CN118119619A - SIK inhibitor and composition, preparation method and application thereof - Google Patents

SIK inhibitor and composition, preparation method and application thereof Download PDF

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CN118119619A
CN118119619A CN202280064115.XA CN202280064115A CN118119619A CN 118119619 A CN118119619 A CN 118119619A CN 202280064115 A CN202280064115 A CN 202280064115A CN 118119619 A CN118119619 A CN 118119619A
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halogen
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姚元山
胡玮
栾林波
陈永凯
王朝东
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Shanghai Meiyue Biotech Development Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

Provides a compound shown in a formula I, racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof, which has good SIK inhibition effect, can be used for treating diseases related to inflammation, and can be used for preparing medicines for treating the diseases or the diseases. Moreover, the compound has good pharmacokinetic and other properties.

Description

SIK inhibitor and composition, preparation method and application thereof
The present invention claims priority from prior applications entitled "SIK inhibitor and its composition, preparation method and use" filed on 18 10 months 2021 to the chinese state intellectual property office, and priority from prior applications entitled "SIK inhibitor and its composition, preparation method and use" filed on 27 months 2022 to the chinese state intellectual property office, patent application entitled "SIK inhibitor and its composition, preparation method and use". The entire contents of both prior applications are incorporated by reference into this invention.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a SIK inhibitor, a composition, a preparation method and application thereof.
Background
Protein kinases belong to a large family of structurally related enzymes responsible for controlling a variety of cellular signal transduction processes. In particular, it has been shown to be a key regulator in cellular functions including, for example, proliferation, metabolism and apoptosis. Thus, defects in the control of protein phosphorylation leading to uncontrolled signaling are associated with a variety of diseases including, for example, inflammation, allergy, cancer, autoimmune diseases, CNS disorders, and angiogenesis.
In healthy individuals, inflammation is self-limiting, and its regression is controlled by the release of anti-inflammatory mediators and cytokines such as interleukin-10 (IL-10), which are produced as part of a negative feedback loop, produced by cells called "inhibitory" or "regulatory". In fact, during normal inflammation of the body, the initial pro-inflammatory response is followed by a pro-resolution response which, after the lesions have resolved, causes the inflammation to disappear, resulting in a decrease in pro-inflammatory cytokines such as tnfα and IL-12 and an increase in the levels of anti-inflammatory cytokines such as IL-10 and TGF- β, thus creating a so-called tolerogenic environment.
Adenosine monophosphate activated protein kinase (AMPK) belongs to a family of protein kinases including salt-inducible kinase (SIK), a family of serine/threonine kinases that are widely expressed in vivo, particularly involved in cellular energy homeostasis. Three SIK isoforms have been identified, designated SIK1, SIK2 and SIK3.
SIK plays a variety of roles in different cell types. They have been found to phosphorylate a variety of substrates including CREB-reactive transcription coactivator (CRTC) proteins and Histone Deacetylase (HDAC) proteins, thereby regulating transcription of a variety of different genes. One of the effects of CRTC signaling involves controlling the phenotype of macrophages, particularly the polarization of macrophages that occurs through CRTC3 phosphorylation, as measured by decreased secretion of the pro-inflammatory cytokine IL-12 and concomitant increased secretion of the pro-fading cytokine IL-10.
Studies have shown that SIK1 is associated with skeletal muscle sensitivity in obese mice and may be a target of interest in preventing type II diabetes and diabetic nephropathy.
The regulation of ALK5 by SIK1 and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis suggest that SIK protein plays a role in fibrotic disease.
Studies have shown that SIK2 and SIK3 play a role in inflammation by secreting high levels of anti-inflammatory cytokines, particularly interleukin-10 (IL-10), and very low levels of pro-inflammatory cytokines such as TNF-alpha.
SIK2 has been shown to be a target of interest for inflammatory diseases by modulating the role of ifnγ and IL-12 signaling in T helper (Th 1 cell differentiation.
Recent studies indicate that small molecule SIK inhibitors cause decreased phosphorylation of HDAC4/5 and CRTC2 and increased nuclear translocation. Treatment with the small molecule SIK inhibitor YKL-05-099 increased bone formation and bone mass in mice, confirming the relevance of SIK inhibition in the treatment of bone turnover diseases.
Furthermore, inhibition of SIK2 after oxygen glucose deprivation has also been demonstrated to enhance neuronal survival or promote melanogenesis in melanoma cells. In this case, rapid activation or degradation of SIK proteins after various stresses makes them interesting targets in inflammatory, cardiac or metabolic diseases and neurodegenerative diseases, as therapeutic strategies are needed to regulate stress cell responses (e.g. during ischemia and after tissue reperfusion, in chronic phases of cardiac remodeling, in diabetes and neurodegenerative disorders). SIK inhibition may also be applied to cosmetic or pigmentation-related diseases to induce melanogenesis.
The regulation of ALK5 by SIK1 and the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis suggest that SIK protein plays a role in fibrotic disease.
In addition to important functions in cellular energy homeostasis, SIK proteins are also involved in the regulation of the cell cycle. Higher SIK2 expression is significantly associated with poor survival in patients with high grade serous ovarian cancer, and furthermore, expression of SIK3 is elevated in ovarian cancer, particularly in serous subtypes and advanced ovarian cancer. Thus, SIK inhibition can be used to treat cancer.
There is a great deal of progress in treating patients with autoimmune diseases based on antibodies that target pro-inflammatory cytokines, such as anti-tnfα, but a significant proportion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Thus, there remains a great unmet medical need for the treatment of these diseases, and there is a great need for new drugs for the prevention and/or treatment of the above-mentioned diseases.
Therefore, the development of the medicine with good anti-inflammatory effect and small side effect has important research significance.
Disclosure of Invention
In order to solve the technical problems, the invention provides a compound shown in a formula I, racemate, stereoisomer, tautomer, isotope label, solvate, pharmaceutically acceptable salt or prodrug thereof;
Wherein X and Y are N or C, and X and Y are not both N or C;
z is N or CH, and X and Z are not both N;
T is selected from N or CR 3;
E is selected from NHR 4a or NR 4b when E is NR 4b where the N atom and R 2 together with the atom to which they are attached form a 5-14 membered heterocyclic ring;
A is selected from 3-14 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-14 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
Each R 1, identical or different, is independently selected from H, OH, halogen, CN, oxo (＝O)、-(CH 2) mNR 5aR 5b、-C(O)NR 6、-S(O) nR 7、-(CH 2) mOR 8、-NH(CH 2) pR 9、-C(O)R 10、, the following groups, unsubstituted or optionally substituted with 1,2 or more R groups: c 1-20 alkyl; m is a positive integer from 0 to 5 (e.g., 0,1,2,3,4, 5); n is a positive integer from 0 to 2 (e.g., 0,1, 2); p is a positive integer from 0 to 5 (e.g., 0,1,2,3,4, 5);
Each R is the same or different and is selected from OH, CN, halogen, NH 2、-S(O) 2R 7、OR 8、NR 5aR 5b, 4-6 membered heterocyclic groups;
R 2 is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-20 alkyl, C 1-20 alkoxy;
R 3 is selected from H, halogen, hydroxy, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-20 alkyl, C 1-20 alkoxy;
R 4a and R 4b are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-20 alkyl, C 3-20 cycloalkyl, 3-14 membered heterocyclyl;
Rx is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-20 alkoxy;
R 5a、R 5b、R 6、R 7 are identical or different and are selected, independently of one another, from H, radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-20 alkyl, C 3-20 cycloalkyl;
R 8、R 9 and R 10 are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1,2 or more OH, CN, halogen, NH 2、-S(O) 2R 7、C 1-20 alkyl, C 1-20 alkoxy: c 1-20 alkyl, 3-14 membered heterocyclyl, C 3-20 cycloalkyl.
According to an embodiment of the invention, when X is N, Y is C and Z is CH; when X is C, Y is N, Z is N or CH;
T is selected from N or CR 3;
E is selected from NHR 4a or NR 4b when E is NR 4b where the N atom and R 2 together with the atom to which they are attached form a 5-8 membered heterocyclic ring;
A is selected from 3-8 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-8 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
each R 1, identical or different, is independently selected from H, OH, halogen, CN, oxo (＝O)、-(CH 2) mNR 5aR 5b、-C(O)NR 6、-S(O) nR 7、-(CH 2) mOR 8、-NH(CH 2) pR 9、-C(O)R 10、, the following groups, unsubstituted or optionally substituted with 1,2 or more R groups: c 1-12 alkyl; m is a positive integer from 0 to 5; n is a positive integer from 0 to 2; p is a positive integer from 0 to 5;
Each R is the same or different and is selected from OH, CN, halogen, NH 2、-S(O) 2R 7、OR 8、NR 5aR 5b, 4-6 membered heterocyclic groups;
R 2 is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-12 alkyl, C 1-12 alkoxy;
R 3 is selected from H, halogen, hydroxy, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-12 alkyl, C 1-12 alkoxy;
R 4a and R 4b are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-12 alkyl, C 3-12 cycloalkyl, 3-8 membered heterocyclyl;
Rx is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-12 alkoxy;
R 5a、R 5b、R 6、R 7 are identical or different and are selected, independently of one another, from H, radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-12 alkyl, C 3-12 cycloalkyl;
R 8、R 9 and R 10 are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1,2 or more OH, CN, halogen, NH 2、-S(O) 2R 7、C 1-12 alkyl, C 1-12 alkoxy: c 1-12 alkyl, 3-8 membered heterocyclyl, C 3-12 cycloalkyl.
According to an embodiment of the invention, when X is N, Y is C and Z is CH; when X is C, Y is N, Z is N or CH;
T is selected from CR 3;
E may be selected from NHR 4a or NR 4b when E is NR 4b where N and R 2 together with the atom to which they are attached form a 5-8 membered heterocyclic ring;
a may be selected from 3-8 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-8 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
Each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=o), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, OH substituted C 1-6 alkyl, OH substituted C 1-6 alkoxy, di (C 1-6 alkyl) amino, di (C 1-6 alkyl) amino-C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl;
R 2 can be selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, deuterated C 1-6 alkoxy, haloalkyl;
R 3 can be selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy;
R 4a can be selected from halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl;
R 4b can be selected from H, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl;
Rx may be selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy.
According to an embodiment of the invention, when X is N, Y is C and Z is CH; when X is C, Y is N, Z is N or CH;
T is selected from CR 3;R 3 selected from methoxy, hydroxy, halogen, deuterated methoxy, CHF 2 O-;
E may be selected from NHR 4a or NR 4b when E is NR 4b where N and R 2 together with the atom to which they are attached form a piperidine ring;
A may be selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1,2 or more R 1, R1 can replace hydrogen on heterocyclic NH;
Each R 1, which may be the same or different, is independently selected from H, OH, F, oxo (=O), methyl, isopropyl, methoxy, methoxymethyl, acetyl, hydroxymethyl, hydroxyethyl, hydroxyethoxy, methylaminomethyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, trifluoromethyl, CF 3CH 2-、CNCH 2 -,
R 2 can be selected from methoxy, tridentate methoxy, difluoromethoxy, difluoromethylene;
R 3 can be selected from methoxy, tridentate methoxy, difluoromethoxy;
R 4a is selected from CF 3CH 2 -, cyclopropyl;
R 4b is selected from H, CF 3CH 2-、CN-CH 2 -;
Rx may be selected from H, F.
In some embodiments of the invention, A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1, 2 or more R 1, R 1 can replace H on heterocyclic NH; each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, C 1-6 alkoxy-C 1-6 alkyl C (O) -, OH-substituted C 1-6 alkyl, OH-substituted C 1-6 alkoxy, N (C 1-6 alkyl) 2、(C 1-6 alkyl) 2N-C 1-6 alkyl, NH (C 1-6 alkyl), C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl.
In some embodiments of the invention, a may be selected from:
In some embodiments, the compound of formula I is a compound of formula II:
wherein A, E, T, X, Y, R 2 and R x have the above-described definitions independently of each other.
In some embodiments, the compound of formula I is a compound of formula Ia or formula Ib:
Wherein X, Y, Z, T, R x、R 4a、R 4b and A independently of one another have the above-described definition.
In some embodiments, the compound of formula I is a compound of formula iia or formula iib:
Wherein X, Y, T, R x、R 4a、R 4b and A independently of one another have the above-described definition.
In some embodiments, when X is C, Y is N and Z is CH.
In some embodiments, T is selected from CR 3;R 3 may be selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy.
In some embodiments, rx is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy.
In some embodiments, R 4b is selected from H, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl.
In some embodiments, R 4a is selected from halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl.
In some embodiments, a compound of formula Ia, wherein when X is C, Y is N and Z is CH; a is selected from the group consisting of azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1, 2 or more R 1,R 1 can replace H on heterocyclic NH; each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, C 1-6 alkoxy-C 1-6 alkyl C (O) -, OH-substituted C 1-6 alkyl, OH-substituted C 1-6 alkoxy, N (C 1-6 alkyl) 2、(C 1-6 alkyl) 2N-C 1-6 alkyl, NH (C 1-6 alkyl), C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkoxyc 1- 6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl; t is selected from CR 3;R 3 may be selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy; rx is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy; r 4b is selected from H, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl.
In some embodiments, a compound of formula Ib, wherein when X is C, Y is N and Z is CH; a is selected from the group consisting of azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1, 2 or more R 1,R 1 can replace H on heterocyclic NH; each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, C 1-6 alkoxy-C 1-6 alkyl C (O) -, OH-substituted C 1-6 alkyl, OH-substituted C 1-6 alkoxy, N (C 1-6 alkyl) 2、(C 1-6 alkyl) 2N-C 1-6 alkyl, NH (C 1-6 alkyl), C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkoxyc 1- 6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl; t is selected from CR 3;R 3 may be selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy; rx is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy; r 4a is selected from halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl.
In some embodiments, a compound of formula IIa, wherein when X is C, Y is N; a is selected from the group consisting of azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1, 2 or more R 1, R 1 can replace H on heterocyclic NH; each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, C 1-6 alkoxy-C 1-6 alkyl C (O) -, OH-substituted C 1-6 alkyl, OH-substituted C 1-6 alkoxy, N (C 1-6 alkyl) 2、(C 1- 6 alkyl) 2N-C 1-6 alkyl, NH (C 1-6 alkyl), C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkoxyc 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl; t is selected from CR 3;R 3 may be selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy; rx is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy; r 4b is selected from H, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl.
In some embodiments, a compound of formula IIb, wherein when X is C, Y is N and Z is CH; a is selected from the group consisting of azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1, 2 or more R 1,R 1 can replace H on heterocyclic NH; each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, C 1-6 alkoxy-C 1-6 alkyl C (O) -, OH-substituted C 1-6 alkyl, OH-substituted C 1-6 alkoxy, N (C 1-6 alkyl) 2、(C 1-6 alkyl) 2N-C 1-6 alkyl, NH (C 1-6 alkyl), C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkoxyc 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl; t is selected from CR 3;R 3 may be selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy; rx is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy; r 4a is selected from halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl.
According to an embodiment of the invention, the compound of formula i is selected from the following structures:
According to an embodiment of the present invention, the compound of formula I has the following structure:
The invention provides a preparation method of a compound shown in a formula I, which comprises the following steps: the compound a and the compound b undergo a coupling reaction to obtain a compound shown in a formula I;
Wherein X, Y, Z, T, E, R x、R 2 and a independently of each other have the definition described above; w is selected from Cl, br or I;
According to an embodiment of the invention, the reaction is carried out in the presence of a catalyst and/or a base.
