36 (5.2 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43-7.34 (m, 2H), 6.65 (d, J=8.5 Hz, 1H), 4.92 (dd, J=6.4, 4.0 Hz, 1H), 3.66 (s, 3H), 2.82-2.72 (m, 1H), 2.64-2.54 (m, 1H), 2.19-1.96 (m, 2H).
Step 3: Preparation of Compound 37
In a sealed tube, to a stirred mixture solution of compound 36 (4 g, 12.57 mmol), oxalic acid (3.2 g, 12.57 mmol), Pd(OAc)2 (282 mg, 1.26 mmol) and Xantphos (28 mg, 1.26 mmol) in DMF (20 mL) was added DIEA (3.25 g, 25.1 mmol) and Ac2O (2.57 g, 25.1 mmol) at 0° C., then the resulting mixture was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 37 (2.5 g, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.67 (dt, J=4.9, 2.1 Hz, 2H), 6.89 (d, J=9.0 Hz, 1H), 5.02 (dd, J=6.3, 4.1 Hz, 1H), 3.69 (s, 3H), 2.83 (dt, J=16.8, 6.2 Hz, 1H), 2.65 (dt, J=16.3, 7.1 Hz, 1H), 2.22-2.01 (m, 2H).
Step 4: Preparation of Compound 38
To a stirred mixture solution of compound 37 (3.8 g, 16.09 mmol) in TFA (50 mL) was added NBS (1.1 g, 19.3 mmol) and CF3SO3H (0.24 g, 1.61 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 38 (3.0 g, 59.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.65 (s, 1H), 5.20-5.16 (m, 1H), 3.68 (s, 3H), 2.85 (dt, J=17.0, 5.8 Hz, 1H), 2.65 (dt, J=16.2, 7.5 Hz, 1H), 2.10-2.20 (m, 2H).
Step 5: Preparation of Compound 39
To a stirred mixture solution of compound 38 (1 g, 3.17 mmol) in THF (10 mL) was added 1.0 M BH3-THF solution (9.5 mL, 9.52 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 39 (600 mg, 62.8%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (s, 1H), 6.99 (s, 1H), 5.13 (t, J=5.7 Hz, 1H), 5.07 (t, J=5.0 Hz, 1H), 4.36 (d, J=5.7 Hz, 2H), 3.36 (s, 3H), 2.79 (dt, J=16.9, 5.8 Hz, 1H), 2.60 (m, 1H), 2.22-2.03 (m, 2H).
Step 6: Preparation of Intermediate 9
A mixture solution of compound 39 (1.8 g, 5.98 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (3.0 g, 17.9 mmol), Pd(dppf)Cl2 (0.44 g, 0.6 mmol) and potassium metaphosphate (3.81 g, 17.93 mmol) in Dioxane (16 mL) and water (3.2 mL) was stirred at 80° C. for 4 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 9 (1.2 g, 77%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 6.88 (s, 1H), 6.84 (s, 1H), 6.05-5.89 (m, 1H), 5.10-4.89 (m, 3H), 4.33 (s, 2H), 4.32-4.30 (m, 1H), 3.68 (s, 3H), 3.29 (q, J=7.6, 6.7 Hz, 2H), 2.75 (dt, J=16.6, 6.1 Hz, 1H), 2.50-2.60 (m, 1H), 2.20-1.98 (m, 2H).
Intermediate 10
Step 1: Preparation of Compound 41
To a stirred mixture solution of compound 40 (5.0 g, 30.5 mmol) in AcOH (50 mL) was added benzyltrimethylammonium dichloroiodate (12.7 g, 36.5 mmol) and ZnCl2 (4.98 g, 36.5 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 15 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 41 (6.5 g) as a yellow solid. MS: 289.0 (M−H)−.
Step 2: Preparation of Compound 42
To a stirred mixture solution of compound 41 (1 g, 3.45 mmol) in MeOH (10 mL) was added SOCl2 (1.23 g, 10.34 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 42 (0.9 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.72 (d, J=8.5 Hz, 1H), 5.36 (dd, J=10.7, 6.0 Hz, 1H), 3.69 (s, 3H), 3.60-3.53 (m, 1H), 3.30 (d, J=6.6 Hz, 1H).
Step 3: Preparation of Compound 43
In a sealed tube, to a stirred mixture solution of compound 42 (4.8 g, 15.8 mmol), oxalic acid (2.84 g, 31.6 mmol), Pd(OAc)2 (0.18 g, 0.79 mmol) and Xantphos (0.91 g, 1.58 mmol) in DMF (50 mL) was added DIEA (4.1 g, 31.6 mmol) and Ac2O (3.22 g, 31.6 mmol) at 0° C., then the resulting mixture was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 43 (3.0 g, 86%) as a yellow solid.
Step 4: Preparation of Compound 44
To a stirred mixture solution of compound 43 (3.1 g, 13.95 mmol) in TFA (50 mL) was added NBS (1.1 g, 19.3 mmol) and CF3SO3H (2.09 g, 13.95 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 44 (2.4 g, 57.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 5.57 (dd, J=10.8, 6.3 Hz, 1H), 3.76-3.69 (m, 4H), 3.45 (dd, J=16.5, 6.4 Hz, 1H).
Step 5: Preparation of Compound 45
To a stirred mixture solution of compound 44 (2.4 g, 7.97 mmol) in THF (20 mL) was added 1.0 M BH3-THF solution (15.9 mL, 15.94 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 45 (1.1 g, 63.1%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (s, 1H), 7.14 (s, 1H), 5.47-5.39 (m, 1H), 5.15 (td, J=5.8, 1.8 Hz, 1H), 4.38 (d, J=5.8 Hz, 2H), 3.71 (s, 3H), 3.69-3.61 (m, 1H), 3.37 (dd, J=16.3, 6.2 Hz, 1H).
Step 6: Preparation of Intermediate 10
A mixture solution of compound 45 (1.1 g, 3.83 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (1.93 g, 11.49 mmol), Pd(dppf)Cl2 (0.28 g, 0.38 mmol) and potassium metaphosphate (2.44 g, 11.49 mmol) in Dioxane (10 mL) and water (2 mL) was stirred at 80° C. for 4 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 10 (0.6 g, 77%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.01 (s, 1H), 6.88 (s, 1H), 5.94 (ddt, J=16.9, 10.1, 6.7 Hz, 1H), 5.33 (dd, J=10.6, 5.7 Hz, 1H), 5.09-4.98 (m, 3H), 4.36 (d, J=4.8 Hz, 2H), 3.68 (d, J=1.7 Hz, 3H), 3.54 (dd, J=16.1, 10.6 Hz, 1H), 3.27 (d, J=6.5 Hz, 3H).
Intermediate 11
Step 1: Preparation of Compound 47
To a stirred mixture solution of compound 46 (4.50 g, 25.3 mmol) in AcOH (100 mL) was added benzyltrimethylammonium dichloroiodate (10.57 g, 30.4 mmol) and ZnCl2 (4.13 g, 30.4 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 15 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 47 (5.0 g) as a yellow solid. MS: 303.0 (M−H)−.
Step 2: Preparation of Compound 48
To a stirred mixture solution of compound 47 (5.0 g, 16.45 mmol) in MeOH (50 mL) was added SOCl2 (3.74 g, 32.89 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 48 (4.5 g, 86%) as a white solid.
Step 3: Preparation of Compound 49
In a sealed tube, to a stirred mixture solution of compound 48 (4.5 g, 14.15 mmol), oxalic acid (3.56 g, 28.3 mmol), Pd(OAc)2 (317 mg, 1.4 mmol) and Xantphos (816 mg, 1.4 mmol) in DMF (20 mL) was added DIEA (2.7 g, 21.22 mmol) and Ac2O (2.2 g, 21.22 mmol) at 0° C., then the resulting mixture was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 49 (3.3 g, 98%) as a white solid.
Step 4: Preparation of Compound 50
To a stirred mixture solution of compound 49 (3.3 g, 13.98 mmol) in TFA (50 mL) was added NBS (2.7 g, 15.38 mmol) and CF3SO3H (0.21 g, 1.4 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 50 (3.7 g, 76%) as a yellow solid.
Step 5: Preparation of Compound 51
To a stirred mixture solution of compound 50 (2 g, 6.35 mmol) in THF (10 mL) was added 1.0 M BH3-THF solution (12.7 mL, 12.69 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 51 (740 mg, 38.7%) as a colorless oil. MS: 283.1 (M−H2O)+.
Step 6: Preparation of Intermediate 11
A mixture solution of compound 51 (740 mg, 2.46 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (2.07 g, 12.30 mmol), Pd(dppf)Cl2 (0.18 g, 0.246 mmol) and potassium metaphosphate (1.04 g, 4.92 mmol) in Dioxane (10 mL) and water (2 mL) was stirred at 80° C. for 4 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 11 (0.61 g, 95%) as a colorless oil. MS: 245.2 (M−H2O)+.
Intermediate 12
Step 1: Preparation of Compound 53
A mixture solution of compound 52 (10.0 g, 47.4 mmol), NaH (5.7 g, 142.2 mmol) and dimethyl carbonate (6.4 g, 71.1 mmol) in THF (80 mL) was stirred at 65° C. for 1 hour under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with 3M HCl solution, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 53 (9.5 g, 74%).
Step 2: Preparation of Compound 54
A mixture solution of compound 53 (4.5 g, 16.8 mmol) and Et3SiH (11.7 g, 100.7 mmol) in TFA (70 mL) was stirred at 80° C. for 1 hour under N2 protected. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 54 (2.5 g, 58.8%) as a light brown solid. MS: 255.2 (M+H)+.
Step 3: Preparation of Compound 55
To a stirred mixture solution of compound 54 (2.5 g, 9.33 mmol) in THF (40 mL) was added LiHMDS (1.0 M, 18.66 mL, 18.7 mmol) at −78° C., then the resulting mixture was stirred at −40° C. for 1 hour. CH3I (10 mmol) was added to the above mixture solution at −78° C. and the resulting mixture was stirred at −40° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 55 (1.5 g, 63%) as a white solid. MS: 270.1 (M+H)+
Step 4: Preparation of Compound 56
In a sealed tube, to a stirred mixture solution of compound 55 (2.0 g, 7.46 mmol), oxalic acid (1.88 g, 14.93 mmol), Pd(OAc)2 (167 mg, 0.75 mmol) and Xantphos (432 mg, 0.75 mmol) in DMF (35 mL) was added DIEA (1.45 g, 11.19 mmol) and Ac2O (1.14 g, 11.19 mmol) at 0° C., then the resulting mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 56 (1.15 g, 66%) as a white solid. MS: 235.2 (M+H)+.