According to an embodiment of the present invention, the catalyst may be a palladium catalyst, for example at least one of Pa (dppf) Cl 2 (1, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride), pa 2(dba) 3 (tris (dibenzylideneacetone) dipalladium), pd (OAc) 2 (palladium acetate).
According to an embodiment of the present invention, the base may be selected from at least one of sodium carbonate, potassium acetate, triethylamine and pyridine.
The invention also provides the use of at least one of a compound shown in formula (I), a racemate, a stereoisomer, a tautomer, an isotope label, a solvate, a pharmaceutically acceptable salt or a prodrug compound thereof in the preparation of a medicament; the drug is preferably a SIK inhibitor, more preferably a SIK2 inhibitor.
According to embodiments of the invention, the medicament may be for the treatment and/or prophylaxis of inflammatory diseases, auto-inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, graft rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with hypersecretion of tnfα, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases and/or diseases associated with abnormal angiogenesis; also for example psoriasis, inflammatory Bowel Disease (IBD), rheumatoid Arthritis (RA), primary sjogren's syndrome, ankylosing spondylitis, cold-related periodic syndrome (CAPS).
According to an embodiment of the invention, the inflammatory disease may be selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g. asthma), chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel diseases (e.g. crohn's disease, ulcerative colitis). More particularly, the inflammatory disease refers to rheumatoid arthritis, chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease (e.g. crohn's disease, ulcerative colitis).
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula (I), racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug compound thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. The compounds of the present invention are preferably formulated as injectable or oral compositions or ointments, emulsions or patches, all for transdermal administration.
Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. However, the compositions are more typically presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, adjuvant or carrier. Typical unit dosage forms include pre-filled, pre-measured vials or syringes of liquid compositions or, in the case of solid compositions, pills, tablets, capsules, and the like. In such compositions, the compounds of the present invention of formula I are typically small amounts of the components (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight) with the remainder being various adjuvants or carriers and processing aids that assist in forming the desired dosage form.
Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous excipients including buffers, suspending and dispersing agents, colorants, flavoring agents, and the like. Solid forms may include, for example, any of the following ingredients or compounds of the invention having similar properties: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose; disintegrants, for example alginic acid or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or a flavoring agent, such as peppermint or orange flavoring.
Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As previously mentioned, the active compounds of the present invention of formula I in the compositions are typically small amounts of components, often about 0.05 to 10% by weight, with the remainder being injectable carriers and the like.
The transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient, typically in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 10% by weight, more preferably from about 0.5 to about 15% by weight. When formulated as ointments, the active ingredients are typically combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include additional ingredients to enhance skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope of the present invention.
The compounds of the invention may also be administered via a transdermal device. Thus, transdermal administration may be achieved using reservoir or porous membrane type patches or solid matrix type patches.
The invention also provides the use of a compound shown in the formula (I), a racemate, a stereoisomer, a tautomer, an isotope label, a solvate, a pharmaceutically acceptable salt or a prodrug compound thereof in preventing and/or treating inflammatory diseases.
According to an embodiment of the invention, the inflammatory disease may be selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g. asthma), chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel diseases (e.g. crohn's disease, ulcerative colitis). More particularly, the inflammatory disease refers to rheumatoid arthritis, chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease (e.g. crohn's disease, ulcerative colitis).
The present invention also provides a method for treating a disease, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound of formula (I), racemate, stereoisomer, tautomer, isotopic label, solvate, pharmaceutically acceptable salt or prodrug compound thereof, or administering to a patient a prophylactically or therapeutically effective amount of a pharmaceutical composition as described above.
Advantageous effects
The compounds of the present invention have good SIK inhibition and are useful in the treatment of SIK related diseases, such as inflammatory related diseases, and in the preparation of medicaments for such conditions or diseases. Moreover, the compound has good pharmacokinetic and other properties.
Definition and description of terms
Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures should be understood to be within the scope of the present description and/or claims.
The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, a numerical range "1-20" corresponds to each of the integer numbers recited in the numerical range "1-20," i.e., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. Furthermore, when certain numerical ranges are defined as "numbers," it is to be understood that both endpoints of the range, each integer within the range, and each fraction within the range are delineated. For example, a "number of 0 to 10" should be understood to describe not only each integer of 0, 1, 2, 3,4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.
It should be understood that in describing one, two or more herein, "more" shall mean an integer greater than 2, such as greater than or equal to 3, such as 3, 4,5,6,7, 8, 9 or 10.
The term "halogen" means fluorine, chlorine, bromine and iodine.
The term "C 1-20 alkyl" is understood to mean a straight or branched saturated monovalent hydrocarbon radical having from 1 to 20 carbon atoms. For example, "C 1- 12 alkyl" represents straight and branched alkyl groups having 1,2,3,4, 5, 6, 7, 8, 9,10, 11, or 12 carbon atoms, and "C 1-6 alkyl" represents straight and branched alkyl groups having 1,2,3,4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof.
The term "C 3-14 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) hydrocarbon ring or tricyclic hydrocarbon ring having 3 to 14 carbon atoms, preferably "C 3-12 cycloalkyl", more preferably "C 3-8 cycloalkyl". The term "C 3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. bridged, spiro) hydrocarbon ring or tricyclic hydrocarbon ring having 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. The C 3-12 cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as campholyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6-dimethylbicyclo [3.1.1] heptyl, 2, 6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 2, 7-diazaspiro [3,5] nonyl, 2, 6-diazaspiro [3,4] octyl, or a tricyclic hydrocarbon group such as adamantyl.
The term "3-14 membered heterocyclyl" refers to a saturated or unsaturated, non-aromatic ring or ring system, unless otherwise defined, which is, for example, a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic (e.g., fused, bridged, spiro) or tricyclic ring system, and contains at least one, e.g., 1,2,3, 4,5, or more heteroatoms selected from O, S and N, wherein N and S may also optionally be oxidized to various oxidation states to form the nitrogen oxides, -S (O) -or-S (O) 2 -state. Preferably, the heterocyclic group may be selected from "3-8 membered heterocyclic groups". The term "3-8 membered heterocyclyl" means a saturated or unsaturated, non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present. The heterocyclic group may include fused or bridged rings as well as spiro rings. In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclyl may be bicyclic, for example, but not limited to, a 5,5 membered ring such as hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl ring, or a 5,6 membered bicyclic ring such as 3, 8-diazabicyclo [3.2.1] octane, hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl ring, or a spiro ring such as 2, 7-diazaspiro [3.5] nonane, 7-oxa-2-azaspiro [3.5] nonane. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2, 5-dihydro-1H-pyrrolyl, 4H- [1,3,4] thiadiazinyl, 1,2,3, 5-tetrahydrooxazolyl, or 4H- [1,4] thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14 membered heterocyclic group is linked to other groups to form the compound of the present invention, the carbon atom on the 3-14 membered heterocyclic group may be linked to other groups, or the heterocyclic atom on the 3-14 membered heterocyclic ring may be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl, it may be that the nitrogen atom on the piperazinyl group is attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidyl, it may be that the nitrogen atom on the piperidyl ring and the carbon atom at the para position thereof are attached to other groups.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
The experimental procedures, which are not specified in the following examples, were carried out according to conventional methods and conditions, or according to the commercial specifications.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). The NMR shift (. Delta.) is given in units of 10 -6 (ppm). NMR was performed using a Bruker AVANCE III MHz nuclear magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and internal standard Tetramethylsilane (TMS).
The Mass Spectrum (MS) was determined by a Waters 2767 HPLC/WATERS SQD, waters H-class UPLC-SQD2, AGILENT HPLC/Waters liquid phase Mass Spectrometry.
Chiral HPLC analysis assay was performed using Shimadzu LC-20 AD.
The thin layer chromatography silica gel plate is used for forming GF254 silica gel plate of chemical industry (Shanghai) limited company, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.2-0.25 mm, and the specification of the silica gel plate used by the thin layer chromatography separation and purification product is 0.4-0.5 mm.
Column chromatography is generally used for 100-200 mesh silica gel of chemical industry (Shanghai) limited company as a carrier.
High performance liquid phase preparation using WATERS HPLC, gilson HPLC and Biotage MPLC preparative chromatography.
Chiral preparation was performed using GilsonGX-281 preparative HPLC.
In the following examples, unless otherwise specified, the reactions were carried out under nitrogen atmosphere. The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1 liter volume.
The temperature range of room temperature is 20-30 ℃.
Synthesis of intermediate A1
First step
Compound A1-1 (8.00 g, 0.03200 mol) was added to methanol (100 mL) and a 42% sodium methoxide methanol solution (10.3 g,0.08 mol) was slowly added under ice bath and nitrogen protection. After the addition was completed, the ice bath was removed, and the temperature was raised to 60℃and the reaction was continued with stirring for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (300 mL), ph=4-5 was adjusted with 1mol/L dilute hydrochloric acid, extracted with ethyl acetate (100 ml×3), the organic phases combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude compound A1-2 (8 g).
MS m/z(ESI):261.1(M+H)。
Second step
Compound A1-2 (8.00 g,0.0308 mol) was added to a methanol (100 mL) solvent, concentrated sulfuric acid (5 mL) was added under an ice bath, the ice bath was removed after the addition, and the reaction was heated to 80℃and stirred overnight. LCMS monitored completion of the reaction, the reaction was cooled to room temperature and poured into ice water (300 mL), extracted with ethyl acetate (100 mL x 3), the organic phases combined, washed sequentially with saturated sodium bicarbonate (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude compound A1-3 (8.00 g).
MS m/z(ESI):251.1(M+H)。
Third step
Compounds A1-3 (8.00 g,0.0278 mol) were added to anhydrous tetrahydrofuran (100 mL) and 1mol/L BCl 3 solution (33.4 mL,0.0334 mol) was slowly added under nitrogen protection at-65℃to-60℃and the reaction was allowed to proceed with stirring. LCMS monitored completion of the reaction, the reaction was poured into ice water (200 mL), extracted with ethyl acetate (100 mL x 3), the organic phases combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-2:1) to give compound A1-4 (5 g, 65.6% yield).
MS m/z(ESI):275.1(M+H)。
Fourth step
Compounds A1-4 (5.00 g,0.0182 mol) were dissolved in acetonitrile (20 mL) and water (20 mL) and potassium hydroxide (10.2 g,0.182 mol) was slowly added under ice-bath. After the addition was completed, the ice bath was removed, and the reaction solution was stirred at room temperature for 1 hour, then diethyl (bromodifluoromethyl) phosphonate (7.26 g,0.0273 mol) was slowly added under ice bath, and the reaction solution was slowly warmed to room temperature and stirred for 4 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (30 mL) and extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-2:1) to give compound A1-5 (4.10 g, yield 69.6%).
MS m/z(ESI):325.1(M+H)。
Fifth step
Compounds A1-5 (4.10 g,0.0126 mol) were dissolved in methanol (10 mL) and 2mol/L aqueous sodium hydroxide solution (3 mL) was added dropwise under ice-bath, after which the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (30 mL), ph=4-5 was adjusted with 1mol/L dilute hydrochloric acid solution, and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude A1-6 (4 g).
MS m/z(ESI):297.1(M+H)。
Sixth step
Compound A1-6 (2.00 g,6.76 mmol) was dissolved in dichloromethane (15 mL) and then 2, 2-trifluoroethylamine (803 mg,8.11 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (3.84 g,10.1 mmol) and N, N-diisopropylethylamine (3.35 mL,20.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. LCMS monitored completion of the reaction, the reaction was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-2:1) to give intermediate A1 (2.30 g, yield 90.2%).
MS m/z(ESI):378.1(M+H)。
Synthesis of intermediate A2
First step
A1-6 (400 mg,1.35 mmol) was dissolved in dichloromethane (5 mL) and then cyclopropylamine (100 mg,1.76 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate (770 mg,2.03 mmol) and N, N-diisopropylethylamine (522 mg,4.05 mmol) were added sequentially, and after the addition, the reaction was stirred at room temperature overnight. LCMS monitored completion of the reaction, the reaction was poured into ice water (50 mL), extracted with dichloromethane (20 mL x 3), the organic phases combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-2:1) to afford intermediate A2 (280 mg, yield 61.7%).
MS m/z(ESI):336.0(M+H)。
Synthesis of intermediate 41-3
First step
A3-1 (5.00 g,0.0255 mol), N-Boc-piperazine (6.18 g,33.2 mol), sodium t-butoxide (7.35 g,0.0765 mol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (2.00 g,5.10 mmol), tris (dibenzylideneacetone) dipalladium (2.30 g,0.00255 mol) were added to toluene (50 mL) and the reaction mixture was heated to 100deg.C under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound A3-2 (2.60 g, 33.8% yield).
MS m/z(ESI):303.1(M+H)。
Second step
A3-2 (2.60 g,8.61 mmol) was added to anhydrous N, N-dimethylformamide (20 mL) as a solvent, N-bromosuccinimide (1.69 g,9.47 mmol) was added under nitrogen, and after the addition was completed, the reaction was stirred at room temperature under nitrogen protection overnight. LCMS monitored completion of the reaction, the reaction was poured into ice water (100 mL), extracted with ethyl acetate (80 mL x 3), the organic phases combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (petroleum ether: ethyl acetate=2:1) to afford intermediate 41-3 (2.00 g, 61.2% yield).
MS m/z(ESI):381.1(M+H)。
EXAMPLE 1 Synthesis of Compound 1
First step
Compound 1-1 (500 mg,2.55 mmol), compound 1-2 (222 mg,2.55 mmol), sodium t-butoxide (356 mg,7.65 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (162 mg,0.26 mmol) and tris (dibenzylideneacetone) dipalladium (117 mg,0.13 mmol) were added to toluene (5 mL). The reaction was heated to 100 ℃ under nitrogen and stirred overnight. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to obtain compound 1-3 (500 mg, yield 96.5%).
MS m/z(ESI):203.9(M+H)。
Second step
Compounds 1-3 (100 mg,0.49 mmol), compounds 1-4 (166 mg,0.49 mmol), trimethylacetic acid (50 mg,0.49 mmol), anhydrous potassium carbonate (204 mg,1.48 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (16.8 mg,0.024 mmol) were added to 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to obtain the crude product, followed by reverse phase preparation to obtain compound 1 (11.1 mg, yield 4.90%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.7Hz,1H),7.60(s,1H),7.18(s,1H),7.11(s,1H),6.72(d,J＝7.6Hz,1H),6.40(s,1H),4.34(q,J＝9.2Hz,2H),3.94(s,3H),3.71(t,J＝6.2Hz,2H),3.64–3.54(m,2H),3.56–3.46(m,2H),3.39–3.33(m,1H),3.06(t,J＝6.2Hz,2H),2.25–2.15(m,1H),2.14–2.04(m,1H).
MS m/z(ESI):461.2(M+H)。
According to the procedure of example 1, the chiral pure compounds are prepared respectivelyThe corresponding chiral pure products 1-P1 and 1-P2 are obtained:
EXAMPLE 2 Synthesis of Compound 2
First step
Compound 1-1 (500 mg,2.55 mmol), compound 2-2 (258 mg,2.55 mmol), sodium t-butoxide (356 mg,7.65 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (162 mg,0.26 mmol), tris (dibenzylideneacetone) dipalladium (117 mg,0.13 mmol) were added to toluene (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to obtain compound 2-3 (500 mg, yield 90.3%).