Step 5: Preparation of Compound 57
To a stirred mixture solution of compound 56 (800 mg, 3.42 mmol) in TFA (10 mL) was added NB S (730 mg, 4.1 mmol) and CF3SO3H (0.05 mL) at 0° C., then the resulting mixture was stirred at 10° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 57 (750 mg, 70%). MS: 314.3 (M+H)+.
Step 6: Preparation of Compound 58
To a stirred mixture solution of compound 57 (750 mg, 2.4 mmol) in THF (10 mL) was added 1.0 M BH3-THF solution (12 mL, 12 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 58 (650 mg) as a colorless oil.
Step 7: Preparation of Intermediate 12
A mixture solution of compound 58 (650 mg, 2.17 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (730 mg, 4.35 mmol), Pd(dppf)Cl2 (159 mg, 0.22 mmol) and potassium metaphosphate (923 mg, 4.35 mmol) in Dioxane (20 mL) and water (2 mL) was stirred at 100° C. for 2 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 12 (500 mg, 88%) as a colorless oil. MS: 261.2 (M+H)+.
Intermediate 13
Step 1: Preparation of Compound 60
A mixture solution of compound 59 (10 g, 27.0 mmol), bis(pinacolato)diboron (13.72 g, 54.0 mmol), Pd(dppf)Cl2 (1.98 g, 2.70 mmol) and potassium metaphosphate (7.95 g, 81 mmol) in Dioxane (200 mL) was stirred at 80° C. for 2 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 60 (10.5 g, 93%) as a yellow solid. MS: 418.3 (M+H)+.
Step 2: Preparation of Intermediate 13
To a stirred mixture solution of compound 60 (10.5 g, 25.2 mmol) in Ethanol (50 mL) and water (25 mL) was added mCPBA (5.2 g, 30.2 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 13 (7.5 g, 97%) as a white solid. MS: 308.2 (M+H)+.
Intermediate 14
Step 1: Preparation of Compound 62
To a stirred mixture solution of compound 61 (Trans-, 5.0 g, 4.7 mmol) in THF (50 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (69.2 mL, 173 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 62 (2 g, 49.6%) as a colorless oil.
Step 2: Preparation of Compound 63
To a stirred mixture solution of compound 62 (2.0 g) in THF (15 mL) was added NaH (124 mg, 5.2 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. Then TBDPSCl (1.2 g, 4.3 mmol) was added to the above mixture solution at 0° C. and the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 63 (110 mg, 72.1%) as a colorless oil.
Step 3: Preparation of Compound 64
To a stirred mixture solution of compound 63 (3 g, 8.5 mmol) in DCM (50 mL) was added PPh3 (3.3 g, 12.7 mmol) and CBr4 (4.2 g, 12.7 mmol), then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 64 (3.2 g, 91%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=6.9 Hz, 4H), 7.41 (dd, J=10.7, 7.0 Hz, 6H), 3.60-3.70 (m, 2H), 3.49 (dd, J=9.7, 6.5 Hz, 1H), 3.38 (t, J=8.8 Hz, 1H), 2.56 (h, J=8.0 Hz, 1H), 2.25 (d, J=7.0 Hz, 1H), 2.03 (q, J=11.1, 9.9 Hz, 1H), 1.85 (q, J=10.0, 9.2 Hz, 1H), 1.60-1.80 (m, 2H), 1.06 (s, 9H).
Step 4: Preparation of Compound 65
A mixture solution of Intermediate 13 (1 g, 3.25 mmol), compound 64 (1.4 g, 3.3 mmol) and Cs2CO3 (2.1 g, 6.5 mmol) in DMF (10 mL) was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 65 (1.4 g, 66.8%) as a colorless oil. MS: 644.4 (M+H)+.
Step 5: Preparation of Intermediate 14
To a stirred mixture solution of compound 65 (1.4 g, 2.2 mmol) in THF (20 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (0.87 mL, 2.2 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 14 (Trans-, 1.1 g, 82%) as a colorless oil. MS: 616.4 (M+H)+.
Intermediate 15
Step 1: Preparation of Compound 67
To a stirred mixture solution of compound 66 (5.0 g, 36.0 mmol) in DMF (80 mL) was added NaH (1.72 g, 43.2 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 0.5 hour. Then TBDPSCl (11.87 g, 43.2 mmol) was added to the above mixture solution at 0° C. and the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 67 (3.5 g, 25.8%) as a colorless oil.
Step 2: Preparation of Compound 68
A mixture solution of Intermediate B13 (1 g, 3.25 mmol), compound 67 (1.2 g, 3.3 mmol) and Cs2CO3 (2.1 g, 6.5 mmol) in DMF (10 mL) was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 68 (1.4 g, 73%) as a colorless oil. MS: 604.4 (M+H)+.
Step 3: Preparation of Intermediate 15
To a stirred mixture solution of compound 68 (1.4 g, 2.34 mmol) in THF (20 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (0.92 mL, 2.3 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 15 (1.05 g, 82%) as a colorless oil. MS: 576.3 (M+H)+.
Intermediate 16
Step 1: Preparation of Compound 70
To a stirred mixture solution of compound 69 (5 g, 32.3 mmol) in DMF (80 mL) was added NaH (1.6 g, 39.5 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 0.5 hour. Then TBDPSCl (10.9 g, 39.5 mmol) was added to the above mixture solution at 0° C. and the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 70 (3.0 g, 22.4%) as a colorless oil.
Step 2: Preparation of Compound 71
A mixture solution of Intermediate B13 (1 g, 3.25 mmol), compound 70 (1.2 g, 3.3 mmol) and Cs2CO3 (2.1 g, 6.5 mmol) in DMF (10 mL) was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 71 (1.5 g, 75%) as a colorless oil. MS: 618.4 (M+H)+.
Step 3: Preparation of Intermediate 16
To a stirred mixture solution of compound 71 (0.7 g, 1.2 mmol) in THF (20 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (0.92 mL, 2.3 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 16 (0.55 g, 82%) as a colorless oil. MS: 590.4 (M+H)+.
Intermediate 17
Step 1: Preparation of Compound 73
To a stirred mixture solution of compound 72 (Trans-, 5.0 g, 31.6 mmol) in THF (50 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (50.56 mL, 126.4 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 15 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 73 (500 mg, 15.5%) as a colorless oil.
Step 2: Preparation of Compound 74
To a stirred mixture solution of compound 73 (500 mg, 4.9 mmol) in DMF (10 mL) was added NaH (235 mg, 5.87 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 1 hour. Then TBDPSCl (1.61 g, 5.87 mmol) was added to the above mixture solution at 0° C. and the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 74 (400 mg, 23.9%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.64-7.58 (m, 4H), 7.49-7.38 (m, 6H), 4.40 (t, J=5.6 Hz, 1H), 3.59 (dd, J=10.7, 5.9 Hz, 1H), 3.50 (dd, J=10.7, 6.3 Hz, 1H), 3.27 (t, J=5.6 Hz, 1H), 3.18 (dt, J=11.2, 6.0 Hz, 1H), 0.98 (s, 9H), 0.90 (dt, J=11.4, 5.7 Hz, 1H), 0.84-0.76 (m, 1H), 0.25-0.35 (m, 2H).
Step 3: Preparation of Compound 75
To a stirred mixture solution of compound 74 (400 mg, 1.18 mmol) in DCM (10 mL) was added PPh3 (462 mg, 1.76 mmol) and CBr4 (584 mg, 1.76 mmol), then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 75 (250 mg, 52.8%) as a colorless oil.
Step 4: Preparation of Compound 76
A mixture solution of Intermediate B13 (190 mg, 0.62 mmol), compound 75 (249 mg, 0.618 mmol) and Cs2CO3 (604 mg, 1.86 mmol) in DMF (5 mL) was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 76 (320 mg, 82%) as a white solid. MS: 630.4 (M+H)+.
Step 5: Preparation of Intermediate 17
To a stirred mixture solution of compound 76 (320 mg, 0.51 mmol) in THF (5 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (0.5 mL, 0.51 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 17 (250 mg, 82%) as a white solid. MS: 602.4 (M+H)+.
Intermediate 18 Mixture
Step 1: Preparation of Compound 77-2
To a stirred mixture solution of compound 77-1 (20 g, 144.8 mmol) in MeOH (200 mL) was added a solution of Br2 (31.28 g, 173.76 mmol) in MeOH (100 mL) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water, filtered and purified by silica gel flash chromatography to afford compound 77-2 (20 g, 63.65%) as a brown solid. MS: 219.0 (M+H)+.
Step 2: Preparation of Compound 77-3
To a stirred mixture solution of compound 77-2 (10 g, 46.08 mmol) in MeOH (100 mL) was added NaBH4 (2.63 g, 69.12 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hour2. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 77-3 (7.9 g, 78.27%) as a yellow solid.
Step 3: Preparation of Compound 77-4
To a stirred mixture solution of compound 77-3 (7.9 g, 36.1 mmol), DMAP (4.41 g, 36.07 mmol) and imidazole (4.91 g, 72.14 mmol) in DCM (150 mL) was added TBDPSCl (8.91 g, 108.20 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 10 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 77-4 (2.2 g, 18.30%) as a yellow solid.
Step 4: Preparation of Compound 77
A suspension of compound 77-4 (2.2 g, 6.6 mmol), methyl 2,3-dibromopropanoate (1.79 g, 7.28 mmol) and K2CO3 (2.74 g, 19.8 mmol) in DMF (33 mL) was stirred at 50° C. for 5 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 77 (2.10 g, 76.2%) as a white solid. MS: 379.5 (M+H)+.
Step 5: Preparation of Compound 78
A mixture solution of compound 77 (1.5 g, 3.59 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (1.81 g, 10.78 mmol), Pd(dppf)Cl2 (260 mg, 0.32 mmol) and potassium metaphosphate (2.29 g, 10.78 mmol) in Dioxane (5 mL) and water (1 mL) was stirred at 80° C. for 2 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 78 (1.2 g, 88%) as a colorless oil.
Step 6: Preparation of Intermediate 18 Mixture
A mixture solution of compound 78 (1.2 g, 3.17 mmol), 1.0 M TBAF solution in THF (3.17 mL, 3.17 mmol) in THF (15 mL) was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 18 mixture (600 mg, 71.6%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 6.71 (d, J=31.7 Hz, 1H), 6.64 (s, 1H), 6.01-5.81 (m, 1H), 5.15 (d, J=2.8 Hz, 1H), 5.10-4.97 (m, 2H), 4.40-4.50 (m 1H), 4.33 (d, J=9.6 Hz, 2H), 4.23 (dd, J=11.8, 2.6 Hz, 1H), 3.90-1.05 (m, 1H), 3.31 (t, J=6.9 Hz, 1H), 3.24 (t, J=5.6 Hz, 1H).