MS m/z(ESI):218.1(M+H)。
Second step
Compound 2-3 (100 mg,0.46 mmol), compound 1-4 (155 mg,0.46 mmol), trimethylacetic acid (47.0 mg,0.46 mmol), anhydrous potassium carbonate (190 mg,1.38 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (16.8 mg,0.024 mmol) were added to 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to obtain the crude product, followed by reverse phase preparation to obtain compound 2 (30.0 mg, yield 13.8%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.5Hz,1H),7.56(s,1H),7.17(s,1H),7.10(s,1H),6.68(d,J＝8.0Hz,1H),6.39(s,1H),4.32(t,J＝9.5Hz,2H),4.19(s,1H),3.94(s,3H),3.71(t,J＝5.9Hz,2H),3.59(d,J＝10.7Hz,1H),3.47(t,J＝11.4Hz,4H),3.39(s,3H),3.06(t,J＝6.1Hz,2H),2.22(s,1H).
MS m/z(ESI):475.2(M+H)。
According to the procedure of example 2, the chiral pure compounds are prepared respectivelyThe corresponding chiral pure products 2-P1 and 2-P2 are obtained:
Compounds of formula (I) 2-P1： 1H NMR(400MHz,CD 3OD)δ8.45(d,J＝7.6Hz,1H),7.69(s,1H),7.22(s,1H),7.13(s,1H),6.82(d,J＝7.6Hz,1H),6.46(s,1H),4.34(q,J＝9.1Hz,2H),4.20(s,1H),3.94(s,3H),3.72(t,J＝5.9Hz,2H),3.56(dt,J＝36.0,8.7Hz,4H),3.39(s,3H),3.07(t,J＝5.9Hz,2H),2.31–2.14(m,2H).
MS m/z(ESI):475.2(M+H)；
Compounds of formula (I) 2-P2： 1H NMR(400MHz,CD 3OD)δ8.41(d,J＝7.7Hz,1H),7.55(s,1H),7.16(s,1H),7.08(s,1H),6.66(d,J＝7.0Hz,1H),6.37(s,1H),4.33(q,J＝9.2Hz,2H),4.18(s,1H),3.94(s,3H),3.70(t,J＝6.0Hz,2H),3.57(dd,J＝10.9,4.3Hz,1H),3.46(t,J＝11.1Hz,3H),3.39(s,3H),3.05(t,J＝5.8Hz,2H),2.17(dd,J＝14.2,9.2Hz,2H).
MS m/z(ESI):475.2(M+H)。
EXAMPLE 3 Synthesis of Compounds 3-P1 and 3-P2
Compound 3-1 (100 mg,0.46 mmol), compound A1 (186 mg,0.49 mmol), trimethylacetic acid (50 mg,0.49 mmol), anhydrous potassium carbonate (204 mg,1.48 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (41 mg,0.049 mmol) were added sequentially to 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 3-P1 (25 mg, yield 10.2%).
1H NMR(400MHz,CD 3OD)δ8.33(d,J＝7.6Hz,1H),7.50(s,1H),7.12(s,1H),7.08(s,0.25H),7.01(s,1H),6.90(s,0.5H),6.72(s,0.25H),6.68(d,J＝7.7,2.3Hz,1H),6.38(s,1H),4.08(q,J＝9.3Hz,2H),3.92(s,3H),3.64–3.53(m,2H),3.53–3.44(m,1H),3.38–3.33(m,2H),2.26–2.14(m,1H),2.13–2.04(m,1H).
MS m/z(ESI):501.1(M+H)。
Referring to the synthetic method of 3-P1, compound 3-P2 is obtained from compound 3-3 and compound A1.
1H NMR(400MHz,DMSO-d 6)δ9.01(t,J＝6.4Hz,1H),8.43(d,J＝7.7Hz,1H),7.60(s,1H),7.44(s,0.25H),7.26(s,0.5H),7.12(d,J＝1.3Hz,1H),7.07(s,0.25H),6.98(d,J＝1.1Hz,1H),6.62(dd,J＝7.7,2.5Hz,1H),6.33(d,J＝2.3Hz,1H),5.07(d,J＝3.6Hz,1H),4.11–3.98(m,2H),3.87(s,3H),3.53–3.45(m,2H),3.34–3.27(m,2H),3.19(d,J＝10.5Hz,1H),2.14–2.00(m,1H),1.92(dd,J＝12.8,3.7Hz,1H).
MS m/z(ESI):501.1(M+H)。
EXAMPLE 4 Synthesis of Compound 4
The first step:
Compound 1-1 (200 mg,1.03 mmol), compound 4-2 (121 mg,1.03 mmol), sodium t-butoxide (293 mg,3.09 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (128 mg,0.206 mmol), tris (dibenzylideneacetone) dipalladium (94.0 mg,0.103 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 4-3 (100 mg, yield 41.6%). MS M/z (ESI): 234.1 (M+H).
And a second step of:
Compounds 4-3 (100 mg,0.429 mmol), compounds 1-4 (145 mg,0.429 mmol), trimethylacetic acid (44.0 mg,0.429 mmol), anhydrous potassium carbonate (178 mg,1.29 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (32.0 mg,0.0429 mmol) were added to 1, 4-dioxane (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 4 (25.0 mg, 11.9% yield).
1H NMR(400MHz,CD 3OD)δ8.45(d,J＝7.8Hz,1H),7.63(s,1H),7.18(s,1H),7.10(s,1H),6.94(d,J＝7.8Hz,1H),6.78(s,1H),4.33(q,J＝9.2Hz,2H),4.07(d,J＝11.6Hz,1H),3.94(s,3H),3.81–3.61(m,8H),3.05(t,J＝6.2Hz,2H),2.91(td,J＝12.3,3.5Hz,1H),2.68(t,J＝10.9Hz,1H).
MS m/z(ESI):491.1(M+H)。
EXAMPLE 5 Synthesis of Compound 5
The first step:
Compound 1-1 (100 mg,0.510 mmol), compound 5-2 (44.7 mg,0.612 mmol), sodium t-butoxide (123 mg,1.28 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63.5 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (46.7 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 5-3 (80.0 mg, 83.0% yield). MS M/z (ESI): 190.1 (M+H).
And a second step of:
Compounds 5-3 (80.0 mg,0.423 mmol), compounds 1-4 (142 mg,0.423 mmol), trimethylacetic acid (43.1 mg,0.423 mmol), anhydrous potassium carbonate (175 mg,1.27 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (30.9 mg,0.0423 mmol) were added to 1, 4-dioxane (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 5 (20.0 mg, yield 10.6%).
1H NMR(400MHz,CD 3OD)δ8.40(d,J＝7.5Hz,1H),7.56(s,1H),7.11(d,J＝33.2Hz,2H),6.45(dd,J＝7.6,2.3Hz,1H),6.29(d,J＝2.3Hz,1H),4.80–4.65(m,1H),4.40–4.19(m,4H),3.93(s,3H),3.82–3.71(m,2H),3.70(t,J＝6.3Hz,2H),3.04(t,J＝6.3Hz,2H).
MS m/z(ESI):447.2(M+H)。
EXAMPLE 6 Synthesis of Compound 6
The first step:
Compound 1-1 (100 mg,0.510 mmol), compound 6-2 (61.8 mg,0.612 mmol), sodium t-butoxide (123 mg,1.28 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63.5 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (46.7 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 6-3 (70.0 mg, 63.2% yield). MS M/z (ESI): 218.1 (M+H).
Second step
Compounds 6-3 (70.0 mg,0.323 mmol), compounds 1-4 (109 mg,0.323 mmol), trimethylacetic acid (32.9 mg,0.323 mmol), anhydrous potassium carbonate (134 mg,0.969 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (23.6 mg,0.0323 mmol) were added to 1, 4-dioxane (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was prepared in reverse phase to give compound 6 (26.0 mg, 17.0% yield).
1H NMR(400MHz,CD 3OD)δ8.46(d,J＝7.9Hz,1H),7.75(s,1H),7.23(s,1H),7.15(s,1H),7.11(d,J＝7.7Hz,1H),6.84(s,1H),4.35(q,J＝18.2,9.1Hz,2H),3.99–3.80(m,6H),3.72(t,J＝6.0Hz,2H),3.26(t,J＝10.8Hz,2H),3.07(t,J＝6.0Hz,2H),2.05–1.93(m,2H),1.67–1.56(m,2H).
MS m/z(ESI):475.2(M+H)。
EXAMPLE 7 Synthesis of Compound 7
The first step:
Compound 1-1 (100 mg,0.510 mmol), compound 7-2 (61.2 mg,0.612 mmol), sodium t-butoxide (123 mg,1.28 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63.5 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (46.7 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 7-3 (100 mg, yield 90.7%). MS M/z (ESI): 217.1 (M+H).
And a second step of:
Compounds 7-3 (100 mg,0.463 mmol), compounds 1-4 (156 mg,0.463 mmol), trimethylacetic acid (47.2 mg,0.463 mmol), anhydrous potassium carbonate (192 mg,1.39 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (33.8 mg,0.0463 mmol) were added sequentially to 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was prepared in reverse phase to give compound 7 (20.0 mg, 9.13% yield).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.7Hz,1H),7.63(s,1H),7.18(s,1H),7.10(s,1H),6.93(d,J＝7.7Hz,1H),6.78(s,1H),4.33(q,J＝9.1Hz,2H),3.94(s,3H),3.71(t,J＝6.0Hz,2H),3.44–3.34(m,4H),3.05(t,J＝6.0Hz,2H),2.70–2.56(m,4H),2.38(s,3H).
MS m/z(ESI):474.2(M+H)。
EXAMPLE 8 Synthesis of Compound 8
First step
Compound 1-3 (440 mg,2.17 mmol) was dissolved in dimethylformamide (10 mL) and sodium hydrogen (262 mg,6.51mmol, 60%) was slowly added under ice-bath and nitrogen protection. The reaction was stirred under ice bath conditions for 20 minutes. At this temperature, compound 8-1 (678 mg,3.26 mmol) was slowly added. The reaction was then allowed to slowly warm to room temperature and stirred overnight. LCMS monitored reaction was complete. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 8-2 (120 mg, yield 16.7%).
MS m/z(ESI):332.1(M+H)。
Second step
Compound 8-2 (120 mg,0.36 mmol), compound 1-4 (121 mg,0.36 mmol), trimethylacetic acid (37 mg,0.36 mmol), potassium carbonate (150 mg,1.09 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (30 mg,0.036 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 8-3 (70 mg, yield 33.2%).
MS m/z(ESI):589.2(M+H)。
Third step
Compound 8-3 (70 mg,0.12 mmol) was dissolved in dichloromethane (3 mL) and 4mol/L dioxane hydrochloride (1 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by reverse production to give compound 8 (2.8 mg, yield 4.67%).
1H NMR(400MHz,CD 3OD)δ8.43(d,J＝7.7Hz,1H),7.58(s,1H),7.18(s,1H),7.10(s,1H),6.70(dd,J＝7.7,2.2Hz,1H),6.39(s,1H),4.39–4.27(m,3H),3.94(s,3H),3.74–3.65(m,4H),3.64–3.56(m,3H),3.54–3.46(m,3H),3.05(t,J＝6.2Hz,2H),2.30–2.09(m,2H).
MS m/z(ESI):505.3(M+H)。
EXAMPLE 9 Synthesis of Compound 9
First step
Compound 1-1 (250 mg,1.27 mmol), compound 9-2 (155 mg,1.53 mmol), sodium t-butoxide (365 mg,3.81 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (158 mg,0.254 mmol), tris (dibenzylideneacetone) dipalladium (116 mg,0.127 mmol) were added to toluene (10 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 9-3 (220 mg, 79.8% yield). MS M/z (ESI): 218.1 (M+H).
Second step
Compounds 9-3 (100 mg, 0.463mmol), compounds 1-4 (155 mg, 0.463mmol), trimethylacetic acid (47.0 mg, 0.463mmol), anhydrous potassium carbonate (191 mg,1.38 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (33.7 mg,0.0461 mmol) were added sequentially to 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 9 (20.0 mg, 9.15% yield).
1H NMR(400MHz,CD 3OD)δ8.46(s,1H),7.74(s,1H),7.24(s,1H),7.15(s,1H),6.87(d,J＝7.8Hz,1H),6.48(s,1H),4.35(q,J＝9.2Hz,2H),3.95(s,3H),3.79–3.42(m,8H),3.07(t,J＝6.3Hz,2H),2.69–2.54(m,1H),2.28–2.14(m,1H),1.98–1.81(m,1H).
MS m/z(ESI):475.2(M+H)。
EXAMPLE 10 Synthesis of Compound 10
First step
Compound 1-1 (200 mg,1.02 mmol), compound 10-1 (218 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.20 mmol), tris (dibenzylideneacetone) dipalladium (94 mg,0.10 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 10-2 (140 mg, yield 41.5%).
MS m/z(ESI):331.2(M+H)。
Second step
Compound 10-2 (140 mg,0.42 mmol), compound 1-4 (143 mg,0.42 mmol), trimethylacetic acid (43 mg,0.42 mmol), potassium carbonate (175 mg,1.27 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (35 mg,0.042 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 10-3 (140 mg, yield 41.5%).
MS m/z(ESI):588.3(M+H)。
Third step
Compound 10-3 (140 mg,0.24 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by reverse direction preparation to give compound 10 (25 mg, yield 21.6%).
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.6Hz,1H),7.55(s,1H),7.12(d,J＝29.2Hz,2H),6.66(dd,J＝7.6,2.2Hz,1H),6.37(s,1H),4.33(q,J＝9.3Hz,2H),3.94(s,3H),3.70(t,J＝6.2Hz,2H),3.61(t,J＝8.6Hz,1H),3.53(dt,J＝11.3,5.7Hz,1H),3.42(q,J＝8.4Hz,1H),3.13(t,J＝8.7Hz,1H),3.05(t,J＝6.3Hz,2H),2.77(d,J＝7.1Hz,2H),2.60(p,J＝7.5Hz,1H),2.49(s,3H),2.32–2.22(m,1H),1.91–1.76(m,1H).
MS m/z(ESI):488.2(M+H)。
EXAMPLE 11 Synthesis of Compound 11
Compound 9-3 (100 mg, 0.463mmol), compound A1 (174 mg, 0.463mmol), trimethylacetic acid (47.0 mg, 0.463mmol), anhydrous potassium carbonate (191 mg,1.38 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (33.7 mg,0.0461 mmol) were added sequentially to 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 11 (15.0 mg, yield 5.05%).
1H NMR(400MHz,CD 3OD)δ8.44(s,1H),8.37(d,J＝7.7Hz,1H),7.73(s,1H),7.21(s,1H),6.93–6.87(m,1.65H),6.73(s,0.35H),6.49(s,1H),4.09(q,J＝9.2Hz,2H),3.93(s,3H),3.72–3.44(m,6H),2.68–2.57(m,1H),2.30–2.15(m,1H),2.00–1.86(m,1H).
MS m/z(ESI):515.2(M+H)。
EXAMPLE 12 Synthesis of Compound 12
The first step:
Compound 1-1 (250 mg,1.27 mmol), compound 12-2 (199mg, 1.53 mmol), sodium t-butoxide (366 mg,3.81 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (158 mg,0.254 mmol), tris (dibenzylideneacetone) dipalladium (116 mg,0.127 mmol) were added to toluene (10 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 12-3 (210 mg, 67.2% yield). MS M/z (ESI): 247.2 (M+H).
And a second step of:
Compounds 12-3 (100 mg,0.406 mmol), compounds 1-4 (137 mg,0.406 mmol), trimethylacetic acid (41.4 mg,0.406 mmol), anhydrous potassium carbonate (168 mg,1.22 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (29.7 mg,0.0406 mmol) were added to 1, 4-dioxane (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 12 (30.0 mg, 14.7% yield).
1H NMR(400MHz,CD 3OD)δ8.45(d,J＝7.7Hz,1H),7.62(s,1H),7.19(s,1H),7.11(s,1H),6.93(d,J＝7.9Hz,1H),6.77(s,1H),4.34(q,J＝9.2Hz,2H),3.94(s,3H),3.79–3.67(m,4H),3.41–3.34(m,4H),3.06(t,J＝6.3Hz,2H),2.78–2.69(m,4H),2.61(t,J＝6.0Hz,2H).
MS m/z(ESI):504.2(M+H)。
EXAMPLE 13 Synthesis of Compound 13
The first step:
Compound 1-1 (200 mg,1.02 mmol), compound 13-2 (116 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (127 mg,0.204 mmol) and tris (dibenzylideneacetone) dipalladium (94 mg,0.102 mmol) were added sequentially to toluene (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 13-3 (160 mg, yield 68.4%). MS M/z (ESI): 231.1 (M+H) +.
And a second step of:
Compounds 13-3 (160 mg,0.684 mmol), compounds 1-4 (231 mg,0.684 mmol), trimethylacetic acid (70.0 mg,0.684 mmol), potassium carbonate (284 mg,2.05 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (56.0 mg,0.0684 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, followed by reverse preparation to isolate and purify compound 13 (22.0 mg, yield 6.61%).
1H NMR(400MHz,CD 3OD)δ8.40(d,J＝7.5Hz,1H),7.55(s,1H),7.15(s,1H),7.07(s,1H), 6.42(dd,J＝7.4,2.2Hz,1H),6.26(s,1H),4.33(q,J＝9.2Hz,2H),4.13(t,J＝7.8Hz,2H),3.93(s,3H),3.68(dt,J＝12.9,6.3Hz,4H),3.04(t,J＝6.1Hz,2H),3.01(s,1H),2.67(d,J＝7.3Hz,2H),2.29(s,6H).
MS m/z(ESI):488.2(M+H)。
EXAMPLE 14 Synthesis of Compound 14
First step
Compound 1-1 (200 mg,1.02 mmol), compound 14-2 (102 mg,1.02 mmol), sodium t-butoxide (295 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (127 mg,0.204 mmol) and tris (dibenzylideneacetone) dipalladium (93.0 mg,0.102 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 14-3 (150 mg, yield 68.1%).
MS m/z(ESI):217.14(M+H)
Second step
Compound 14-3 (150 mg,0.694 mmol), compound 1-4 (233 mg,0.694 mmol), trimethylacetic acid (71.0 mg,0.694 mmol), anhydrous potassium carbonate (288 mg,2.08 mmol), 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (50.0 mg,0.0694 mmol) were added to 1, 4-dioxane (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, which was then prepared in reverse phase to give compound 14 (5.0 mg, yield 1.52%).
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.5Hz,1H),7.58(s,1H),7.16(s,1H),7.08(s,1H),6.48(dd,J＝7.5,2.1Hz,1H),6.32(d,J＝2.2Hz,1H),4.33(q,J＝9.2Hz,2H),4.12(t,J＝7.5Hz,2H),3.93(s,3H),3.82(dd,J＝8.0,5.3Hz,2H),3.70(t,J＝6.2Hz,2H),3.35(d,J＝5.8Hz,1H),3.04(t,J＝6.2Hz,2H),2.26(s,6H).
MS m/z(ESI):474.2(M+H)。
EXAMPLE 15 Synthesis of Compound 15
The first step:
Compound 1-1 (200 mg,1.02 mmol), compound 15-2 (89.0 mg,1.02 mmol), sodium t-butoxide (295 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (93.0 mg,0.102 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 15-3 (130 mg, yield 68.1%). MS M/z (ESI): 203.1 (M+H).
And a second step of:
Compounds 15-3 (130 mg, 0.640 mmol), compounds 1-4 (216 mg, 0.640 mmol), trimethylacetic acid (65.0 mg, 0.640 mmol), potassium carbonate (266 mg,1.923 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (53.0 mg,0.0641 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 15 (4.70 mg, 6.61% yield).
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.5Hz,1H),7.57(s,1H),7.17(s,1H),7.09(s,1H),6.46(d,J＝7.5Hz,1H),6.27(s,1H),4.33(q,J＝9.2Hz,2H),4.06(t,J＝7.9Hz,2H),3.94(s,3H),3.78(t,J＝6.4Hz,4H),3.71(t,J＝6.2Hz,2H),3.05(t,J＝6.1Hz,2H),2.94(d,J＝8.5Hz,1H).
MS m/z(ESI):461.2(M+H)。
EXAMPLE 16 Synthesis of Compound 16
The first step:
Compound 16-1 (300 mg,1.49 mmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added under ice-bath. After the addition was completed, the ice bath was removed, and the reaction solution was stirred at room temperature for 2 hours. LCMS monitored completion of the reaction and the reaction was concentrated under reduced pressure to give crude 16-2 (150 mg, 99.1% yield). MS M/z (ESI): 102.1 (M+H).
And a second step of:
Compound 1-1 (294 mg,1.50 mmol), compound 16-2 (150 mg,1.50 mmol), sodium t-butoxide (433 mg,4.50 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (125 mg,0.300 mmol), tris (dibenzylideneacetone) dipalladium (92.0 mg,0.150 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 16-3 (100 mg, yield 30.7%). MS M/z (ESI): 218.1 (M+H) +.
And a third step of:
Compounds 16-3 (100 mg,0.460 mmol), compounds 1-4 (155 mg,0.460 mmol), trimethylacetic acid (47.0 mg,0.460 mmol), potassium carbonate (191 mg,1.38 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (40 mg,0.046 mmol) were added sequentially to anhydrous 1, 4-dioxane (5 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, followed by reverse preparation to give compound 16 (8.70 mg, yield 4.10%).
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.5Hz,1H),7.55(s,1H),7.17(s,1H),7.09(s,1H),6.44(d,J＝7.4Hz,1H),6.26(s,1H),4.33(q,J＝9.2Hz,2H),4.14(t,J＝7.7Hz,2H),3.94(s,3H),3.70(dd,J＝10.5,6.0Hz,4H),3.63(t,J＝6.3Hz,2H),3.05(t,J＝6.2Hz,2H),2.96–2.79(m,1H), 1.92(q,J＝6.7Hz,2H).
MS m/z(ESI):475.2(M+H)。
EXAMPLE 17 Synthesis of Compound 17
First step
Compound 16 (60 mg,0.13 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (40 mg,0.39 mmol) and methanesulfonyl chloride (23 mg,0.20 mmol) were added in this order under the ice bath and nitrogen protection, and after the addition was completed, the reaction was stirred at room temperature for 1 hour. LCMS monitored completion of the reaction, the reaction was poured into ice water (10 mL), extracted with dichloromethane (30 ml×3), the organic phases combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude compound 17-1 (65 mg, yield 91.5%).
MS m/z(ESI):553.1(M+H) +。
Second step
Compound 17-1 (65 mg,0.12 mmol) was dissolved in acetonitrile (2 mL), followed by addition of potassium carbonate (50 mg,0.36 mmol) and a 2mol/L solution of dimethylamine in tetrahydrofuran (0.18 mL), and after completion of the addition, the reaction mixture was heated to 80℃and stirred for overnight. TLC was used to monitor completion of the reaction, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was isolated and purified by reverse direction preparation to give compound 17 (1.9 mg, yield 3.2%).
1H NMR(400MHz,CD 3OD)δ8.47(d,J＝7.4Hz,1H),7.81(s,1H),7.26(s,1H),7.16(s,1H),6.70(d,J＝7.7Hz,1H),6.39(s,1H),4.37–4.31(m,4H),3.95(s,4H),3.73(s,2H),3.18(s,2H),3.08(s,2H),2.99(s,2H),2.93(s,6H),2.19(d,J＝9.0Hz,2H)
MS m/z(ESI):502.2(M+H)。
EXAMPLE 18 Synthesis of Compound 18
Compound 10 (50 mg,0.10 mmol) and 37% aqueous formaldehyde (25 mg,0.31 mmol) were dissolved in methanol (2 mL mmol) in sequence, sodium triacetylborohydride (65 mg,0.31 mmol) was slowly added under ice-bath, after the addition was completed, slowly warmed to room temperature and stirred overnight. LCMS monitored completion of the reaction, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (20 ml×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by reverse production to give compound 18 (4.0 mg, yield 7.7%).
1H NMR(400MHz,CD 3OD)δ8.43(d,J＝7.6Hz,1H),7.55(s,1H),7.17(s,1H),7.10(s,1H),6.66(dd,J＝8.0,2.1Hz,1H),6.37(s,1H),4.33(q,J＝9.3Hz,2H),3.94(s,3H),3.71(t,J＝6.3Hz,2H),3.61(t,J＝8.7Hz,1H),3.50(d,J＝9.6Hz,1H),3.43(t,J＝8.2Hz,1H),3.09(dt,J＝23.2,7.2Hz,3H),2.69–2.58(m,1H),2.46(dd,J＝7.3,3.4Hz,2H),2.31(s,7H),1.86–1.73(m,1H).
MS m/z(ESI):502.3(M+H)。
EXAMPLE 19 Synthesis of Compound 19
First step
Compound 1-1 (100 mg,0.51 mmol), compound 19-2 (59.0 mg,0.510 mmol), sodium t-butoxide (147 mg,1.53 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (64.0 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (30.0 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 19-3 (90 mg, 81.2% yield). MS M/z (ESI): 218.12 (M+H).
Second step
Compounds 19-3 (90.0 mg,0.420 mmol), compounds 1-4 (142 mg,0.420 mmol), trimethylacetic acid (43.0 mg,0.420 mmol), potassium carbonate (174 mg,1.26 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (35.0 mg,0.0420 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to afford compound 19 (10.0 mg, yield 5.10%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.6Hz,1H),7.79(s,1H),7.26(d,J＝1.5Hz,1H),7.16(d,J＝1.5Hz,1H),6.69(dd,J＝7.6,2.2Hz,1H),6.36(d,J＝2.2Hz,1H),4.35(q,J＝9.2Hz,2H),4.23(t,J＝8.5Hz,2H),3.94(s,5H),3.72(t,J＝6.2Hz,2H),3.62(d,J＝5.9Hz,2H),3.40(s, 3H),3.09(dt,J＝12.5,5.9Hz,3H).
MS m/z(ESI):475.2(M+H)。
EXAMPLE 20 Synthesis of Compound 20
First step
Compound 1-1 (200 mg,1.02 mmol), compound 20-2 (117 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (94 mg,0.102 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 20-3 (100 mg, 42.4% yield). MS M/z (ESI): 232.1 (M+H).
Second step
Compounds 20-3 (100 mg,0.433 mmol), compounds 1-4 (146 mg,0.433 mmol), trimethylacetic acid (44.0 mg,0.433 mmol), potassium carbonate (180 mg,1.299 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (36.0 mg,0.0433 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 20 (5.00 mg, yield 2.40%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.6Hz,1H),7.65(s,1H),7.20(s,1H),7.12(s,1H),6.76(d,J＝7.8Hz,1H),6.41(s,1H),4.34(q,J＝9.2Hz,2H),3.94(s,3H),3.71(t,J＝6.2Hz,2H),3.53(dt,J＝29.1,7.8Hz,3H),3.44(d,J＝8.1Hz,2H),3.37(s,3H),3.23(t,J＝8.5Hz,1H),3.06(t,J＝6.2Hz,2H),2.76–2.64(m,1H),2.20(d,J＝11.9Hz,1H),1.94–1.83(m,1H).
MS m/z(ESI):489.2(M+H)。
EXAMPLE 21 Synthesis of Compound 21
First step
Compound 1-1 (200 mg,1.02 mmol), compound 21-2 (190 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (94.0 mg,0.102 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 21-3 (90.0 mg, 29.2% yield). MS M/z (ESI): 303.2 (M+H) +.
Second step
Compounds 21-3 (90.0 mg,0.298 mmol), compounds 1-4 (100 mg,0.298 mmol), trimethylacetic acid (31.0 mg,0.298 mmol), potassium carbonate (124 mg,0.894 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (25.0 mg,0.0298 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 21-5 (70.0 mg, 41.9% yield). MS M/z (ESI): 560.2 (M+H).
Third step
Compound 21-5 (70.0 mg,0.125 mmol) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by reverse direction preparation to give compound 21 (25.0 mg, yield 43.9%).
1H NMR(400MHz,CD 3OD)δ8.46(d,J＝7.7Hz,1H),7.64(s,1H),7.19(s,1H),7.12(s,1H),6.94(dd,J＝7.9,2.4Hz,1H),6.80(d,J＝2.3Hz,1H),4.34(q,J＝9.2Hz,2H),3.94(s,3H),3.71(t,J＝6.2Hz,2H),3.36(t,J＝5.1Hz,4H),3.07(dt,J＝11.3,5.6Hz,6H).
MS m/z(ESI):460.2(M+H)。
EXAMPLE 22 Synthesis of Compound 22
First step
Compound 1-1 (100 mg,0.510 mmol), compound 22-2 (65.0 mg,0.510 mmol), sodium t-butoxide (147 mg,1.53 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63.0 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (30.0 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 22-3 (80.0 mg, yield 64.0%). MS M/z (ESI): 245.1 (M+H).
Second step
Compounds 22-3 (80.0 mg,0.330 mmol), compounds 1-4 (111 mg,0.330 mmol), trimethylacetic acid (34.0 mg,0.330 mmol), potassium carbonate (137 mg,0.990 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (27.0 mg,0.0330 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 22 (10.0 mg, 6.10% yield).
1H NMR(400MHz,CD 3OD)δ8.46(d,J＝7.7Hz,1H),7.63(s,1H),7.20(d,J＝1.5Hz,1H),7.12(s,1H),6.94(dd,J＝7.8,2.5Hz,1H),6.78(d,J＝2.5Hz,1H),4.34(d,J＝9.2Hz,2H),3.95(s,3H),3.71(t,J＝6.3Hz,2H),3.38(t,J＝5.1Hz,4H),3.13(d,J＝2.3Hz,1H),3.06(t,J＝6.3Hz,2H),2.80–2.73(m,4H),1.14(d,J＝6.5Hz,6H).
MS m/z(ESI):502.2(M+H)。
EXAMPLE 23 Synthesis of Compound 23
Compound 21 was dissolved in anhydrous dichloromethane (5 mL), and triethylamine (27 mg,0.26 mmol) and acetyl chloride (10 mg,0.13 mmol) were added in this order under ice bath and nitrogen protection, and after the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (10 mL) and extracted with dichloromethane (20 ml×3). The organic phases were combined, washed with saturated brine (50 mL. Times.1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude product, which was purified by reverse phase preparation to give compound 23 (15 mg, yield 34.1%).