Intermediate 19
Step 1: Preparation of Compound 79-1
To a stirred mixture solution of compound 79 (641 mg, 4.92 mmol) in THF (15 mL) was added NaH (124 mg, 5.2 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. Then TBDPSCl (1.2 g, 4.3 mmol) was added to the above mixture solution at 0° C. and the resulting mixture was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 79-1 (1.31 g, 72.1%) as a colorless oil.
Step 2: Preparation of Compound 79-2
To a stirred mixture solution of compound 79-1 (3.11 g, 8.46 mmol) in DCM (50 mL) was added PPh3 (3.3 g, 12.7 mmol) and CBr4 (4.2 g, 12.7 mmol), then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 79-2 (3.31 g, 91%) as a colorless oil.
Step 3: Preparation of Compound 79-3
A mixture solution of Intermediate B13 (1 g, 3.25 mmol), compound 79-2 (1.4 g, 3.3 mmol) and Cs2CO3 (2.1 g, 6.5 mmol) in DMF (10 mL) was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 79-3 (1.4 g, 67%) as a colorless oil. MS: 658.5 (M+H)+.
Step 4: Preparation of Intermediate 19
To a stirred mixture solution of compound 79-3 (1.43 g, 2.17 mmol) in THF (20 mL) was added 2.5 M lithium aluminum tetrahydride solution in THF (0.87 mL, 2.2 mmol) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 19 (1.12 g, 82%) as a colorless oil. MS: 630.8 (M+H)+.
Intermediate 20
The title compound Intermediate 20 was prepared in analogy to the preparation of Intermediate 13 by using compound 32 as a start material.
Intermediate 21
Step 1: Preparation of Compound 80-1
To a stirred mixture solution of 1-bromo-3-methoxy-5-toluene (40.2 g, 200 mmol) in CCl4 (300 mL) was added NBS (39.1 g, 220 mmol) and AIBN (3.28 g, 20 mmol), then the resulting mixture was stirred at 80° C. for 13 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-1 (54 g, 96%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ (ppm) 7.27-6.52 (m, 3H), 4.38 (s, 2H), 3.80 (s, 3H).
Step 2: Preparation of Compound 80-2
To a stirred mixture solution of compound 80-1 (20.0 g, 71.4 mmol) in ACN (150 mL) was added trimethylcyanosilane (108 mmol) at 0° C. and the resulting mixture was stirred at 20° C. for 0.5 hour. Then 1.0 M TBAF solution in THF (108 mL, 108 mmol) was stirred at 50° C. for 8 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-2 (12.54 g, 78%) as a yellow oil. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 7.04 (s, 1H), 7.00 (s, 1H), 6.79 (s, 1H), 3.793 (s, 3H), 3.68 (s, 2H).
Step 3: Preparation of Compound 80-3
A mixture solution of compound 80-2 (1.2 g, 5.31 mmol), Raney Nickel (1.0 g) and NH3HO2 (8 mL) in MeOH (8 mL) was stirred at 20° C. for 13 hours under H2 50 psi pressure. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to afford compound 80-3 (420 mg, 34.4%) as a yellow oil. MS: 230.0 (M+H)+.
Step 4: Preparation of Compound 80-4
To a stirred mixture solution of compound 80-3 (420 mg, 1.83 mmol) in formic acid (6 mL) was added paraformaldehyde (66 mg, 0.733 mmol) at 20° C. and the resulting mixture was stirred at 50° C. for 16 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-4 (177 mg, 40.1%) as a red oil. MS: 256, 258 (M+H)+. 1H-NMR (CDCl3, 400 MHz): δ (ppm) 6.95 (s, 1H), 6.61 (s, 1H), 3.75 (s, 3H), 3.48 (s, 2H), 2.88 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H), 2.48 (s, 3H).
Step 5: Preparation of Compound 80-5
A mixture solution of compound 80-4 (1.65 g, 6.82 mmol) in 40% HBr solution (25 mL) was stirred at 100° C. for 36 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo, cooled and filtered to afford compound 80-5 (2.11 g) as a yellow solid. MS: 228.3 (M+H)+.
Step 6: Preparation of Compound 80-6
To a stirred mixture solution of compound 80-5 (15.61 g, 50.51 mmol) in THF (150 mL) and H2O (150 mL) was added Boc2O (11.02 g, 50.5 mmol) and TEA (24.85 mL, 177 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-6 (10.64 g, 64.2%) as a yellow solid.
Step 7: Preparation of Compound 80-7
A mixture solution of compound 80-6 (1.0 g, 3.05 mmol), compound 70 (1.19 g, 3.05 mmol) and Cs2CO3 (1.49 g, 4.57 mmol) in DME (10 mL) was stirred at 100° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-7 (1.3 g, 66.8%) as a colorless oil. MS: 638.3 (M+H)+.
Step 8: Preparation of compound 80-8 In a sealed tube, to a stirred mixture solution of compound 80-7 (1.3 g, 2.03 mmol), oxalic acid (0.37 g, 4.07 mmol), Pd(OAc)2 (0.046 g, 0.204 mmol) and Xantphos (0.12 g, 0.20 mmol) in DME (10 mL) was added DIEA (0.26 g, 2.04 mmol) and Ac2O (0.42 g, 4.07 mmol) at 0° C., then the resulting mixture was stirred at 100° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-8 (77.6 mg, 63.3%) as a colorless oil. MS: 602.2 (M+H)+.
Step 9: Preparation of Intermediate 21
To a stirred mixture solution of compound 80-8 (1.2 g, 1.99 mmol) in THF (10 mL) was added 1.0 M BH3-THF solution (3.0 mL, 3.0 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 21 (1.0 g, 85%) as a colorless oil. MS: 590.4 (M+H)+.
Intermediate 22
Step 1: Preparation of Compound 80-9
To a stirred mixture solution of 5-bromo-2,3-dihydrobenzofuran-7-carboxylic acid (2.5 g, 10.29 mmol) in THF (30 mL) was added 1.0 M BH3-THF solution (15.4 mL, 15.4 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80-9 (2.2 g, 93%) as a colorless oil.
Step 2: Preparation of Intermediate 22
A mixture solution of compound 80-9 (2.2 g, 9.60 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (4.84 g, 28.8 mmol), Pd(dppf)Cl2 (0.7 g, 0.96 mmol) and potassium metaphosphate (6.12 g, 28.8 mmol) in Dioxane (15 mL) and water (3 mL) was stirred at 80° C. for 2 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford Intermediate 22 (1.5 g, 82%) as a colorless oil.
Step 1: Preparation of Compound 80
To a stirred mixture solution of Intermediate 1 (450 mg, 0.84 mmol) and Intermediate 4 (242 mg, 0.84 mmol) in THF (10 mL) was added PPh3 (329 mg, 1.26 mmol) and DIAD (254 mg, 1.26 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 80 (600 mg, 89%) as a yellow oil. MS: 809.4 (M+H)+.
Step 2: Preparation of Compound 81
To a stirred mixture solution of compound 80 (520 mg, 0.643 mmol) in DCM (200 mL) was added Grubbs' II reagent (109 mg, 0.13 mmol) under N2 protected, then the resulting mixture was stirred at 20° C. for 12 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 81 (401 mg, 80%) as a yellow solid. MS: 781.4 (M+H)+.
Step 3: Preparation of Compound 82
To a stirred mixture solution of compound 81 (220 mg, 0.28 mmol) in AcOH (5 mL) was added Zn (92 mg, 1.41 mmol) under N2 protected, then the resulting mixture was stirred at 70° C. for 0.5 hour. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 82 (130 mg, 65.5%) as a white solid. MS: 704.4 (M+H)+.
Step 4: Preparation of Compound 83
A mixture solution of compound 82 (130 mg, 0.18 mmol) and LiOH (37 mg, 0.9 mmol) in THF (1 mL) and water (1 mL) was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was adjusted pH to 5, filtered and dried to afford compound 83 (100 mg, 76.9%) as a white solid. MS: 677.3 (M+H)+.
Step 5: Preparation of Compound I-1 and Compound I-2
A mixture solution of compound 83 (100 mg, 0.15 mmol) in TFA (5 mL) was stirred at 70° C. for 0.5 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-1 and Compound I-2.
Compound I-1 (white solid, 20 mg, 31%). MS: 436.9 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (s, 1H), 9.88 (s, 1H), 8.08 (s, 1H), 7.44 (s, 1H), 6.40 (s, 2H), 5.78-5.68 (m, 1H), 5.62 (d, J=9.0 Hz, 1H), 4.92 (br, 2H), 4.50-4.42 (m, 4H), 4.23 (br, 2H), 3.38 (br, 2H), 2.34 (br, 2H).
Compound I-2 (white solid, 20 mg, 31%). MS: 436.9 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (s, 1H), 9.88 (s, 1H), 8.35 (s, 1H), 7.45 (s, 1H), 6.40 (s, 2H), 5.75 (dt, J=14.8, 7.1 Hz, 1H), 5.51 (dt, J=15.3, 7.4 Hz, 1H), 4.93 (br, 2H), 4.72 (d, J=5.7 Hz, 2H), 4.40 (br, 2H), 4.25 (br, 2H), 3.24 (d, J=7.1 Hz, 2H), 2.44 (br, 2H).
Step 1: Preparation of Compound 84
A mixture solution of compound 83 (250 mg, 0.36 mmol) and Pd/C (100 mg) in EA (10 mL) under H2 atmosphere was stirred at 25° C. for 4 hours. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to afford compound 84 (240 mg, 96%) as a white solid. MS: 707.4 (M+H)+.
Step 2: Preparation of Compound 85
A mixture solution of compound 84 (120 mg, 0.18 mmol) and LiOH (37 mg, 0.9 mmol) in THF (2 mL) and water (2 mL) was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was adjusted pH to 5, filtered and dried to afford compound 85 (70 mg, 60.8%) as a white solid. MS: 679.3 (M+H)+.
Step 3: Preparation of Compound I-3
A mixture solution of compound 84 (70 mg, 0.1 mmol) in TFA (5 mL) was stirred at 70° C. for 0.5 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-3 (white solid, 21 mg, 46.7%). MS: 438.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 9.95 (s, 1H), 7.89 (s, 1H), 7.27 (s, 1H), 6.35 (s, 2H), 4.94 (br, 2H), 4.42 (br, 2H), 4.23 (d, J=5.2 Hz, 4H), 2.71 (d, J=7.3 Hz, 2H), 1.74 (br, 2H), 1.35-1.29 (m, 4H).
The title Compound I-4 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 5 as a start material. MS: 393.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.30 (s, 1H), 7.40 (s, 1H), 6.42 (s, 2H), 5.79-5.69 (m, 1H), 5.56-5.45 (m, 1H), 4.91 (s, 2H), 4.72 (s, 2H), 4.34 (s, 2H), 3.22 (d, J=7.1 Hz, 2H), 3.04 (s, 3H), 2.44 (s, 2H).
The title Compound I-5 was prepared in analogy to the preparation of Compound I-3. MS: 395.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.82 (s, 1H), 7.20 (s, 1H), 6.43 (s, 2H), 4.93 (s, 2H), 4.37 (s, 2H), 4.23 (d, J=7.1 Hz, 2H), 3.02 (s, 3H), 2.70 (br, 2H), 1.75 (br, 2H), 1.31 (br, 4H).
The title Compound I-6 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 6 as a start material. MS: 475.9 (M+H)+.
The title Compound I-6 was prepared in analogy to the preparation of Compound I-2 by using Intermediate 1 and Intermediate 6 as a start material. MS: 475.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.46 (s, 1H), 6.40 (s, 2H), 5.78 (dd, J=15.4, 7.5 Hz, 1H), 5.56-5.46 (m, 1H), 4.93 (s, 2H), 4.71 (br, 2H), 4.41 (br, 2H), 3.86 (t, J=5.8 Hz, 2H), 3.56 (br, 2H), 3.45 (d, J=6.0 Hz, 2H), 3.24 (d, J=6.9 Hz, 2H), 3.05 (br, 2H), 2.44 (br, 2H), 1.98 (br, 2H), 1.75-1.85 (m, 2H).
The title Compound I-8 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 7 as a start material. MS: 379.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.73 (s, 1H), 7.00 (s, 1H), 6.41 (s, 2H), 5.69 (t, J=8.6 Hz, 1H), 5.60 (dt, J=10.7, 6.6 Hz, 1H), 4.79 (br, 2H), 4.41 (t, J=8.5 Hz, 2H), 4.22 (br, 2H), 3.28 (d, J=6.6 Hz, 2H), 3.21 (d, J=7.6 Hz, 2H), 2.84 (t, J=6.2 Hz, 2H), 2.26 (d, J=8.4 Hz, 2H).
The title Compound I-9 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 7 as a start material. MS: 379.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.04 (s, 1H), 7.01 (s, 1H), 6.43 (s, 2H), 5.74 (dt, J=15.0, 7.2 Hz, 1H), 5.43 (dt, J=15.2, 7.4 Hz, 1H), 4.79 (s, 2H), 4.71 (d, J=6.0 Hz, 2H), 4.24 (d, J=5.1 Hz, 2H), 3.36 (d, J=6.4 Hz, 2H), 3.09 (d, J=7.1 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.43 (d, J=5.7 Hz, 2H).
The title Compound I-10 was prepared in analogy to the preparation of Compound I-3. MS: 381.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.57 (s, 1H), 6.86 (s, 1H), 6.39 (s, 2H), 4.80 (d, J=5.5 Hz, 2H), 4.21 (d, J=10.9 Hz, 4H), 3.43 (d, J=3.6 Hz, 2H), 2.84 (t, J=6.5 Hz, 2H), 2.63 (br, 2H), 1.68 (br, 2H), 1.46-1.24 (m, 4H).
The title Compound I-11 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 8 as a start material. MS: 379.10 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.70 (s, 1H), 7.01 (s, 1H), 6.42 (s, 2H), 5.73-5.57 (m, 2H), 4.79 (s, 2H), 4.42 (t, J=7.2 Hz, 2H), 4.18 (s, 2H), 3.30-3.27 (m, 2H), 3.18-3.17 (m, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.32-2.24 (m, 2H).
The title Compound I-12 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 8 as a start material. MS: 379.10 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.01 (s, 1H), 7.01 (s, 1H), 6.42 (s, 2H), 5.77-5.69 (m, 1H), 5.47-5.39 (m, 1H), 4.78 (s, 2H), 4.72 (s, 2H), 4.12 (br, 2H), 3.28 (s, 2H), 3.05 (d, J=6.8 Hz, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.46-2.39 (m, 2H).
The title Compound I-13 was prepared in analogy to the preparation of Compound I-3. MS: 381.00 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.55 (s, 1H), 6.88 (s, 1H), 6.46 (s, 2H), 4.81 (s, 2H), 4.25 (t, J=6.4 Hz, 2H), 4.17 (s, 2H), 3.28-3.27 (m, 2H), 2.92 (t, J=5.6 Hz, 2H), 2.59-2.56 (m, 2H), 1.69-1.67 (m, 2H), 1.41-1.68 (m, 4H).
The title Compound I-14 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 9 as a start material. MS: 423.70 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.89 (s, 1H), 6.80 (s, 1H), 6.42 (s, 2H), 5.64 (s, 1H), 5.35-5.045 (m, 1H), 4.75-4.43 (m, 5H), 3.05 (d, J=7.2 Hz, 2H), 2.70-2.50 (m, 2H), 2.39 (s, 2H), 2.05-1.92 (m, 3H).
The title Compound I-15 was prepared in analogy to the preparation of Compound I-3. MS: 425.70 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.38 (s, 1H), 6.66 (s, 1H), 6.36 (s, 2H), 4.74 (d, J=16.2 Hz, 3H), 4.21 (t, J=7.0 Hz, 2H), 2.67 (d, J=16.5 Hz, 1H), 2.58 (br, 2H), 2.54 (d, J=7.7 Hz, 1H), 1.95-2.05 (m, 2H), 1.73 (br, 1H), 1.62 (br, 1H), 1.30-1.42 (m, 2H), 1.28 (br, 2H).
The title Compound I-16 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 10 as a start material. MS: 410.10 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.84 (s, 1H), 7.93 (d, J=10.7 Hz, 1H), 6.98 (s, 1H), 6.37 (s, 2H), 5.60-5.75 (dm, J=14.6, 7.1 Hz, 1H), 5.40-5.50 (m, 1H), 5.17 (dd, J=10.7, 6.4 Hz, 1H), 4.72 (br, 3H), 4.69-4.65 (m, 1H), 3.49-3.44 (m, 2H), 3.20-3.10 (m, 2H), 2.88-2.57 (m, 1H), 2.35-2.45 (m, J=5.9 Hz, 1H).
The title Compound I-17 was prepared in analogy to the preparation of Compound I-3. MS: 412.10 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.39 (s, 1H), 6.81 (s, 1H), 6.34 (s, 2H), 5.14 (dd, J=10.6, 6.2 Hz, 1H), 4.75 (s, 2H), 4.15-4.25 (m, 2H), 3.14 (dd, J=16.3, 6.1 Hz, 1H), 2.58 (d, J=5.8 Hz, 2H), 1.65-1.75 (m, 2H), 1.41-1.26 (m, 5H).
The title Compound I-18 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 11 as a start material. MS: 424.30 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.91 (s, 1H), 6.88 (s, 1H), 6.37 (s, 1H), 5.68-5.61 (m, 1H), 5.39 (dd, J=15.2, 7.4 Hz, 1H), 4.70 (s, 2H), 4.28 (d, J=10.7 Hz, 1H), 4.10 (dd, J=10.5, 6.7 Hz, 1H), 3.49 (d, J=5.7 Hz, 2H), 3.28 (br, 2H), 3.01 (d, J=7.2 Hz, 1H), 2.89 (br, 2H), 2.53 (br, 2H), 2.41 (d, J=7.6 Hz, 2H).
The title Compound I-19 was prepared in analogy to the preparation of Example 3 by using Compound I-18 as a start material. MS: 426.30 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.88 (s, 1H), 7.40 (s, 1H), 6.74 (s, 1H), 6.33 (s, 2H), 4.72 (q, J=14.2 Hz, 2H), 4.28 (d, J=10.3 Hz, 2H), 4.22 (br, 1H), 4.04 (br, 1H), 2.86 (br, 3H), 2.54 (d, J=10.4 Hz, 2H), 1.73-1.21 (m, 6H).
The title Compound I-20A and Compound I-20B mixture was prepared in analogy to the preparation of Compound I-1 and Compound I-3 by using Intermediate 1 and Intermediate 18 as a start material. MS: 428.20 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (d, J=5.8 Hz, 1H), 7.14 (s, 1H), 6.49 (s, 1H), 6.39 (s, 2H), 4.97 (d, J=38.1 Hz, 1H), 4.82-4.71 (m, 1H), 4.36 (d, J=11.8 Hz, 1H), 4.16 (d, J=15.0 Hz, 3H), 2.61 (d, J=18.6 Hz, 2H), 1.75-1.62 (m, 3H), 1.34-1.22 (m, 5H).
The title Compound I-21 was prepared in analogy to the preparation of Example 1 by using Intermediate 1 and Intermediate 12 as a start material. MS: 437.00 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.84 (s, 1H), 7.93 (s, 1H), 6.95 (s, 1H), 6.37 (s, 2H), 5.65-5.75 (m, 1H), 5.35-5.48 (m, 1H), 4.75 (s, 2H), 4.70 (s, 2H), 3.19 (d, J=16.2 Hz, 1H), 3.07 (t, J=7.0 Hz, 2H), 2.71 (d, J=16.4 Hz, 1H), 2.62 (d, J=16.3 Hz, 1H), 2.41 (d, J=6.1 Hz, 2H), 1.23 (s, 3H).
Step 1: Preparation of Compound 86
The title compound 86 was prepared in analogy to the preparation of compound 81 by using Intermediate 1 and Intermediate 7 as a start material.
Step 2: Preparation of Compound 87
A mixture solution of compound 86 (500 mg, 629 mmol) in TFA (10 mL) was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford compound 87 (300 mg) as a solid.
Step 3: Preparation of Compound 88
A mixture solution of compound 87 (300 mg, 0.44 mmol), tert-butyl 2-bromoacetate (85 mg, 0.44 mmol) and 2,2,6,6-tetramethylpiperidine (246 mg, 1.74 mmol) in DMF (5 mL) was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 88 (120 mg, 40.0%) as a yellow solid. MS: 689.0 (M+H)+.
Step 4: Preparation of Compound 89
To a stirred mixture solution of compound 88 (110 mg, 0.16 mmol) in AcOH (7.5 mL) was added Zn (52.2 mg, 0.80 mmol) under N2 protected, then the resulting mixture was stirred at 80° C. for 0.5 hour. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 89 (52 mg, 53.1%) as a colorless oil. MS: 613.0 (M+H)+.
Step 5: Preparation of Compound I-22
A mixture solution of compound 89 (52 mg) in TFA (5 mL) was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-22 (7.28 mg, 19.5%) as a white solid. MS: 437.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6)) δ 9.92 (s, 1H), 8.08 (s, 1H), 6.99 (s, 1H), 6.42 (s, 2H), 5.70-7.80 (m, 1H), 5.40-4.50 (m, 1H), 4.80 (nr, 2H), 4.73 (br, 2H), 4.36 (br, 2H), 4.11 (br, 2H), 3.47 (br, 2H), 3.10 (d, J=7.2 Hz, 2H), 2.89 (d, J=6.3 Hz, 2H), 2.44 (d, J=6.0 Hz, 2H).