1H NMR(400MHz,CD 3OD)δ8.48(d,J＝7.7Hz,1H),7.66(s,1H),7.21(s,1H),7.13(s,1H),6.97(d,J＝8.1Hz,1H),6.81(s,1H),4.34(q,J＝9.2Hz,2H),3.95(s,3H),3.78–3.71(m,6H),3.43(d,J＝5.0Hz,2H),3.37(s,2H),3.07(s,2H),2.17(s,3H).
MS m/z(ESI):502.2(M+H)。
EXAMPLE 24 Synthesis of Compound 24
First step
Compound 1-1 (500 mg,2.55 mmol), compound 24-2 (383 mg,3.83 mmol), potassium phosphate (1.63 g,7.65 mmol), [ (2, 6-xylyl) amino ] (oxy) acetic acid (99.0 mg,0.510 mmol), and cuprous iodide (49.0 mg,0.255 mmol) were added sequentially to dimethyl sulfoxide (5 mL). The reaction mixture was heated to 90 ℃ under nitrogen and stirred for 48 hours. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 24-3 (50 mg, yield 9.1%).
MS m/z(ESI):217.1(M+H)。
And a second step of:
Compounds 24-3 (50.0 mg,0.230 mmol), compounds 1-4 (78.0 mg,0.230 mmol), trimethylacetic acid (23.0 mg,0.230 mmol), potassium carbonate (95.0 mg,0.690 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (19.0 mg,0.0230 mmol) were added sequentially to anhydrous 1, 4-dioxane (5 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 24 (11 mg, yield 10.1%).
1H NMR(400MHz,CD 3OD)δ8.49(d,J＝7.7Hz,1H),7.64(s,1H),7.19(s,1H),7.12(s,1H),6.93(dd,J＝7.8,2.4Hz,1H),6.77(d,J＝2.4Hz,1H),4.34(d,J＝9.2Hz,2H),3.99(s,2H),3.95(s,3H),3.71(t,J＝6.2Hz,2H),3.63(t,J＝5.3Hz,2H),3.51(t,J＝5.4Hz,2H),3.06(t,J＝6.2Hz,2H).
MS m/z(ESI):474.1(M+H)。
EXAMPLE 25 Synthesis of Compound 25
First step
Compound 1-1 (100 mg,0.510 mmol), compound 25-2 (58.0 mg,0.510 mmol), sodium t-butoxide (147 mg,1.53 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63.0 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (47.0 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 25-3 (48.0 mg, yield 41.1%). MS M/z (ESI): 231.1 (M+H).
And a second step of:
Compounds 25-3 (48.0 mg,0.210 mmol), compounds 1-4 (71.0 mg,0.210 mmol), trimethylacetic acid (22.0 mg,0.210 mmol), potassium carbonate (87.0 mg,0.630 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (18.0 mg,0.0210 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 25 (5.00 mg, yield 4.90%).
1H NMR(400MHz,CD 3OD)δ8.51(d,J＝7.8Hz,1H),7.65(s,1H),7.20(s,1H),7.13(s,1H),6.94(d,J＝7.9Hz,1H),6.78(s,1H),4.34(d,J＝9.3Hz,2H),4.00(s,2H),3.95(s,3H),3.70(t,J＝6.6Hz,4H),3.59(d,J＝5.4Hz,2H),3.06(d,J＝6.1Hz,5H).
MS m/z(ESI):488.1(M+H)。
EXAMPLE 26 Synthesis of Compound 26
First step
Compound 1-1 (200 mg,1.02 mmol), compound 26-2 (58 mg,1.02 mmol), sodium t-butoxide (295 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (127 mg,0.20 mmol), tris (dibenzylideneacetone) dipalladium (94 mg,0.10 mmol) were added to toluene (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 26-3 (130 mg, yield 44.8%).
MS m/z(ESI):285.1(M+H)。
Second step
Compounds 26-3 (130 mg,0.46 mmol), compounds 1-4 (155 mg,0.46 mmol), trimethylacetic acid (47 mg,0.46 mmol), potassium carbonate (191 mg,1.38 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (38 mg,0.046 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and reversely preparing, separating and purifying to obtain the compound 26 (5.7 mg, yield 2.1%).
1H NMR(400MHz,CD 3OD)δ8.45(d,J＝7.8Hz,1H),7.63(s,1H),7.19(s,1H),7.11(s,1H),6.93(dd,J＝7.8,2.4Hz,1H),6.77(d,J＝2.4Hz,1H),4.34(q,J＝9.3Hz,2H),3.94(s,3H),3.71(t,J＝6.2Hz,2H),3.37(t,J＝5.0Hz,4H),3.16(q,J＝9.7Hz,2H),3.06(t,J＝6.3Hz,2H),2.86(t,J＝4.9Hz,4H).
MS m/z(ESI):542.1(M+H)。
EXAMPLE 27 Synthesis of Compound 27
First step
Compound 1-1 (100 mg,0.51 mmol), compound 27-2 (45 mg,0.51 mmol), sodium t-butoxide (147 mg,1.53 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63 mg,0.10 mmol), tris (dibenzylideneacetone) dipalladium (47 mg,0.051 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 27-3 (60 mg, yield 57.7%).
MS m/z(ESI):204.1(M+H)。
Second step
Compounds 27-3 (60 mg,0.30 mmol), compounds 1-4 (101 mg,0.30 mmol), trimethylacetic acid (31 mg,0.30 mmol), potassium carbonate (124 mg,0.90 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (25 mg,0.030 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and reversely preparing, separating and purifying to obtain the compound 27 (25 mg, yield 18.1%).
1H NMR(400MHz,CD 3OD)δ8.47(d,J＝7.8Hz,1H),7.63(s,1H),7.19(d,J＝1.4Hz,1H),7.12(d,J＝1.5Hz,1H),6.94(dd,J＝7.8,2.5Hz,1H),6.78(d,J＝2.4Hz,1H),4.34(q,J＝9.3Hz,2H),3.94(s,3H),3.90–3.83(m,4H),3.71(t,J＝6.2Hz,2H),3.29(d,J＝5.9Hz,4H),3.06(t,J＝6.2Hz,2H).
MS m/z(ESI):461.2(M+H)。
EXAMPLE 28 Synthesis of Compound 28
First step
Compound 1-1 (300 mg,1.53 mmol), compound 21-2 (284 mg,1.53 mmol), sodium t-butoxide (441 mg,4.59 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (191 mg,0.31 mmol), tris (dibenzylideneacetone) dipalladium (140 mg,0.15 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 28-1 (150 mg, yield 32.5%).
MS m/z(ESI):303.1(M+H)。
Second step
Compound 28-1 (150 mg,0.50 mmol) was dissolved in dichloromethane (5 mL) and 4mol/L dioxane hydrochloride solution (2 mL) was slowly added under ice bath protection, after which the ice bath was removed and the reaction stirred at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to give crude compound 28-2 (130 mg).
MS m/z(ESI):203.1(M+H) +。
Third step
The crude compound 28-2 (58 mg,0.64 mmol) was dissolved in dichloromethane (10 mL) and then compound 28-3 (130 mg,0.64 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (367 mg,0.97 mmol) and N, N-diisopropylethylamine (0.32 mL,1.93 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. LCMS monitored reaction was complete. The reaction mixture was poured into ice water (30 mL), extracted with dichloromethane (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 28-4 (90 mg, yield 50.8%).
MS m/z(ESI):275.1(M+H) +。
Fourth step
Compound 28-4 (130 mg,0.33 mmol), 6-bromo-8-methoxy-2- (2, 2-trifluoroethyl) -3, 4-dihydroisoquinolin-1 (2H) -one 1-4 (111 mg,0.33 mmol), trimethylacetic acid (34 mg,0.33 mmol), potassium carbonate (136 mg,0.98 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (34 mg,0.033 mmol) were added to anhydrous 1, 4-dioxane (10 mL) in this order. The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, separating and purifying by a preparation plate (dichloromethane: methanol=10:1) to obtain crude product, and reversely preparing, separating and purifying to obtain compound 28 (3.1 mg, yield 1.7%).
1H NMR(400MHz,CD 3OD)δ8.51(d,J＝7.8Hz,1H),7.75(s,1H),7.24(s,1H),7.15(s,1H),7.09(d,J＝7.8Hz,1H),6.86(s,1H),4.35(q,J＝9.2Hz,2H),4.23(s,2H),3.95(s,3H),3.79(s,2H),3.72(t,J＝6.2Hz,4H),3.51(s,4H),3.43(s,3H),3.08(t,J＝6.2Hz,2H).
MS m/z(ESI):532.2(M+H)。
EXAMPLE 29 Synthesis of Compound 29
The first step:
Compound 1-1 (100 mg,0.51 mmol), compound 29-2 (58.0 mg,0.510 mmol), sodium t-butoxide (147 mg,1.53 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (63.0 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (47.0 mg,0.0510 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 29-3 (110 mg, yield 94.1%). MS M/z (ESI): 231.1 (M+H).
And a second step of:
Compounds 29-3 (110 mg,0.480 mmol), compounds 1-4 (162 mg,0.480 mmol), trimethylacetic acid (49.0 mg,0.480 mmol), potassium carbonate (199mg, 1.44 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (39.0 mg,0.0480 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 29 (5.00 mg, yield 2.10%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.7Hz,1H),7.62(s,1H),7.19(s,1H),7.11(s,1H),6.93(dd,J＝7.8,2.4Hz,1H),6.77(d,J＝2.4Hz,1H),4.34(q,J＝9.3Hz,2H),3.94(s,3H),3.80–3.66(m,4H),3.10–2.93(m,4H),2.62(t,J＝11.3Hz,1H),2.52–2.41(m,1H),2.37(s,4H),1.20(d,J＝6.2Hz,3H).
MS m/z(ESI):488.2(M+H)。
EXAMPLE 30 Synthesis of Compound 30
The first step:
Compound 1-1 (150 mg,0.765 mmol), compound 30-2 (117 mg, 0.178 mmol), sodium t-butoxide (292 mg,2.30 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (95.3 mg,0.153 mmol), tris (dibenzylideneacetone) dipalladium (70.1 mg,0.0765 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 30-3 (120 mg, yield 64.6%).
MS m/z(ESI):245.1(M+H)。
And a second step of:
Compounds 30-3 (120 mg,0.494 mmol), compounds 1-4 (166 mg,0.494 mmol), trimethylacetic acid (50.4 mg,0.494 mmol), potassium carbonate (205 mg,1.48 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (40.4 mg,0.0494 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to afford compound 30 (15.0 mg, 6.07% yield).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.7Hz,1H),7.64(s,1H),7.18(s,1H),7.11(s,1H),6.96(d,J＝7.9Hz,1H),6.78(s,1H),4.33(q,J＝9.2Hz,2H),3.94(s,3H),3.78(d,J＝12.4Hz,2H),3.71(t,J＝6.3Hz,2H),3.06(t,J＝6.2Hz,2H),2.71(t,J＝11.7Hz,2H),2.56(s,2H),2.42(s,3H),1.26(d,J＝6.1Hz,6H).
MS m/z(ESI):502.2(M+H)。
EXAMPLE 31 Synthesis of Compound 31
First step
Compound 1-1 (200 mg,1.02 mmol), compound 31-2 (216 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.20 mmol), tris (dibenzylideneacetone) dipalladium (94 mg,0.10 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 31-3 (180 mg, yield 53.7%).
MS m/z(ESI):329.2(M+H)。
Second step
Compounds 31-3 (80 mg,0.24 mmol), compounds 1-4 (100 mg,0.24 mmol), trimethylacetic acid (31 mg,0.24 mmol), potassium carbonate (101 mg,0.73 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (20 mg,0.024 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 31-4 (120 mg, yield 83.9%).
MS m/z(ESI):586.2(M+H)。
Third step
Compound 31-4 (120 mg,0.21 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3 mL) was slowly added under ice-bath conditions, and the reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction was concentrated under reduced pressure to give crude 31-5 (70 mg).
MS m/z(ESI):486.2(M+H)。
Fourth step
Compound 31-5 (70 mg,0.14 mmol) was dissolved in methanol (3 mL) and under ice-bath, 35% aqueous formaldehyde (0.05 mL) and sodium cyanoborohydride (27 mg,0.29 mmol) were added sequentially. The reaction was stirred at room temperature overnight. LCMS monitored completion of the reaction, and the reaction was concentrated under reduced pressure to give crude product, which was isolated and purified by reverse phase preparation to give compound 31 (14 mg, 13.7% yield in two steps).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.8Hz,1H),7.61(s,1H),7.19(s,1H),7.11(s,1H),6.89(dd,J＝7.8,2.5Hz,1H),6.66(d,J＝2.4Hz,1H),4.34(q,J＝9.3Hz,2H),3.94(s,3H),3.71(t,J＝6.2Hz,2H),3.61–3.54(m,2H),3.39(s,2H),3.15–3.03(m,4H),2.39(s,3H),2.18–2.11(m,2H),1.81(d,J＝7.8Hz,2H).
MS m/z(ESI):500.2(M+H)。
EXAMPLE 32 Synthesis of Compound 32
First step
Compound 1-1 (250 mg,1.28 mmol), compound 32-2 (197mg, 1.28 mmol), sodium t-butoxide (369 mg,3.84 mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (101 mg,0.256 mmol), tris (dibenzylideneacetone) dipalladium (117 mg,0.128 mmol) were added sequentially to toluene (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 32-3 (110 mg, 31.8% yield). MS M/z (ESI): 271.1 (M+H).
Second step
Compound 32-3 (110 mg,0.407 mmol) was dissolved in methanol (5 mL), 30% aqueous formaldehyde (83.0 mg,0.814 mmol) was added under ice-bath and nitrogen protection, stirring was continued for 20 min with ice-bath, and then sodium cyanoborohydride (51.0 mg,0.814 mmol) was slowly added. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 32-4 (60.0 mg, yield 51.7%).
MS m/z(ESI):285.1(M+H)。
Third step
Compounds 32-4 (60.0 mg,0.211 mmol), compounds 1-4 (71.0 mg,0.211 mmol), trimethylacetic acid (22.0 mg,0.211 mmol), potassium carbonate (87.0 mg,0.633 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (17.0 mg,0.0211 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 32 (6 mg, yield 5.30%).
1H NMR(400MHz,CD 3OD)δ8.49(d,J＝7.9Hz,1H),7.69(s,1H),7.21(s,1H),7.13(s,1H),6.98(d,J＝7.7Hz,1H),6.80(s,1H),4.34(q,J＝9.0Hz,2H),3.94(s,3H),3.83–3.74(m,2H),3.74–3.68(m,2H),3.56–3.45(m,2H),3.41–3.34(m,1H),3.27–3.21(m,1H),3.10–3.03(m,2H),2.82–2.72(m,1H),2.57(s,3H).
MS m/z(ESI):542.2(M+H)。
EXAMPLE 33 Synthesis of Compound 33
First step
Compound 1-1 (200 mg,1.02 mmol), compound 33-1 (231 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (81 mg,0.20 mmol), tris (dibenzylideneacetone) dipalladium (93 mg,0.10 mmol) were added to toluene (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 33-2 (190 mg, yield 54.4%).