The title Compound I-23 was prepared in analogy to the preparation of Compound I-3 by using compound 89 as a start material. MS: 439.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.58 (s, 1H), 6.83 (s, 1H), 6.36 (s, 2H), 4.81 (s, 2H), 4.32 (s, 2H), 4.23 (t, J=6.6 Hz, 2H), 4.07 (s, 2H), 3.50-3.60 (m, 2H), 2.94 (d, J=6.5 Hz, 2H), 2.62 (d, J=6.1 Hz, 2H), 2.38-2.50 (m, 1H), 1.69 (br, 2H), 1.38 (t, J=7.2 Hz, 2H), 1.31 (br, 2H).
The title Compound I-24 was prepared in analogy to the preparation of Compound I-1 and Compound I-22 by using Intermediate 1 and Intermediate 8 as a start material. MS: 437.2
The title Compound I-25 was prepared in analogy to the preparation of Compound I-23 by using Intermediate 1 and Intermediate 8 as a start material. MS: 439.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.43 (s, 1H), 6.76 (s, 1H), 6.35 (s, 2H), 4.77 (s, 2H), 4.28-4.20 (m, 2H), 3.65-3.75 (m, 2H), 3.35-3.30 (m, 2H), 2.83-2.73 (m, 4H), 2.56-2.51 (m, 2H), 1.65 (br, 2H), 1.43-1.25 (m, 4H).
The title Compound I-26 was prepared in analogy to the preparation of Compound I-22 and Compound I-3 by using compound 87 and ethyl 2-bromo-2-methylpropanoate as a start material. MS: 467.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.57 (s, 1H), 6.91 (s, 1H), 6.37 (s, 2H), 4.82 (, 2H), 4.32 (s, 2H), 4.15-4.25 (m, 2H), 3.30 (m, 2H), 2.95 (m, 2H), 2.66 (m, 2H), 1.69 (br, 2H), 1.51 (s, 6H), 1.35 (m, 4H).
The title Compound I-27 was prepared in analogy to the preparation of Compound I-22 and Compound I-3 by using compound 87 and ethyl 2,2′-dimethyl-3-bromopropionate as a start material. MS: 481.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.67 (s, 1H), 6.87 (s, 1H), 6.38 (s, 2H), 4.82 (m, 2H), 4.26-4.32 (m, 4H), 3.60 (m, 2H), 3.26 (br, 2H), 2.95 (br, 2H), 2.49-2.62 (m, 2H), 1.70 (br, 2H), 1.31-1.42 (m, 4H), 1.21 (s, 6H).
The title Compound I-28 was prepared in analogy to the preparation of Compound I-1 and Compound I-3 by using Intermediate 3 and Intermediate 7 as a start material. MS: 383.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.50 (br, 1H), 7.37 (s, 1H), 6.43 (s, 2H), 4.80 (s, 2H), 4.41 (t, J=6.4 Hz, 2H), 4.23 (s, 2H), 3.34 (br, J=6.1 Hz, 2H), 2.83 (br, 2H), 2.61-2.53 (m, 2H), 1.56-1.48 (m, 4H), 1.31 (s, 4H).
Step 1: Preparation of Compound 90
To a stirred mixture solution of compound 6 (0.5 g, 0.97 mmol) and Intermediate 14 (0.61 g, 0.97 mmol) in THF (15 mL) was added PPh3 (0.38 g, 1.46 mmol) and DIAD (295 mg, 1.46 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 90 (0.85 g, 79%) as a yellow solid.
Step 2: Preparation of Compound 91
A mixture solution of compound 90 (0.85 g, 0.77 mmol), 1.0 M TBAF solution in THF (0.77 mmol, 0.76 mL) in THF (10 mL) was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 91 (0.55 g, 82%) as a yellow solid. MS: 872.4 (M+H)+.
Step 3: Preparation of Compound 92
To a stirred mixture solution of compound 91 (0.55 g, 0.63 mmol) in DCM (20 mL) was added mCPBA (0.13 g, 0.76 mmol) at 0° C., then the resulting mixture was stirred at 5° C. for 1 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 92 (0.53 g) as a yellow solid. MS: 888.4 (M+H)+.
Step 4: Preparation of Compound 93
A mixture solution of compound 92 (0.55 g, 0.63 mmol) and Cs2CO3 (606 mg, 1.86 mmol) in THF (10 mL) was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with DCM. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 93 (0.16 g, 31.3%) as a yellow solid. MS: 825.4 (M+H)+.
Step 5: Preparation of Compound 94
To a stirred mixture solution of compound 93 (160 mg, 0.19 mmol) in AcOH (5 mL) was added Zn (63.4 mg, 0.97 mmol) under N2 protected, then the resulting mixture was stirred at 70° C. for 0.5 hour. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 94 (50 mg, 34.4%) as a white solid. MS: 749.4 (M+H)+.
Step 6: Preparation of Compound I-29
A mixture solution of compound 94 (50 mg, 0.067 mmol) in TFA (5 mL) was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-29 (13.45 mg, 49.3%) as a white solid. MS: 507.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.50 (s, 1H), 6.68 (s, 1H), 6.43 (s, 2H), 4.94 (d, J=13.8 Hz, 1H), 4.77 (br, 1H), 4.58 (dd, J=21.7, 13.5 Hz, 2H), 4.19 (br, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.04 (d, J=13.6 Hz, 1H), 3.93 (br, 1H), 3.30-3.38 (m, 2H), 2.70-2.85 (m, 2H), 2.30-2.40 (m, 8.9 Hz, 2H), 1.89 (q, J=9.4, 8.7 Hz, 1H), 1.85-1.73 (m, 1H), 1.66 (d, J=8.9 Hz, 2H).
The title Compound I-30 was prepared in analogy to the preparation of Compound I-29 by using Intermediate 6 and Intermediate 15 as a start material. MS: 369.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.83 (s, 1H), 6.72 (s, 1H), 6.45 (s, 2H), 4.85 (s, 2H), 4.44 (s, 2H), 4.34 (t, J=6.9 Hz, 2H), 4.18 (s, 1H), 4.18 (d, J=9.0 Hz, 1H), 3.31 (s, 2H), 2.71 (t, J=6.4 Hz, 2H), 1.86 (s, 2H).
The title Compound I-31 was prepared in analogy to the preparation of Compound I-29 by using Intermediate 6 and Intermediate 16 as a start material. MS: 383.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.82 (s, 1H), 6.69 (s, 1H), 6.42 (s, 2H), 4.80 (s, 2H), 4.56 (d, J=6.8 Hz, 2H), 4.35 (t, J=6.7 Hz, 2H), 4.18 (d, J=4.9 Hz, 2H), 3.31 (d, J=6.7 Hz, 2H), 2.72 (t, J=6.4 Hz, 2H), 1.63 (d, J=7.5 Hz, 2H), 1.53 (d, J=7.5 Hz, 2H).
The title Compound I-32 was prepared in analogy to the preparation of Compound I-29 by using Intermediate 6 and Intermediate 17 as a start material. MS: 394.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.52 (s, 1H), 6.73 (s, 1H), 6.42 (s, 2H), 4.97 (d, J=13.9 Hz, 1H), 4.88 (d, J=11.4 Hz, 1H), 4.55-4.67 (m, 2H), 4.17 (br, 2H), 3.90-4.00 (m, J=12.8, 4.4 Hz, 1H), 3.53-3.45 (m, 1H), 3.32-3.13 (m, 2H), 2.65-2.75 (m, 2H), 1.17 (br, 1H), 0.94 (br, 1H), 0.58-0.40 (m, 2H).
The title Compound I-33 was prepared in analogy to the preparation of Compound I-29 by using Intermediate 6 and Intermediate 19 as a start material. MS: 422.5 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.76 (s, 1H), 6.80 (s, 1H), 4.94 (s, 2H), 4.82-4.78 (m, 1H), 4.45-4.38 (m, 1H), 4.26 (br, 3H), 3.50-3.40 (m, 2H), 2.91 (t, J=6.5 Hz, 2H), 2.12 (br, 1H), 1.93 (br, 1H), 1.80-1.45 (m, 7H).
Step 1: Preparation of Compound 95
To a stirred mixture solution of Intermediate 2 (1.25 g, 4.45 mmol) and Intermediate 7 (0.9 g, 2.97 mmol) in THF (30 mL) was added PPh3 (1.56 g, 5.93 mmol) and DIAD (0.90 g, 4.45 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 95 (1.3 g, 78%) as a yellow oil. MS: 509.1 (M+H)+.
Step 2: Preparation of Compound 96
To a stirred mixture solution of compound 95 (1.3 g, 2.3 mmol), DMAP (12 g, 98.2 mmol) and TEA (0.465 g, 4.60 mmol) in DCM (10 mL) was added bis (4-methoxybenzyl) amine (0.65 g, 2.53 mmol) at 0° C., then the resulting mixture was stirred at 20° C. for 7 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 96 (330 mg, 18.3%) as a yellow oil. MS: 786.1 (M+H)+.
Step 3: Preparation of Compound 97
To a stirred mixture solution of butyl-3-ene-1-ol (605 mg, 8.39 mmol) in THF (3 mL) was added NaH (50.4 mg, 1.26 mmol) at 25° C., then the resulting mixture was stirred at 25° C. for 35 mins. A solution of compound 96 (330 mg, 0.42 mmol) in THF (3 mL) was added to the above mixture solution at 0° C., then the resulting mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 97 (320 mg, 93%) as a yellow oil. MS: 822.1 (M+H)+.
Step 4: Preparation of Compound 98
To a stirred mixture solution of compound 97 (320 mg, 0.389 mmol) in DCM (100 mL) was added Grubbs' II reagent (66.1 mg, 0.078 mmol) under N2 protected, then the resulting mixture was stirred at 20° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 98 (190 mg, 61.5%) as a yellow oil. MS: 794.4 (M+H)+.
Step 5: Preparation of Compound 99
To a stirred mixture solution of compound 98 (190 mg, 0.24 mmol) in AcOH (10 mL) and water (1 mL) was added Zn (78 mg, 1.2 mmol) under N2 protected, then the resulting mixture was stirred at 70° C. for 3 hours. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 99 (50 mg, 29.1%) as a yellow oil. MS: 718.5 (M+H)+.