MS m/z(ESI):343.2(M+H) +。
Second step
Compound 33-2 (190 mg,0.56 mmol), compound 1-4 (87 mg,0.56 mmol), trimethylacetic acid (57 mg,0.56 mmol), potassium carbonate (230 mg,1.67 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (46 mg,0.056 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 33-3 (120 mg, yield 36.1%).
MS m/z(ESI):600.2(M+H) +。
Third step
Compound 33-3 (120 mg,0.20 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 33-4 (100 mg).
MS m/z(ESI):500.2(M+H) +。
Fourth step
The crude compound 33-4 (100 mg,0.20 mmol) was dissolved in methanol (5 mL), 30% aqueous formaldehyde (40 mg,0.40 mmol) was added under ice-bath, stirring was continued for 20min with ice-bath, after which sodium cyanoborohydride (25 mg,0.40 mmol) was slowly added. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (20 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phases washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude, which was isolated and purified by reverse direction to give compound 33 (10 mg, yield 9.8%).
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.5Hz,1H),7.56(s,1H),7.16(s,1H),7.09(s,1H),6.46(d,J＝7.4Hz,1H),6.29(d,J＝2.2Hz,1H),4.33(q,J＝9.2Hz,2H),3.94(s,3H),3.75(s,3H),3.70(t,J＝6.3Hz,2H),3.05(t,J＝6.3Hz,2H),2.34(s,6H),1.93(d,J＝6.1Hz,4H),1.29(s,2H).
MS m/z(ESI):514.2(M+H)。
EXAMPLE 34 Synthesis of Compound 34
First step
Compound 1-1 (150 mg,0.765 mmol), compound 34-2 (117 mg, 0.178 mmol), sodium t-butoxide (292 mg,2.30 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (95.3 mg,0.153 mmol), tris (dibenzylideneacetone) dipalladium (70.1 mg,0.0765 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 34-3 (120 mg, yield 64.6%).
MS m/z(ESI):244.1(M+H)。
Second step
Compounds 34-3 (120 mg,0.494 mmol), compounds 1-4 (166 mg,0.494 mmol), trimethylacetic acid (50.4 mg,0.494 mmol), potassium carbonate (205 mg,1.48 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (40.4 mg,0.0494 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude product which was isolated and purified by reverse direction to give compound 34 (15.0 mg, 6.07% yield).
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.5Hz,1H),7.56(s,1H),7.16(s,1H),7.09(s,1H),6.47(d,J＝7.8Hz,1H),6.30(s,1H),4.33(q,J＝9.2Hz,2H),3.94(s,3H),3.79(s,4H),3.70(q,J＝5.6,4.8Hz,6H),3.05(t,J＝6.3Hz,2H),1.87(t,J＝5.1Hz,4H).
MS m/z(ESI):501.2(M+H)。
EXAMPLE 35 Synthesis of Compound 35
First step
Compound 35-1 (5.00 g,0.022 mol) was dissolved in anhydrous tetrahydrofuran (50 mL). 2mol/L lithium diisopropylamide (16.4 mL,0.033mol, 2M) was slowly added dropwise under nitrogen protection at a controlled temperature of-65℃to-60 ℃. The resulting reaction solution was kept at-65℃to-60℃for further stirring for 30 minutes, after which compound 35-2 (8.25 g,0.026 mol) was added in portions. The reaction was slowly warmed to room temperature and stirred overnight. TLC monitored completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (150 ml×3). The organic phases were combined, washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 35-3 (1.30 g).
MS m/z(ESI):248.1(M+H)。
Second step
The crude compound 35-3 (1.30 g,5.26 mmol) was dissolved in methanol (10 mL) and 2mol/L LiOH solution (3 mL) was added dropwise under ice-bath conditions, after which the reaction was allowed to slowly warm to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (30 mL), ph=4 to 5 was adjusted with 1mol/L dilute hydrochloric acid solution, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 35-4 (1.10 g).
MS m/z(ESI):234.1(M+H)。
Third step
The crude compound 35-4 (1.10 g,7.33 mmol) was dissolved in dichloromethane (15 mL) and then a solution of 2mol/L dimethylamine in tetrahydrofuran (4.72 mL,9.44 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (2.69 g,7.08 mmol) and N, N-diisopropylethylamine (2.40 mL,14.2 mmol) were added sequentially. The resulting reaction solution was allowed to stand at room temperature with stirring overnight. LCMS monitored completion of the reaction, the reaction was poured into ice water (50 mL) and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-2:1) to give compound 35-5 (1.10 g, three-step yield 19.3%)
MS m/z(ESI):261.1(M+H)。
Fourth step
Compound 35-5 (1.10 g,4.23 mmol) was dissolved in tetrahydrofuran (10 mL). 1mol/L of borane in tetrahydrofuran (42.3 mL,42.3 mmol) was slowly added dropwise to the reaction solution under ice bath and nitrogen protection, after the addition was completed, the ice bath was removed and the reaction was continued stirring at room temperature overnight. TLC monitored reaction was complete. The reaction mixture was placed in an ice bath, quenched with methanol (20 mL) and concentrated under reduced pressure to give crude product. The crude product was dissolved in ethanol (30 mL) and heated to 90℃and stirred for 2 hours. LCMS monitored completion of the reaction, and the reaction mixture was concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 35-6 (500 mg, yield 48.1%).
MS m/z(ESI):247.1(M+H)。
Fifth step
Compound 35-6 (250 mg) was dissolved in methylene chloride (3 mL) and a 4mol/L dioxane hydrochloride solution (2 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude 35-7 (150 mg).
MS m/z(ESI):147.1(M+H)。
Sixth step
Compounds 1-1 (202 mg,1.03 mmol), crude compound 35-7 (150 mg,1.03 mmol), sodium t-butoxide (293 mg,3.09 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (129 mg,0.206 mmol), tris (dibenzylideneacetone) dipalladium (95 mg,0.103 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 35-8 (130 mg, yield 48.1%).
MS m/z(ESI):263.1(M+H)。
Seventh step
Compounds 35-8 (130 mg,0.496 mmol), compounds 1-4 (167 mg,0.496 mmol), trimethylacetic acid (51.0 mg,0.496 mmol), potassium carbonate (206 mg,1.49 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (41.0 mg,0.0496 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, followed by reverse preparation to give compound 35 (23.6 mg, 9.1% yield).
1H NMR(400MHz,CD 3OD)δ8.54(d,J＝7.7Hz,1H),7.86(s,1H),7.28(d,J＝1.5Hz,1H),7.19(d,J＝1.5Hz,1H),6.99(dd,J＝7.8,2.4Hz,1H),6.68(d,J＝2.3Hz,1H),4.35(q,J＝9.2Hz,2H),4.03(dd,J＝21.6,12.6Hz,1H),3.95(s,3H),3.91(d,J＝8.7Hz,2H),3.86(d,J＝6.8Hz,2H),3.78–3.69(m,3H),3.09(s,8H),2.65(td,J＝15.6,15.2,6.5Hz,1H),2.46(ddt,J＝39.2,13.8,9.9Hz,1H).
MS m/z(ESI):520.2(M+H)。
EXAMPLE 36 Synthesis of Compound 36
First step
Compound 36-1 (10.0 g,0.0465 mol) was dissolved in anhydrous tetrahydrofuran (50 mL), 2mol/L of lithium diisopropylamide (34.9 mL,0.0698 mol) was slowly added dropwise under nitrogen protection at-65℃to-60℃and stirring was continued for 30 minutes at-65℃to-60℃and then compound 35-2 (17.6 g,0.0262 mol) was added in portions. The reaction was slowly warmed to room temperature and stirred overnight. TLC monitored completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (150 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 36-3 (2.30 g).
MS m/z(ESI):234.1(M+H)。
Second step
Compound 36-3 (2.30 g,9.87 mmol) was dissolved in methanol (20 mL), and 2mol/L LiOH solution (3 mL) was added dropwise under ice-bath conditions, and after the addition was completed, the reaction was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (30 mL), ph=4 to 5 was adjusted with 1mol/L dilute hydrochloric acid solution, and extracted with ethyl acetate (50 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 36-4 (2.10 g). MS M/z (ESI): 220.1 (M+H).
Third step
The crude compound 36-4 (2.10 g,9.59 mmol) was dissolved in acetonitrile (15 mL) and then a solution of 2mol/L dimethylamine in tetrahydrofuran (9.60 mL,19.2 mmol), 1-propylphosphoric anhydride (11.45 mL,19.2 mmol) and N, N-diisopropylethylamine (4.75 mL,28.8 mmol) were added sequentially. The reaction mixture was then stirred at room temperature overnight. LCMS monitored completion of the reaction, the reaction was poured into ice water (50 mL) and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 36-5 (430 mg, 3.76% yield in the first three steps). MS M/z (ESI): 247.1 (M+H).
Fourth step
Compound 36-5 (430 mg,1.75 mmol) was dissolved in tetrahydrofuran (10 mL), and 1mol/L borane in tetrahydrofuran (17.5 mL,17.5 mmol) was slowly added dropwise to the reaction solution under ice-bath and nitrogen protection, after the addition was complete, the ice-bath was removed and the reaction was continued under stirring at room temperature overnight. TLC monitored completion of the reaction, quenched with methanol (20 mL) in an ice bath, concentrated under reduced pressure to give crude product which was dissolved in ethanol (30 mL) and heated to 90 ℃ and stirred for 2 hours. LCMS monitored completion of the reaction, and the reaction mixture was concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 36-6 (220 mg, yield 54.2%). MS M/z (ESI): 233.1 (M+H).
Fifth step
Compound 36-6 (220 mg) was dissolved in methylene chloride (3 mL), and a 4mol/L dioxane hydrochloride solution (2 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 36-7 (180 mg). MS M/z (ESI): 133.1 (M+H).
Sixth step
Compound 1-1 (267 mg,1.36 mmol), compound 36-7 (180 mg,1.36 mmol), sodium t-butoxide (390 mg,4.08 mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (107 mg,0.272 mmol), tris (dibenzylideneacetone) dipalladium (125 mg,0.136 mmol) were added to toluene (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 36-8 (80.0 mg, yield 23.7%). MS M/z (ESI): 249.1 (M+H).
Seventh step
Compounds 36-8 (80.0 mg,0.323 mmol), compounds 1-4 (109 mg,0.323 mmol), trimethylacetic acid (33.0 mg,0.323 mmol), potassium carbonate (134 mg,0.969 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (26.0 mg,0.0323 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography over silica gel (dichloromethane: methanol=1:0-10:1) to give crude product, followed by reverse preparation to give compound 36 (1.20 mg, yield 0.74%).
1H NMR(400MHz,CD 3OD)δ8.56(d,J＝7.5Hz,1H),7.89(s,1H),7.27(d,J＝1.5Hz,1H),7.17(d,J＝1.5Hz,1H),6.80(dd,J＝7.6,2.3Hz,1H),6.59(d,J＝2.3Hz,1H),4.55(d,J＝1.9Hz,2H),4.53–4.46(m,2H),4.35(q,J＝9.2Hz,2H),4.03–3.87(m,5H),3.73(t,J＝6.2Hz,2H),3.08(t,J＝6.2Hz,2H),3.02(s,6H).
MS m/z(ESI):506.2(M+H)。
EXAMPLE 37 Synthesis of Compound 37
First step
Compound 9 (100 mg,0.22 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (66 mg,0.65 mmol) and methanesulfonyl chloride (38 mg,0.323 mmol) were added dropwise in sequence under ice-bath and nitrogen. After the completion of the dropwise addition, the reaction solution was allowed to stand at room temperature with stirring for 1 hour. LCMS monitored completion of the reaction, the reaction was poured into ice water (10 mL), extracted with dichloromethane (30 mL x 3), the organic phases combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to give crude compound 37-1 (80 mg, yield 68.4%).
MS m/z(ESI):539.1(M+H)。
Second step
Compound 37-1 (80 mg,0.15 mmol) was dissolved in acetonitrile (2 mL), followed by the addition of potassium carbonate (62 mg,0.45 mmol) and N-methylethylamine (18 mg,0.30 mmol). After the addition was completed, the reaction mixture was heated to 80℃and stirred overnight. TLC was used to monitor completion of the reaction, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was isolated and purified by reverse direction preparation to give compound 37 (12 mg, yield 16.1%).
1H NMR(400MHz,CD 3OD)δ8.50(d,J＝7.6Hz,1H),7.84(s,1H),7.26(s,1H),7.16(s,1H),6.72(d,J＝7.7Hz,1H),6.44(s,1H),4.44–4.31(m,4H),4.02(t,J＝7.2Hz,2H),3.94(s,3H),3.73(t,J＝6.2Hz,2H),3.68–3.59(m,1H),3.56–3.47(m,1H),3.45–3.37(m,1H),3.27–3.16(m,2H),3.08(t,J＝6.2Hz,2H),2.89(s,3H),1.38(t,J＝7.1Hz,3H).
MS m/z(ESI):502.2(M+H)。
EXAMPLE 38 Synthesis of Compound 38
Compound 37-1 (80.0 mg,0.149 mmol) was dissolved in acetonitrile (2 mL), followed by addition of potassium carbonate (62.0 mg,0.447 mmol) and N-methylpropan-2-amine (22.0 mg,0.298 mmol), and after completion of the addition, the reaction mixture was heated to 80℃and stirred overnight. The reaction was monitored by TLC, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by reverse direction preparation (dichloromethane: methanol=1:0-10:1) to give compound 38 (16.5 mg, yield 20.8%).
1H NMR(400MHz,CD 3OD)δ8.52(s,1H),7.62(s,1H),7.17(d,J＝31.0Hz,2H),6.43(s,1H),6.23(s,1H),4.35(q,J＝9.3Hz,2H),4.16(t,J＝7.4Hz,2H),3.96(s,3H),3.80–3.63(m,4H),3.14–2.98(m,4H),2.97–2.85(m,2H),2.39(s,3H),1.15(d,J＝6.6Hz,6H).
MS m/z(ESI):516.2(M+H)。
EXAMPLE 39 Synthesis of Compound 39
First step
Compound 39-1 (250 mg,1.03 mmol) was added to a tetrahydrofuran (10 mL) solvent, and a 1mol/L solution of LiHMDS in tetrahydrofuran (1.6 mL,1.60 mmol) was added under ice-bath and nitrogen protection, and the resulting reaction solution was stirred for a further 30 minutes at this temperature. To the reaction solution was added dropwise compound 39-2 (178 mg,2.06 mmol) at this temperature. After the completion of the dropwise addition, the reaction solution was heated at 80℃and stirred for 2 hours. LCMS monitored reaction was complete. The reaction solution was cooled, poured into ice water (20 mL), extracted with ethyl acetate (30 ml×3), and the organic phases were combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=3:1) to give compound 39-3 (220 mg, yield 65.7%).
MS m/z(ESI):326.1(M+H)。
Second step
Compound 1-1 (150 mg,0.765 mmol), compound 39-4 (87.0 mg,0.765 mmol), sodium t-butoxide (220 mg,2.29 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (95.0 mg,0.153 mmol), tris (dibenzylideneacetone) dipalladium (70.0 mg,0.0765 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 39-5 (107 mg, 60.8% yield).
MS m/z(ESI):231.1(M+H)。
Third step
Compound 39-5 (107 mg, 0.463mmol), compound 39-3 (157 mg, 0.463mmol), trimethylacetic acid (48.0 mg, 0.460 mmol), potassium carbonate (192 mg,1.39 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (38.0 mg,0.0465 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 39 (2.70 mg, yield 1.20%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.6Hz,1H),7.60(s,1H),7.37(s,2H),6.49–6.43 (m,1H),6.28(s,1H),4.33(q,J＝9.2Hz,2H),4.15(t,J＝7.9Hz,2H),3.77(t,J＝6.4Hz,2H),3.69(t,J＝6.7Hz,2H),3.13(t,J＝6.3Hz,2H),3.02(s,1H),2.68(d,J＝7.3Hz,2H),2.29(s,6H).
MS m/z(ESI):476.2(M+H)。
EXAMPLE 40 Synthesis of Compound 40
First step
Compounds 1-4 (50 mg,0.15 mmol) were dissolved in anhydrous dichloromethane (2 mL). Under ice bath and nitrogen protection, 1mol/L boron tribromide dichloromethane solution (0.52 mL,0.52 mmol) was slowly added dropwise, and after the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored reaction was complete. The reaction mixture was poured into ice water (20 mL) and extracted with methylene chloride (20 mL ×). The organic phases were combined, washed with saturated brine (50 mL × a), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by preparative plate separation (dichloromethane: methanol=10:1) to give compound 40-2 (40 mg, yield 83.3%).
MS m/z(ESI):324.1(M+H) +。
Second step
Compound 40-3 (29.0 mg,0.124 mmol), compound 40-2 (40.0 mg,0.124 mmol), trimethylacetic acid (13.0 mg,0.124 mmol), potassium carbonate (52.0 mg,0.372 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (10.0 mg,0.0124 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 40 (2 mg, yield 3.40%).
1H NMR(400MHz,CD 3OD)δ8.48(d,J＝7.6Hz,1H),7.79(s,1H),7.09(s,1H),7.01(s,1H),6.73(d,J＝8.5Hz,1H),6.43(s,1H),4.44–4.29(m,4H),4.05–3.99(m,2H),3.83–3.78(m,2H),3.57(d,J＝7.3Hz,2H),3.43–3.36(m,1H),3.16–3.10(m,2H),2.94(s,6H).
MS m/z(ESI):474.2(M+H)。
EXAMPLE 41 Synthesis of Compound 41
First step
Compounds 1-4 (250 mg,0.774 mmol) were dissolved in acetonitrile (10 mL) and cesium carbonate (757 mg,2.32 mmol) and D3-p-toluenesulfonyl methyl ester (190 mg,1.01 mmol) were added sequentially. The reaction was then stirred at room temperature overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 41-1 (160 mg, 60.8% yield).
MS m/z(ESI):341.0(M+H)。
Second step
Compound 41-1 (160 mg,0.471 mmol), pinacol biborate (155 mg,0.612 mmol), potassium acetate (138 mg,1.41 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (38.5 mg,0.0471 mmol) were added sequentially to anhydrous 1, 4-dioxane (5 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 41-2 (160 mg, yield 87.5%).
MS m/z(ESI):389.2(M+H)。
Third step
Compound 41-3 (130 mg,0.343 mmol), compound 41-2 (160 mg,0.412 mmol), potassium carbonate (118 mg,0.858 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (28.1 mg,0.0343 mmol) were added sequentially to anhydrous 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=10:1) to give compound 41-4 (148 mg, 76.7% yield).
MS m/z(ESI):563.3(M+H)。
Fourth step
Compound 41-4 (148 mg,0.263 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL) was added slowly under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 41-5 (130 mg).
MS m/z(ESI):463.3(M+H)。
Fifth step
Compound 41-5 (130 mg, 0.281mmol) was dissolved in acetonitrile (5 mL) and N, N-diisopropylethylamine (109 mg,0.844 mmol) and 2-bromoacetonitrile (50.2 mg, 0.426 mmol) were added sequentially. The reaction was then stirred at room temperature overnight. TLC was used to monitor the completion of the reaction, and the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was then reversely prepared for isolation and purification to give compound 41 (35.0 mg, two-step yield 26.6%).
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),8.01(d,J＝2.0Hz,1H),7.72(d,J＝9.7Hz,1H),7.15(dd,J＝9.6,2.0Hz,1H),7.06(d,J＝1.6Hz,1H),6.98(d,J＝1.5Hz,1H),4.23(q,J＝9.0Hz,2H),3.67(t,J＝6.2Hz,2H),3.62(s,2H),3.19(t,J＝5.0Hz,4H),3.03(t,J＝6.2Hz,2H),2.83(t,J＝4.9Hz,4H).
MS m/z(ESI):502.3(M+H)。
EXAMPLE 42 Synthesis of Compound 42
First step
Compound 1-1 (200 mg,1.02 mmol), compound 42-1 (216 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (93.0 mg,0.102 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 42-2 (110 mg, yield 32.8%).
MS m/z(ESI):329.2(M+H)。
Second step
Compound 42-2 (110 mg,0.335 mmol), compound 1-4 (113 mg,0.335 mmol), trimethylacetic acid (34.0 mg,0.335 mmol), potassium carbonate (139 mg,1.01 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (27.0 mg,0.0335 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 42-3 (120 mg, yield 61.2%).
MS m/z(ESI):586.3(M+H)。
Third step
Compound 42-3 (120 mg,0.205 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 42-4 (100 mg). MS M/z (ESI): 486.2 (M+H) +.
Fourth step
The crude compound 42-4 (100 mg,0.205 mmol) was dissolved in methanol (5 mL), 30% aqueous formaldehyde (40.0 mg,0.410 mmol) was added under ice-bath and nitrogen protection, stirring was continued for 20 min with ice-bath, and then sodium cyanoborohydride (25.0 mg,0.410 mmol) was slowly added. The reaction solution was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (20 mL), extracted with ethyl acetate (30 ml×3), the organic phases combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude compound 42 (11.0 mg, yield 10.8%) which was isolated and purified by reverse phase preparation.
1H NMR(400MHz,CD 3OD)δ8.42(d,J＝7.7Hz,1H),7.58(s,1H),7.17(s,1H),7.10(s,1H),6.81(dd,J＝7.2,2.3Hz,1H),6.66(d,J＝2.4Hz,1H),4.33(q,J＝9.6Hz,4H),3.94(s,3H),3.70(t,J＝6.2Hz,2H),3.05(t,J＝6.2Hz,2H),2.65(d,J＝11.4Hz,2H),2.43(d,J＝11.0Hz,2H),2.18(s,3H),2.05(t,J＝8.1Hz,4H).
MS m/z(ESI):500.2(M+H)。
EXAMPLE 43 Synthesis of Compound 43
First step
Compound 43-1 (1.00 g,4.53 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (1.39 g,13.60 mmol) and methanesulfonyl chloride (775 mg,6.79 mmol) were added sequentially under ice-bath and nitrogen. The reaction mixture was stirred at room temperature for 1 hour. LCMS monitored reaction was complete. The reaction solution was poured into ice water (10 mL), extracted with dichloromethane (30 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 43-2 (1.20 g, yield 88.9%).
MS m/z(ESI):300.1(M+H)。
Second step
The crude compound 43-2 (1.20 g,4.01 mmol) was dissolved in acetonitrile (10 mL) and potassium carbonate (1.66 g,12.00 mmol) and N-methylpropan-2-amine (585 mg,8.02 mmol) were added sequentially. The reaction mixture was stirred overnight by heating to 70 ℃. TLC monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating and purifying by silica gel column (petroleum ether: ethyl acetate=3:1) to obtain compound 43-3 (350 mg, yield 31.8%).
MS m/z(ESI):277.2(M+H)。
Third step
Compound 43-3 (350 mg,1.27 mmol) was added to a solvent of absolute ethanol (10 mL), and 10% palladium on carbon (40 mg) was added. The reaction mixture was heated to 50 ℃ with hydrogen balloon filling and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude compound 43-4 (170 mg, 94.5% yield).
MS m/z(ESI):143.1(M+H)。
Fourth step
Compound 43-4 (170 mg,1.19 mmol), compound 1-1 (233 mg,1.19 mmol), sodium t-butoxide (343 mg,3.57 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (148 mg,0.238 mmol), tris (dibenzylideneacetone) dipalladium (109 mg,0.119 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give 43-5 (68.0 mg, yield 22.1%).
MS m/z(ESI):259.1(M+H)。
Fifth step
Compounds 43-5 (68.0 mg,0.264 mmol), compounds 1-4 (89.0 mg,0.264 mmol), trimethylacetic acid (27.0 mg,0.264 mmol), potassium carbonate (109 mg,0.792 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (22.0 mg,0.0264 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 43 (3.10 mg, yield 2.30%).
1H NMR(400MHz,CD 3OD)δ8.56(d,J＝7.8Hz,1H),7.88(s,1H),7.28(d,J＝1.5Hz,1H),7.19(s,1H),7.02(dd,J＝7.6,2.4Hz,1H),6.69(d,J＝2.4Hz,1H),4.40–4.23(m,3H),4.13–4.05(m,1H),3.95(s,3H),3.87(t,J＝9.6Hz,2H),3.76–3.66(m,3H),3.65–3.56(m,1H),3.09(t,J＝6.2Hz,2H),2.88(s,3H),2.73–2.64(m,1H),2.43–2.31(m,1H),1.43(d,J＝6.3Hz,6H).
MS m/z(ESI):516.2(M+H)。
EXAMPLE 44 Synthesis of Compound 44
First step
Compound 1-1 (200 mg,1.02 mmol), compound 44-1 (218 mg,1.02 mmol), sodium t-butoxide (284 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (93.0 mg,0.102 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 44-2 (100 mg, 29.7% yield).
MS m/z(ESI):331.2(M+H)。
Second step
Compound 44-2 (100 mg,0.303 mmol), compound 1-4 (102 mg,0.303 mmol), trimethylacetic acid (31.0 mg,0.303 mmol), potassium carbonate (126 mg,0.909 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (25.0 mg,0.0303 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 44-3 (130 mg, 73.1% yield).
MS m/z(ESI):588.2(M+H)。
Third step
Compound 44-3 (130 mg,0.221 mmol) was dissolved in dichloromethane (3 mL) and 4mol/L dioxane hydrochloride solution (1 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 44-4 (100 mg).
MS m/z(ESI):488.2(M+H)。
Fourth step
Compound 44-4 (100 mg,0.205 mmol) was dissolved in methanol (5 mL), and a 30% aqueous formaldehyde solution (40 mg,0.410 mmol) was added under ice-bath and nitrogen protection, and stirring was continued for 20 minutes while maintaining the ice-bath. Then, sodium cyanoborohydride (25 mg,0.410 mmol) was slowly added, and after the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was isolated and purified by reverse direction to give compound 44 (4.80 mg, yield 4.70%).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.7Hz,1H),7.61(s,1H),7.19(s,1H),7.12(s,1H),6.95–6.89(m,1H),6.75(s,1H),4.34(q,J＝9.3Hz,2H),3.94(s,3H),3.71(t,J＝6.1Hz,2H),3.37(s,2H),3.12(s,2H),3.06(t,J＝6.2Hz,2H),2.75(t,J＝5.3Hz,2H),2.31(s,3H),1.16(s,6H).
MS m/z(ESI):502.2(M+H)。
EXAMPLE 45 Synthesis of Compound 45
First step
Compound 45-2 (1.50 g,6.33 mmol) was dissolved in dichloromethane (15 mL) and 45-1 (886 mg,6.33 mmol) and trifluoroacetic acid (108 mg,0.95 mmol) were added dropwise in succession under ice-bath and nitrogen protection. The reaction solution was then slowly warmed to room temperature and stirred for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to give crude 45-3 (2.00 g).
MS m/z(ESI):274.1(M+H)。
Second step
Compound 45-3 (2.00 g,7.33 mmol) was dissolved in dichloromethane (30 mL) and then a solution of 2mol/L dimethylamine in tetrahydrofuran (5.5 mL,10.90 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (4.14 g,10.90 mmol) and N, N-diisopropylethylamine (2.83 g,21.90 mmol) were added sequentially. The reaction mixture was then stirred at room temperature overnight. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to obtain compound 45-4 (1.20 g, two-step yield 63.0%).
MS m/z(ESI):301.1(M+H)。
Third step
Compound 45-4 (1.20 g,4.00 mmol) was dissolved in tetrahydrofuran (20 mL) and a 1mol/L solution of borane in tetrahydrofuran (40 mL,40 mmol) was slowly added dropwise to the reaction solution under ice-bath and nitrogen protection. After the addition was complete, the ice bath was removed and the reaction mixture was heated to 60 ℃ and stirred overnight. TLC monitored reaction was complete. The reaction solution was quenched with methanol (100 mL) in an ice bath, concentrated under reduced pressure to give a crude product which was dissolved in ethanol (150 mL) and heated to 90℃and stirred for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 45-5 (680 mg, yield 56.7%).
MS m/z(ESI):287.1(M+H)。
Fourth step
Compound 45-5 (680 mg,2.38 mmol) was dissolved in ethanol (5 mL), and 10% palladium on carbon (70 mg) and 1 drop of acetic acid were added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. LCMS monitored completion of the reaction, the reaction was filtered and the filtrate concentrated under reduced pressure to give crude compound 45-6 (480 mg).
MS m/z(ESI):197.1(M+H) +。
Fifth step
Compounds 1-1 (200 mg,1.02 mmol), compounds 45-6 (200 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -diphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (93.0 mg,0.102 mmol) were added to toluene (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 45-7 (180 mg, 56.6% yield).
MS m/z(ESI):313.1(M+H)。
Sixth step
Compounds 45-7 (90.0 mg,0.288 mmol), compounds 1-4 (97.0 mg,0.288 mmol), trimethylacetic acid (29.0 mg,0.288 mmol), potassium carbonate (119 mg,0.864 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (24.0 mg,0.0288 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 45 (30.0 mg, yield 18.3%).
1H NMR(400MHz,CD 3OD)δ8.47(d,J＝7.6Hz,1H),7.62(s,1H),7.19(s,1H),7.12(s,1H),6.74(dd,J＝7.7,2.3Hz,1H),6.46(d,J＝2.4Hz,1H),4.34(q,J＝9.3Hz,2H),3.94(s,3H),3.71(t,J＝6.2Hz,2H),3.67–3.50(m,4H),3.06(t,J＝6.2Hz,2H),2.69(q,J＝14.7Hz,2H),2.40–2.25(m,8H).
MS m/z(ESI):570.2(M+H)。
EXAMPLE 46 Synthesis of Compound 46
First step
Compound 46-1 (3.00 g,16.20 mmol), p-methoxybenzylamine (2.22 g,16.20 mmol) and 4A molecular sieves (3.00 g) were added sequentially to anhydrous toluene (50 mL). The reaction solution was heated to 30℃under nitrogen and stirred for 2 days. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 46-2 (4.00 g).