Step 6: Preparation of Compound I-34
A mixture solution of compound 99 (50 mg, 0.07 mmol) in TFA (5 mL) was stirred at 80° C. for 3 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-34 (19 mg, 71.9%) as a white solid. MS: 378.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.94 (s, 2H), 7.22 (s, 1H), 6.96 (d, J=5.2 Hz, 1H), 6.09 (s, 1H), 5.69 (dd, J=15.2, 6.8 Hz, 1H), 4.95-5010 (m, 1H), 4.92 (d, J=5.3 Hz, 2H), 4.34 (br, 2H), 4.22 (br, 2H), 3.19 (br, 4H), 2.83 (d, J=6.4 Hz, 2H), 2.37 (br, 2H).
Step 1: Preparation of Compound 100
To a stirred mixture solution of compound 99 (350 mg, 0.51 mmol 1) in MeOH (10 mL) was added acetone (590 mg, 10.16 mmol) at 20° C., then the resulting mixture was stirred at 25° C. for 1 hour. Then NaCNBH3 (63.9 mg, 1.02 mmol) was added to the above mixture solution and the resulting mixture was stirred at 25° C. for 13 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 100 (270 mg) as a yellow oil. MS: 617.0 (M+H)+.
Step 2: Preparation of Compound 101
To a stirred mixture solution of compound 100 (70 mg, 0.44 mmol) in AcOH (7.5 mL) was added Zn (143 mg, 2.19 mmol) under N2 protected, then the resulting mixture was stirred at 80° C. for 0.5 hour. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 101 (90 mg, 27%) as a yellow oil. MS: 541.0 (M+H)+.
Step 3: Preparation of Compound 102
A mixture solution of compound 101 (90 mg, 0.12 mmol) and Pd/C (126 mg) in MeOH (5 mL) and EA (5 mL) under H2 atmosphere was stirred at 25° C. for 14 hours. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to afford compound 102 (39 mg, 60.8%) as a yellow solid. MS: 543.0 (M+H)+.
Step 4: Preparation of Compound I-35
A mixture solution of compound 102 (39 mg, 0.072 mmol) in TFA (7.5 mL) was stirred at 80° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-35 (12.49 mg, 39.7%) as a white solid. MS: 423.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.59 (s, 1H), 6.89 (s, 1H), 6.41 (s, 2H), 4.85 (d, J=14.3 Hz, 1H), 4.79 (d, J=14.4 Hz, 1H), 4.31 (d, J=5.8 Hz, 2H), 4.27-4.14 (m, 2H), 3.68-3.50 (m, 3H), 3.35-3.11 (m, 3H), 3.04-2.85 (m, 2H), 2.64 (br 2H), 1.68 (br, 2H), 1.42-1.20 (m, 7H).
The title Compound I-36 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and paraformaldehyde as a start material. MS: 395.5 (M+H)+.
The title Compound I-37 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and cyclobutanone as a start material. MS: 435.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.59 (s, 1H), 6.89 (s, 1H), 6.40 (s, 2H), 4.87 (d, J=14.4 Hz, 1H), 4.75 (d, J=14.5 Hz, 1H), 4.40 (d, J=15.4 Hz, 1H), 4.26 (br, 1H), 4.15 (d, J=9.5 Hz, 1H), 4.10-4.02 (m, 1H), 3.74-3.68 (m, 1H), 3.60-3.50 (m, 1H), 3.08 (d, J=10.8 Hz, 1H), 2.98-2.83 (m, 2H), 2.62 (br, 2H), 2.28-2.13 (m, 4H), 1.69 (d, J=40.2 Hz, 4H), 1.42-1.26 (m, 4H).
The title Compound I-38 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and 2-hydroxyacetaldehyde as a start material. MS: 425.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.59 (s, 1H), 6.84 (s, 1H), 6.45 (s, 2H), 4.87 (d, J=14.4 Hz, 1H), 4.76 (dd, J=11.7, 5.2 Hz, 3H), 4.40-4.50 (m, 1H), 4.29 (d, J=9.9 Hz, 2H), 4.17 (d, J=8.7 Hz, 1H), 3.70-3.80 (m, 2H), 3.32-3.15 (m, 3H), 2.94 (br, 2H), 2.68-2.57 (m, 2H), 1.68 (d, J=33.6 Hz, 2H), 1.40-1.29 (m, 4H).
The title Compound I-39 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and 2,2,2-trifluoroacetaldehyde as a start material. MS: 463.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.47 (s, 1H), 6.69 (s, 1H), 6.43 (s, 2H), 4.77 (s, 2H), 4.20-4.30 (m, 2H), 3.74 (br, 2H), 3.28 (d, J=10.1 Hz, 2H), 2.89 (d, J=6.0 Hz, 2H), 2.67 (d, J=6.3 Hz, 2H), 2.60-2.54 (m, 2H), 1.67 (br, 2H), 1.44-1.37 (m, 2H), 1.29 (d, J=7.9 Hz, 2H).
The title Compound I-40 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and piperidin-4-one as a start material. MS: 464.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.61 (s, 1H), 6.91 (s, 1H), 6.42 (s, 2H), 4.87 (d, J=14.2 Hz, 1H), 4.78 (d, J=14.4 Hz, 1H), 4.38 (br, 1H), 4.25 (br, 1H), 4.19 (br 1H), 3.52-3.40 (m, 3H), 3.30 (br, 1H), 2.85-2.96 (m, 4H), 2.65 (br, 2H), 2.26 (br, 2H), 1.81 (d, J=12.1 Hz, 2H), 1.73 (br, 2H), 1.66 (br, 1H), 1.30-1.38 (m, 5H).
The title Compound I-41 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and dihydro-2H-pyran-4(3H)-one as a start material. MS: 465.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.60 (s, 1H), 6.91 (s, 1H), 6.41 (s, 2H), 4.87 (d, J=14.4 Hz, 1H), 4.78 (d, J=14.4 Hz, 1H), 4.45 (d, J=15.1 Hz, 1H), 4.25 (br, 1H), 4.19 (br, 1H), 3.97 (d, J=11.0 Hz, 2H), 3.75 (br, 1H), 3.25-3.35 (m, J=18.0, 11.7 Hz, 4H), 3.02 (d, J=17.8 Hz, 1H), 2.96-2.84 (m, 1H), 2.66 (br, 2H), 2.08-1.94 (m, 2H), 1.77-1.60 (m, 4H), 1.25-1.35 (m, 5H).
Step 1: Preparation of Compound 103
To a stirred mixture solution of compound 86 (300 mg, 0.44 mmol) and DIEA (225 mg, 1.743 mmol) in DCM (5 mL) was added AcCl (35.0 mg, 0.45 mmol) at 0° C., then the resulting mixture was stirred at 25° C. for 12 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 103 (110 mg, 36.4%) as a yellow solid. MS: 617.0 (M+H)+.
Step 2: Preparation of Compound 104
To a stirred mixture solution of compound 103 (100 mg, 0.16 mmol) in AcOH (7.5 mL) was added Zn (53.0 mg, 0.81 mmol) under N2 protected, then the resulting mixture was stirred at 80° C. for 0.5 hour. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 104 (110 mg) as a black oil. MS: 541.0 (M+H)+.
Step 3: Preparation of Compound 105
A mixture solution of compound 104 (110 mg) and Pd/C (20 mg) in EA (10 mL) under H2 atmosphere was stirred at 25° C. for 14 hours. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to afford compound 105 (0.11 g) as a yellow oil.
Step 4: Preparation of Compound I-42
A mixture solution of compound 105 (110 mg, 0.2 mmol) in TFA (7.5 mL) was stirred at 70° C. for 0.5 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-42 (7.75 mg) as a yellow solid. MS: 421.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.88, (s, 1H), 7.96 (s, 1H), 6.97 (s, 1H), 6.44 (s, 2H), 5.81-5.32 (m, 2H), 4.85-4.68 (m, 4H), 4.58, (br, 2H), 3.67-3.54 (m, 2H), 3.21 (d, J=7.7 Hz, 2H), 3.09 (d, J=7.2 Hz, 2H), 2.71-2.54 (m, 2H), 2.45-2.35 (m, 2H), 2.04 (s, 3H).
The title Compound I-43 was prepared in analogy to the preparation of Compound I-42 by using compound 86 and methanesulfonyl chloride as a start material. MS: 457.0 (M+H)+. i H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 6.39 (s, 2H), 5.75-5.85 (m, 1H), 5.305.40 (m, 1H), 4.77 (s, 2H), 4.72 (br, 2H), 4.29 (br, 2H), 3.21 (d, J=7.7 Hz, 2H), 3.08 (d, J=J=7.2 Hz, 2H), 2.85-2.95 (m, 3H), 2.75-2.67 (m, 2H), 2.45-2.36 (m, 2H).
The title Compound I-44 was prepared in analogy to the preparation of Compound I-42 by using compound 86 and benzoyl chloride as a start material. MS: 483.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.98 (s, 1H), 7.55-7.22 (m, 5H), 7.67-6.68 (m, 1H), 6.37 (s, 2H), 5.56 (m, 2H), 4.99-4.32 (m, 6H), 3.84-3.48 (m, 2H), 3.07 (d, J=6.9 Hz, 2H), 2.65 (br, 2H), 2.42 (d, J=6.8 Hz, 2H).
The title Compound I-45 was prepared in analogy to the preparation of Compound I-42 by using compound 86 and benzenesulfonyl chloride as a start material. MS: 519.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.93 (s, 1H), 7.80 (d, J=7.8 Hz, 2H), 7.70-7.47 (m, 3H), 6.93 (s, 1H), 6.36 (s, 2H), 5.80-5.27 (m, 2H), 4.86-4.51 (m, 4H), 4.11 (br, 2H), 3.24 (t, J=6.3 Hz, 2H), 3.14-2.93 (m, 2H), 2.64 (t, J=6.2 Hz, 2H), 2.45-2.35 (m, 2H).
A mixture solution of Compound I-10 (40 mg, 0.081 mmol) and 2-chloro-5-methylpyrimidine (20.80 mg, 0.16 mmol) in DMSO (1 mL) was stirred at 120° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-46 (3.34 mg, 7.8%) as a yellow solid. MS: 473.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.48 (s, 1H), 6.86 (s, 1H), 6.45 (s, 2H), 4.80 (br, 2H), 4.73 (br, 2H), 4.20-4.30 (m, 2H), 3.85-3.95 (m, 2H), 2.65-2.75 (m, 2H), 2.64-2.58 (m, 2H), 2.06 (br, 3H), 1.67 (br, 2H), 1.40 (t, J=7.2 Hz, 2H), 1.28 (d, J=8.0 Hz, 2H).
A mixture solution of Compound I-10 (40 mg, 0.081 mmol), 4-(bromomethyl)pyridine (20.46 mg, 0.081 mmol) and DIEA (20.91 mg, 0.162 mmol) in DME (1 mL) was stirred at 20° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-47 (10.23 mg, 26.5%) as a white solid. MS: 472.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.71 (d, J=5.2 Hz, 2H), 7.65-7.48 (m, 3H), 6.84 (s, 1H), 6.43 (s, 2H), 4.80 (br, 2H), 4.42 (br, 2H), 4.33-4.12 (m, 4H), 3.33 (br, 2H), 2.94 (br, 2H), 2.63 (br, 2H), 1.68 (br, 2H), 1.42-1.18 (m, 4H).
The title Compound I-47 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and 2-methoxyacetaldehyde as a start material. MS: 439.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.59 (s, 1H), 6.85 (s, 1H), 6.42 (s, 2H), 4.89-4.74 (m, 2H), 4.46 (d, J=15.5 Hz, 1H), 4.31-4.15 (m, 3H), 3.60-3.70 (m, 2H), 3.37 (br, 2H), 3.30 (br, 5H), 2.94 (d, J=5.8 Hz, 2H), 2.63 (br, 2H), 1.68 (m, 2H), 1.35 (m, 4H).
The title Compound I-49 was prepared in analogy to the preparation of Compound I-25. MS: 453.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.60 (s, 1H), 6.83 (s, 1H), 6.41 (s, 2H), 4.82 (br, 2H), 4.36 (br, 2H), 4.15-4.27 (m, 4H), 3.76 (br, 3H), 2.95 (br 2H), 2.63 (s, 3H), 1.69 (br, 2H), 1.38 (br, 2H), 1.35-1.28 (m, 3H).
The title Compound I-50 was prepared in analogy to the preparation of Compound I-35 by using Compound I-13 and acetone as a start material. MS: 422.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.52 (s, 1H), 6.85 (s, 1H), 6.47 (s, 2H), 4.79 (br, 2H), 4.25 (br, 3H), 3.72-3.48 (m, 1H), 2.94 (br, 3H), 2.60 (br, 2H), 2.47-2.42 (m, 1H), 1.69 (br, 2H), 1.45-1.19 (m, 10H).
The title Compound I-51 was prepared in analogy to the preparation of Compound I-35 by using Compound I-13 and cyclobutanone as a start material. MS: 434.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.54 (s, 1H), 6.88 (s, 1H), 6.36 (s, 2H), 4.80 (br 2H), 4.25 (m, 3H), 3.80-3.90 (m, 1H), 2.90-3.00 (m, 3H), 2.40-2.50 (m, 1H), 2.22 (br, 4H), 1.70 (br, 4H), 1.34 (d, J=35.6 Hz, 4H).
Step 1: Preparation of Compound 106
To a stirred mixture solution of compound 12 (3.6 g, 11.04 mmol) in THF (30 mL) was added lithium aluminum tetrahydride (837.7 mg, 22.1 mmol) solution in THF (30 mL) at 0° C., then the resulting mixture was stirred at 0° C. for 0.5 hour. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 106 (2.6 g, 79%) as a white solid. MS: 300.0 (M+H)+.
Step 2: Preparation of Compound 107
A mixture solution of compound 106 (2.1 g, 7.04 mmol), 4,4,5,5-tetramethyl-2-prop-2-enyl-1,3,2-dioxaborolane (1.78 g, 10.56 mmol), Pd(dppf)Cl2 (514.83 mg, 704.28 mmol) and potassium metaphosphate (2.99 g, 14.09 mmol) in Dioxane (20 mL) and water (5 mL) was stirred at 80° C. for 5 hours under N2 protected. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 107 (500 mg, 88%) as a white solid. MS: 300.0 (M+3H)+. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.42 (s, 1H), 6.00-5.87 (m, 1H), 5.15-5.05 (m, 2H), 4.75 (d, J=5.2 Hz, 2H), 4.36 (s, 2H), 3.42 (d, J=6.5 Hz, 2H), 1.96 (t, J=5.8 Hz, 1H), 1.56 (s, 9H).
Step 3: Preparation of Compound 109
A mixture solution of compound 108 (499.49 mg, 5.67 mmol), K2CO3 (1.78 g, 10.56 mmol) and compound 6 (2 g, 3.78 mmol) in THF (20 mL) was stirred at 20° C. for 5 mins. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 109 (1.73 g, 83%) as a yellow oil. MS: 554.0 (M+H)+.
Step 4: Preparation of Compound 110
To a stirred mixture solution of compound 109 (0.2 g, 0.36 mmol) and compound 107 (93.69 mg, 0.36 mmol) in THF (5 mL) was added PPh3 (142.13 mg, 0.54 mmol) and DIAD (109.57 mg, 0.54 mmol) at 0° C., then the resulting mixture was stirred at 65° C. for 16 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 110 (0.28 g, 97.5%) as a yellow solid. MS: 795.1 (M+H)+.
Step 5: Preparation of Compound 111
To a stirred mixture solution of compound 110 (0.3 g, 0.38 mmol) in DCM (400 mL) was added Grubbs' II reagent (0.38 mmol) under N2 protected, then the resulting mixture was stirred at 20° C. for 24 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 111 (0.13 g, 17.3%) as a yellow solid. MS: 767.4 (M+H)+.
Step 6: Preparation of Compound 112
To a stirred mixture solution of compound 111 (68 mg, 0.09 mmol) in AcOH (5 mL) was added Zn (38.1 mg) under N2 protected, then the resulting mixture was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 112 (56 mg) as a white solid. MS: 691.0 (M+H)+.
Step 7: Preparation of Compound I-52 and Compound I-53
A mixture solution of compound 112 (56 mg) in TFA (2 mL) was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-52 and Compound I-53.
Compound I-52 (white solid, 2.8 mg). MS: 451.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.86 (s, 1H), 7.40 (s, 1H), 6.53 (s, 2H), 5.81-5.60 (m, 2H), 4.93 (s, 2H), 4.52 (s, 2H), 2.39 (s, 2H), 2.05-1.90 (m, 2H), 1.47 (s, 9H).
Compound I-53 (white solid, 3.0 mg). MS: 451.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.18 (s, 1H), 7.40 (s, 1H), 6.51 (s, 2H), 5.80-5.70 (m, 2H), 4.93 (s, 2H), 4.47 (s, 2H), 3.51 (s, 2H), 3.24 (d, J=5.1 Hz, 2H), 2.49-2.44 (m, 2H), 1.47 (s, 9H).
Step 1: Preparation of Compound 113
To a stirred mixture solution of compound 112 (0.035 g, 0.05 mmol) in DCM (4 mL) was added mCPBA (17.49 mg, 0.10 mmol) at 0° C., then the resulting mixture was stirred at 25° C. for 4 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 113 (36 mg). MS: 723.0 (M+H)+.
Step 2: Preparation of Compound I-54 and Compound I-55
A mixture solution of compound 113 (36 mg) in TFA (2 mL) was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-54 and Compound I-55.
Compound I-54 (white solid, 14.8 mg). MS: 483.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.65 (s, 1H), 7.44 (s, 1H), 7.15 (s, 2H), 5.82-5.69 (m, 1H), 5.69-5.56 (m, 1H), 5.04 (s, 2H), 4.51 (s, 2H), 3.83-3.71 (m, 2H), 3.29 (s, 2H), 2.46 (s, 2H), 2.04-1.93 (m, 1H), 1.47 (s, 9H).
Compound I-55 (white solid, 14.8 mg). MS: 483.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.46 (s, 1H), 7.19 (s, 2H), 5.57-5.46 (m, 1H), 5.46-5.37 (m, 1H), 5.02 (s, 2H), 4.47 (s, 2H), 3.86-3.75 (m, 2H), 3.20 (d, J=6.6 Hz, 2H), 2.51 (s, 2H), 2.04-1.93 (m, 1H), 1.47 (s, 9H).
Step 1: Preparation of Compound 114
To a stirred mixture solution of compound 110 (440 mg, 0.55 mmol) in DCM (3 mL) was added a solution of mCPBA (63.68 mg, 0.37 mmol) in DCM (3 mL) at 0° C., then the resulting mixture was stirred at 0° C. for 2 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 114 (450 mg). MS: 811.2 (M+H)+.
Step 2: Preparation of Compound 115
A mixture solution of compound 114 (200 mg, 0.25 mmol), 3-butene-1-amine ((35.08 mg, 493.2 umol) and DIEA (159.37 mg, 1.23 mmol) in DCM (2 mL) and THF (4 mL) was stirred at 20° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 115 (110 mg, 57%) as a white solid. MS: 778.4 (M+H)+.
Step 3: Preparation of Compound 116
To a stirred mixture solution of compound 115 (110 mg, 0.14 mmol) in DCM (200 mL) was added Grubbs' II reagent (30.01 mg, 35.35 umol) under N2 protected, then the resulting mixture was stirred at 20° C. for 24 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 116 (105 mg) as a yellow solid. MS: 750.4 (M+H)+.
Step 4: Preparation of Compound 117
To a stirred mixture solution of compound 116 (60 mg, 0.080 umol) in AcOH (2 mL) was added Zn (26.16 mg, 0.4 mmol) under N2 protected, then the resulting mixture was stirred at 70° C. for 4 hours. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 117 (30 mg). MS: 674.2 (M+H)+.
Step 5: Preparation of Compound I-56 and Compound I-57
A mixture solution of compound 117 (30 mg, 44.52 umol) in TFA (2 mL) was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-56 and Compound I-57.
Compound I-56 (yellow solid, 10.22 mg). MS: 434.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.27 (s, 1H), 7.36 (s, 1H), 6.99 (s, 2H), 5.75 (dt, J=14.5, 7.1 Hz, 1H), 5.66-5.54 (m, 1H), 4.87 (s, 2H), 4.47 (s, 2H), 3.37-3.37 (m, 1H), 3.34-3.31 (m, 2H), 3.26 (d, J=6.4 Hz, 2H), 2.28 (s, 2H), 1.47 (s, 9H).
Compound I-57 (yellow solid, 9.64 mg). MS: 434.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.07 (s, 1H), 7.37 (s, 1H), 6.66 (s, 2H), 5.68 (s, 1H), 5.33 (d, J=4.7 Hz, 1H), 4.85 (s, 2H), 4.50 (s, 2H), 3.34-3.34 (m, 1H), 3.33-3.33 (m, 2H), 3.31-3.31 (m, 2H), 2.02-1.96 (m, 2H), 1.47 (s, 9H).
Step 1: Preparation of Compound 118
A mixture solution of compound 115 (190 mg, 0.24 mmol), CH3I (62.3 mg, 0.44 mmol) and K2CO3 (100 mg, 0.73 mmol) in DMF (5 mL) was stirred at 100° C. for 4 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 118 (80 mg, 41%) as a yellow solid. MS: 792.3 (M+H)+.
Step 2: Preparation of Compound 119
To a stirred mixture solution of compound 118 (80 mg, 0.1 mmol) in DCM (200 mL) was added Grubbs' II reagent (21.44 mg, 0.025 mmol) under N2 protected, then the resulting mixture was stirred at 20° C. for 24 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 119 (30 mg, 38%) as a yellow solid. MS: 764.4 (M+H)+.
Step 3: Preparation of Compound 120
To a stirred mixture solution of compound 119 (30 mg, 0.03 mmol) in AcOH (2 mL) was added Zn (12.84 mg, 0.2 mmol) under N2 protected, then the resulting mixture was stirred at 70° C. for 4 hours. After the reaction was completed, the reaction mixture was filtered and concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography to afford compound 120 (10 mg). MS: 688.1 (M+H)+.
Step 4: Preparation of Compound I-58
A mixture solution of compound 120 (10 mg) in TFA (2 mL) was stirred at 70° C. for 1 hour. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by Pre-HPLC to afford Compound I-58 (white solid, 2.47 mg, mixture of E&Z). MS: 448.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.38 (s, 1H), 7.37 (s, 1H), 6.08 (s, 2H), 5.79-5.70 (m, 1H), 5.52-5.42 (m, 1H), 4.85 (s, 2H), 4.49 (d, J=17.4 Hz, 2H), 3.32-3.28 (m, 2H), 3.24 (s, 2H), 3.05 (s, 3H), 2.35 (s, 1H), 2.02 (dd, J=14.7, 7.1 Hz, 1H), 1.48 (s, 9H).
The title Compound I-59 was prepared in analogy to the preparation of Compound I-35 by using compound 86 and 2-methylsulfonyl acetaldehyde as a start material. MS: 487.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.61 (s, 1H), 6.82 (s, 1H), 6.41 (s, 2H), 4.81 (br, 2H), 4.64-3.91 (m, 4H), 3.76-3.67 (m, 2H), 3.47-3.25 (m, 4H), 3.11 (s, 3H), 2.97 (br, 2H), 2.66 (br, 2H), 1.69 (br, 2H), 1.34 (br, 4H).
The title Compound I-60 was prepared in analogy to the preparation of Compound I-35 by using Compound I-31 and cyclobutanone as a start material. MS: 437.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.84 (s, 1H), 6.73 (s, 1H), 6.42 (s, 2H), 4.87-4.74 (m, 2H), 4.57 (br, 2H), 4.36 (br, 2H), 4.10-4.00 (m, 2H), 3.65-3.75 (m, 1H), 3.45-3.55 (m, 1H), 3.95-3.15 (m, 1H), 2.87 (d, J=17.3 Hz, 1H), 2.75 (dd, J=18.0, 8.4 Hz, 1H), 2.26-2.11 (m, 4H), 1.73 (d, J=9.3 Hz, 2H), 1.63 (d, J=7.0 Hz, 2H), 1.53 (br, 2H).
The title Compound I-61 was prepared in analogy to the preparation of Compound I-53 by using compound 109 and Intermediate 7 as a start material. MS: 429.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.16 (s, 2H), 7.07 (s, 1H), 6.99 (s, 1H), 4.94 (brs, 2H), 4.23 (brs, 2H), 3.41-3.33 (m, 4H), 2.85 (s, 2H), 2.59-2.54 (m, 2H), 1.52 (m, 4H), 1.20 (m, 2H).
The title Compound I-62 was prepared in analogy to the preparation of Compound I-35 by using Compound I-61 and cyclobutanone as a start material. MS: 483.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.17 (s, 2H), 7.13 (s, 1H), 7.00 (s, 1H), 4.95 (d, J=4.8 Hz, 2H), 4.41 (d, J=15.5 Hz, 1H), 4.09 (dd, J=15.5, 8.0 Hz, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.56-3.52 (m, 1H), 3.44-3.38 (m, 2H), 3.13-3.10 (m, 1H), 3.03-2.88 (m, 2H), 2.66-2.63 (m, 1H), 2.30-2.15 (m, 4H), 1.79-1.72 (m, 2H), 1.60-1.43 (m, 4H), 1.27-1.18 (m, 2H).
The title Compound I-63 was prepared in analogy to the preparation of Compound I-35 by using Compound I-61 and acetone as a start material. MS: 471.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.17 (s, 2H), 7.13 (s, 1H), 7.00 (s, 1H), 4.96 (s, 2H), 4.35 (d, J=5.7 Hz, 2H), 3.63-3.52 (m, 3H), 3.30-3.15 (m, 2H), 2.98-2.90 (m, 2H), 2.59-2.50 (m, 2H), 1.61-1.44 (m, 4H), 1.40 (s, 1H), 1.29 (t, 7H).
The title Compound I-64 was prepared in analogy to the preparation of Compound I-29 by using compound 6, Intermediate 20 and acetone as a start material. MS: 425.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.84 (s, 1H), 6.74 (s, 1H), 6.43 (s, 2H), 4.81 (br, 2H), 4.57 (br, 2H), 4.36 (d, J=7.0 Hz, 2H), 4.19 (d, J=15.6 Hz, 1H), 4.11-4.04 (m, 1H), 3.58 (d, J=11.1 Hz, 2H), 3.19-3.10 (m, 1H), 3.03 (d, J=21.4 Hz, 2H), 1.66 (d, J=7.6 Hz, 2H), 1.54 (d, J=7.3 Hz, 2H), 1.29 (dd, J=6.7, 3.7 Hz, 6H).
A mixture solution of Compound I-37 (20 mg, 0.046 mmol), methyl(propyl)carbamic chloride (12.4 mg, 0.092 mmol), DIEA (23.2 mg, 0.23 mmol) and DMAP (5.6 mg, 0.046 mmol) in DMF (1 mL) was stirred at 50° C. for 14 hours. After the reaction was completed, the reaction mixture was concentrated in vacuo and extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-65 (10.0 mg, 40.8%) as a white solid. MS: 543.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 6.74 (s, 1H), 6.24 (s, 2H), 4.82 (br, 2H), 4.25 (br, 2H), 3.46-3.38 (m, 2H), 3.26 (s, 3H), 3.25-3.20 (m, 2H), 3.08-3.05 (m, 2H), 3.03-3.00 (m, 1H), 2.70-2.65 (m, 2H), 2.63-2.58 (m, 2H), 2.06-2.02 (m, 2H), 1.88-1.80 (m, 2H), 1.67-1.60 (m, 6H), 1.37-1.30 (m, 4H), 0.91 (t, J=7.5 Hz, 3H).
The title Compound I-66 was prepared in analogy to the preparation of Compound I-29 by using compound 6, Intermediate 21 as a start material. MS: 383.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.87 (s, 1H), 6.66 (s, 1H), 6.47 (br, 2H), 4.85 (s, 2H), 4.54-4.48 (m, 2H), 4.39-4.35 (m, 2H), 4.32-4.28 (m, 2H), 3.33-3.28 (m, 2H), 2.92-2.86 (m, 2H), 1.69-1.62 (m, 2H), 1.56-1.50 (m, 2H).
The title Compound I-67 was prepared in analogy to the preparation of Example 1 and Example 2 by using Intermediate 1 and Intermediate 22 as a start material. MS: 368.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.19 (s, 1H), 6.90 (s, 1H), 6.37 (s, 2H), 4.77 (s, 2H), 4.39 (t, J=8.6 Hz, 2H), 4.05 (d, J=7.2 Hz, 2H), 3.05 (t, J=8.7 Hz, 2H), 2.55 (t, J=5.5 Hz, 2H), 1.61 (brs, 2H), 1.27 (br, 4H).
The title Compound I-68 was prepared in analogy to the preparation of Compound I-35 by using Compound I-66 and cyclobutanone as a start material. MS: 437.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.71 (d, J=2.7 Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 6.36 (br, 2H), 4.78 (s, 2H), 4.50-4.43 (m, 2H), 4.28-4.22 (m, 2H), 3.61-3.58 (m, 2H), 2.97-2.89 (m, 1H), 2.73-2.67 (m, 2H), 2.11-2.03 (m, 2H), 1.90-1.81 (m, 2H), 1.68-1.63 (m, 4H), 1.56-1.50 (m, 2H).
The title Compound I-69 was prepared in analogy to the preparation of Compound I-65 by using Compound I-37 and butanoyl chloride as a start material. MS: 505.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 6.84 (s, 1H), 4.91 (s, 2H), 4.47-4.43 (m, 2H), 3.46 (s, 2H), 3.19-3.15 (m, 2H), 2.89-2.84 (m, 1H), 2.76-2.73 (m, 2H), 2.64-2.58 (m, 4H), 2.15-2.09 (m, 2H), 2.05-1.95 (m, 2H), 1.80-1.75 (m, 5H), 1.58-1.53 (m, 3H), 1.40-1.35 (m, 2H), 1.05 (t, J=7.4 Hz, 3H).
To a stirred mixture solution of Compound I-65 (30 mg, 0.056 mmol) in THF (2 mL) was added NaH (11.2 mg, 0.28 mmol) at 0° C. and the resulting mixture was stirred at 20° C. for 1 hour. Then butyl carbonochloridate (15.0 mg, 0.11 mmol) was added to the above mixture solution at 0° C. and the resulting mixture was stirred at 20° C. for 16 hours. After the reaction was completed, the reaction mixture was quenched by adding ice-water and extracted with EA. The combined organic layers were washed with a solution of NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by pre-HPLC to afford Compound I-70 (5.0 mg, 14.3%) as a white solid. MS: 634.4 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 5.10-4.85 (m, 2H), 4.10 (s, 2H), 3.80-3.65 (m, 3H), 3.54-3.31 (m, 4H), 3.21 (s, 3H), 3.10-3.02 (m, 2H), 2.83-2.80 (m, 1H), 2.65-2.61 (m, 4H), 2.25-2.22 (m, 2H), 1.95-1.92 (m, 2H), 1.75-1.70 (m, 6H), 1.41-1.37 (m, 5H), 1.02-0.90 (m, 8H).
The TLR7 agonistic activity of the compounds of the invention in HEK-Blue™ hTLR7 cell line with stable expression of human TLR7 were assayed using the following method:
The agonistic effect of the compounds of the invention on human TLR7 can be determined by the above experiments, and the measured EC50 value is shown in Table 1.
In Table 1, reference compounds 1˜3 were prepared in according to patent WO2019209811A1. It can be seen from Table 1 that the compounds of the invention have good TLR7 agonist activity.
It demonstrated that the compounds of the invention can stimulate human peripheral blood monocytes to produce IFN-α.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011035500.0 | Sep 2020 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/120751 | 9/26/2021 | WO |