MS m/z(ESI):305.1(M+H)。
Second step
Compound 46-2 (4.00 g,13.20 mmol) was dissolved in acetonitrile (40 mL). Trifluoroacetic acid (1.96 g,17.20 mmol), potassium bifluoride (827 mg,10.60 mmol) and N, N-dimethylformamide (4 mL) were added sequentially under ice-bath. The resulting reaction solution was stirred under ice bath for 5 minutes, and then trifluoromethyl trimethylsilane (2.93 mL,19.80 mmol) was added. The reaction solution was warmed to room temperature and the reaction was continued with stirring for 16 hours. The reaction was completed. The reaction was poured into ice saturated sodium bicarbonate (50 mL), ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-10:1) to give compound 46-3 (530 mg, two-step yield 8.7%).
MS m/z(ESI):374.1(M+H)。
Third step
To a solution of compound 46-3 (530 mg,1.42 mmol) in anhydrous methanol (10 mL) under nitrogen was added 10% palladium on carbon (50 mg). The nitrogen was replaced with hydrogen three times, and then the reaction solution was placed under a hydrogen atmosphere (hydrogen balloon) and stirred at room temperature overnight. LCMS monitored reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude 46-4 (410 mg).
MS m/z(ESI):255.1(M+H)。
Fourth step
Compound 46-4 (410 mg,1.62 mmol) was dissolved in methanol (5 mL) and 30% aqueous formaldehyde (4817 mg,4.86 mmol) was added under ice-bath and nitrogen protection. The reaction was stirred for an additional 20 minutes with ice bath, and sodium cyanoborohydride (204 mg,3.24 mmol) was added slowly. The reaction solution was then slowly warmed to room temperature and the reaction was continued with stirring for 16 hours. The reaction solution was poured into ice water (20 mL), extracted with ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine (100 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-3:1) to give compound 46-5 (100 mg, yield 21.9%).
MS m/z(ESI):283.1(M+H)。
Fifth step
Compound 46-5 (100 mg,0.36 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 46-6 (70 mg).
MS m/z(ESI):183.1(M+H)。
Sixth step
Compound 1-1 (75.0 mg,0.385 mmol), compound 46-6 (70.0 mg,0.385 mmol), sodium t-butoxide (112 mg,1.16 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (48.0 mg,0.077 mmol), tris (dibenzylideneacetone) dipalladium (35 mg,0.0385 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 110 ℃ under nitrogen and stirred for 24 hours. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 46-7 (45.0 mg, 39.1% yield).
MS m/z(ESI):299.1(M+H)。
Seventh step
Compounds 46-7 (45.0 mg,0.151 mmol), compounds 1-4 (51.0 mg,0.151 mmol), trimethylacetic acid (15.0 mg,0.151 mmol), potassium carbonate (53.0 mg, 0.4573 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (12.0 mg,0.0151 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 46 (1.8 mg, yield 2.20%).
1H NMR(400MHz,CD 3OD)δ8.49(d,J＝7.6Hz,1H),7.73(s,1H),7.24(s,1H),7.15(s,1H),6.87(d,J＝7.5Hz,1H),6.54(s,1H),4.35(q,J＝9.7,9.3Hz,2H),4.03–3.84(m,4H),3.78–3.65(m,4H),3.64–3.50(m,1H),3.07(t,J＝5.8Hz,2H),2.62–2.40(m,8H).
MS m/z(ESI):556.2(M+H)。
EXAMPLE 47 Synthesis of Compound 47
First step
Compound 47-1 (2.00 g,3.87 mmol), p-methoxybenzylamine (530 mg,3.87 mmol) and 4A molecular sieves (2 g) were added sequentially to anhydrous toluene (30 mL). The reaction mixture was heated to 30 ℃ under nitrogen and stirred for 2 days. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give crude compound 47-2 (4.10 g).
MS m/z(ESI):319.1(M+H)。
Second step
The crude compound 47-2 (4.10 g,12.9 mmol) was dissolved in acetonitrile (40 mL), trifluoroacetic acid (1.91 g,16.8 mmol), potassium dihydrofluoride (805 mg,10.3 mmol) and N, N-dimethylformamide (4 mL) were added sequentially under ice bath, stirring was continued under ice bath for 5 minutes after the addition was completed, and then trifluoromethyltrimethylsilane (2.86 mL,19.4 mmol) was added. The ice bath was removed, and the reaction was stirred at room temperature for 16 hours. The reaction was poured into ice saturated sodium bicarbonate (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-10:1) to give compound 47-3 (1.20 g, two-step yield 80.0%).
MS m/z(ESI):389.2(M+H)。
Third step
Compound 47-3 (1.2 g,3.09 mmol) was added to a solvent of anhydrous methanol (10 mL) and 10% palladium on carbon (120 mg) was added under nitrogen. The reaction mixture was stirred at room temperature under hydrogen protection overnight. LCMS monitored completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give crude compound 47-4 (900 mg).
MS m/z(ESI):269.1(M+H)。
Fourth step
The crude compound 47-4 (410 mg,1.62 mmol) was dissolved in methanol (5 mL), 30% aqueous formaldehyde (673 mg,6.72 mmol) was added under ice-bath and nitrogen protection, stirring was continued for 20 min with ice-bath, and then sodium cyanoborohydride (282 mg,4.48 mmol) was slowly added. The reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into ice water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-3:1) to give compound 47-5 (160 mg, yield 24.1%).
MS m/z(ESI):297.1(M+H)。
Fifth step
Compound 47-5 (160 mg,0.541 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 47-6 (100 mg).
MS m/z(ESI):197.1(M+H)。
Sixth step
Compounds 1-1 (100 mg,0.510 mmol), 47-6 (100 mg,0.510 mmol), sodium t-butoxide (147 mg,1.53 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (64.0 mg,0.102 mmol), tris (dibenzylideneacetone) dipalladium (47.0 mg,0.0510 mmol) were added to toluene (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 47-7 (35.0 mg, yield 22.1%).
MS m/z(ESI):313.1(M+H)。
Seventh step
Compounds 47-7 (35.0 mg,0.112 mmol), compounds 1-4 (38.0 mg,0.112 mmol), trimethylacetic acid (11.0 mg,0.112 mmol), potassium carbonate (47.0 mg,0.336 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (10.0 mg, 0.01102 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 47 (3.8 mg, yield 5.90%).
1H NMR(400MHz,CD 3OD)δ8.50(d,J＝7.8Hz,1H),7.83(s,1H),7.27(d,J＝1.5Hz,1H), 7.20(d,J＝18.3Hz,2H),6.88(s,1H),4.35(q,J＝9.2Hz,2H),3.95(s,3H),3.90(d,J＝12.7Hz,2H),3.73(t,J＝6.2Hz,2H),3.08(t,J＝6.2Hz,2H),2.55(q,J＝2.1Hz,6H),2.30(d,J＝14.1Hz,2H),2.19(t,J＝7.6Hz,1H),2.03(d,J＝6.1Hz,1H),1.93–1.83(m,2H).
MS m/z(ESI):570.2(M+H)。
EXAMPLE 48 Synthesis of Compound 48
First step
To a solution of compound 48-1 (1.00 g,8.77 mmol) in anhydrous dichloromethane (10 mL) under ice-bath and nitrogen was added pyridine (0.74 mL,9.21 mmol) and trifluoromethanesulfonic anhydride (1.48 mL,8.77 mmol) in sequence. After the addition was completed, the ice bath was removed, and the reaction mixture was stirred at room temperature for further 30 minutes. The reaction solution was used directly in the next step.
Second step
To a solution of 48-3 (1.90 g,8.77 mmol) of the compound in 1, 4-dioxane (20 mL) was added N, N-diisopropylethylamine (2.89 mL,17.5 mmol) and 48-2 (the reaction liquid of the previous step) in this order under ice bath and nitrogen. After the addition was completed, the reaction mixture was heated to 90℃and stirred for 3 hours. The reaction solution was cooled, concentrated under reduced pressure to give a crude product, and purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-10:1) to give compound 48-4 (168 mg, yield 6.1%).
MS m/z(ESI):317.2(M+H)。
Third step
To a solvent of compound 48-4 (168 mg,0.53 mmol) in absolute ethanol (10 mL) under nitrogen was added 10% palladium on carbon (20 mg). The reaction mixture was replaced with hydrogen three times, and then placed under a hydrogen atmosphere (hydrogen balloon), heated to 40 ℃ and stirred for reaction overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 48-5 (90 mg, yield 92.8%).
MS m/z(ESI):183.1(M+H)。
Fourth step
Crude compound 48-5 (90.0 mg, 0.495mmol), compound 1-1 (97.0 mg, 0.495mmol), sodium t-butoxide (143 mg,1.49 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (62.0 mg,0.0990 mmol), tris (dibenzylidene-propanone) dipalladium (45.0 mg,0.0495 mmol) were added to toluene (5 mL) in this order. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 48-6 (60.0 mg, 40.5% yield).
MS m/z(ESI):299.1(M+H)。
Fifth step
Compounds 48-6 (60.0 mg,0.201 mmol), compounds 1-4 (68.0 mg,0.201 mmol), trimethylacetic acid (21.0 mg,0.201 mmol), potassium carbonate (83.0 mg,0.603 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (17.0 mg,0.0201 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was isolated and purified via reverse prep to give compound 48 (19.2 mg, 16.9% yield).
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.7Hz,1H),7.66(s,1H),7.19(s,1H),7.11(s,1H),6.99–6.92(m,1H),6.77(s,1H),4.34(q,J＝9.2Hz,2H),3.94(s,3H),3.71(t,J＝6.1Hz,2H),3.42(q,J＝7.5Hz,1H),3.35(t,J＝5.0Hz,4H),3.06(t,J＝6.2Hz,2H),2.98–2.84(m,4H),1.29(d,J＝6.9Hz,3H).
MS m/z(ESI):556.2(M+H)。
EXAMPLE 49 Synthesis of Compound 49
First step
To a solution of compound 49-1 (10.00 g,38.90 mmol) in tetrahydrofuran (100 mL) was added sequentially, under ice-bath and nitrogen, trifluoromethyl trimethylsilane (11.00 g,77.80 mmol) and TBAF (tetrabutylammonium fluoride) (3.90 mL,3.9mmol,1M in THF). The resulting reaction was warmed to room temperature and stirred overnight. TLC monitored reaction was complete. The reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (300 ml×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography over silica gel (petroleum ether: ethyl acetate=1:0-3:1) to give compound 49-2 (9.00 g, yield 70.9%).
MS m/z(ESI):328.1(M+H)。
Second step
To a solution of compound 49-2 (9.00 g,27.50 mmol) in pyridine (200 mL) was slowly added dropwise thionyl chloride (33.00 g,0.28 mol) under ice-bath and nitrogen protection. After the completion of the dropwise addition, the ice bath was removed, and the reaction solution was heated to 110℃and stirred for 15 minutes. TLC monitored reaction was complete. The reaction solution was cooled, poured into ice water (400 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-3:1) to give compound 49-3 (2.50 g, yield 29.4%).
Third step
To a solution of compound 49-3 (2.50 g,8.09 mmol) in anhydrous methanol (30 mL) under nitrogen was added 10% palladium on carbon (250 mg). The reaction mixture was replaced three times with hydrogen, placed under a hydrogen atmosphere (hydrogen balloon), and heated to 50℃for 24 hours. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude compound 49-4 (1.70 g, yield 67.5%).
MS m/z(ESI):312.1(M+H)。
Fourth step
To a solution of crude compound 49-4 (1.70 g,5.47 mmol) in methanol (20 mL) was added 2mol/L aqueous NaOH (8.2 mL,16.4 mmol) under ice-bath conditions. After the addition was completed, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. TLC monitored reaction was complete. The reaction solution was poured into ice water (20 mL), ph=4 to 5 was adjusted with 1mol/L of diluted hydrochloric acid, extraction was performed with ethyl acetate (40 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 49-5 (1.50 g, yield 96.8%).
MS m/z(ESI):284.1(M+H)。
Fifth step
The crude compound 49-5 (1.50 g,5.30 mmol) was dissolved in dichloromethane (20 mL) and then a solution of 2mol/L dimethylamine in tetrahydrofuran (5 mL,10.00 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (3.02 g,7.95 mmol) and N, N-diisopropylethylamine (2.05 g,15.9 mmol) were added sequentially. After the addition was completed, the reaction was stirred at room temperature overnight. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-3:1) to obtain compound 49-6 (360 mg, yield 21.9%).
MS m/z(ESI):311.1(M+H)。
Sixth step
Compound 49-6 (360 mg,1.16 mmol) was dissolved in tetrahydrofuran (5 mL), and a 1mol/L borane tetrahydrofuran solution (12 mL,11.6 mmol) was slowly added dropwise to the reaction solution under ice-bath and nitrogen protection. After the addition was completed, the ice bath was removed, and the reaction solution was heated to 60 ℃ and stirred overnight. TLC monitored reaction was complete. The reaction was quenched with methanol (50 mL) in an ice bath. The crude product obtained by concentration under reduced pressure was dissolved in ethanol (50 mL), heated to 90℃and stirred for 2 hours. LCMS monitored reaction was complete. The reaction solution was cooled, concentrated under reduced pressure to give a crude product, and purified by silica gel column separation (petroleum ether: ethyl acetate=1:0-1:1) to give compound 49-7 (300 mg, yield 87.5%).
MS m/z(ESI):297.1(M+H)。
Seventh step
Compound 49-7 (300 mg,1.01 mmol) was dissolved in dichloromethane (3 mL) and 4mol/L dioxane hydrochloride solution (1 mL) was slowly added under ice-bath conditions. After the addition was completed, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to give crude compound 49-8 (200 mg).
MS m/z(ESI):197.1(M+H)。
Eighth step
Compounds 1-1 (200 mg,1.02 mmol), 49-8 (200 mg,1.02 mmol), sodium t-butoxide (254 mg,3.06 mmol), 1 '-binaphthyl-2, 2' -bisdiphenylphosphine (127 mg,0.204 mmol), tris (dibenzylideneacetone) dipalladium (93.0 mg,0.102 mmol) were added to toluene (5 mL) in sequence. The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (dichloromethane: methanol=1:0-10:1) to give compound 49-9 (75.0 mg, 23.6% yield).
MS m/z(ESI):313.2(M+H)。
Ninth step
Compounds 49-9 (75.0 mg,0.240 mmol), compounds 1-4 (81.0 mg,0.240 mmol), trimethylacetic acid (25.0 mg,0.240 mmol), potassium carbonate (100 mg,0.720 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (20.0 mg,0.0240 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction complete, the reaction mixture was filtered, the filtrate concentrated under reduced pressure to give crude product, which was isolated and purified via prep plate (dichloromethane: methanol=10:1) to give crude product, which was then reverse prep isolated and purified to give compound 49 (20.0 mg, 14.6% yield).
1H NMR(400MHz,CD 3OD)δ8.48(d,J＝7.6Hz,1H),7.63(s,1H),7.20(d,J＝1.5Hz,1H),7.12(d,J＝1.5Hz,1H),6.75(dd,J＝7.7,2.4Hz,1H),6.48(d,J＝2.3Hz,1H),4.34(q,J＝9.2Hz,2H),3.94(s,3H),3.78(d,J＝9.4Hz,1H),3.71(t,J＝6.4Hz,2H),3.59(dd,J＝10.9,5.2Hz,1H),3.38–3.34(m,1H),3.22–3.16(m,1H),3.06(t,J＝6.1Hz,2H),2.86–2.81(m,1H),2.50(dd,J＝8.1,2.4Hz,2H),2.33(s,6H),1.37(d,J＝6.6Hz,1H).
MS m/z(ESI):570.2(M+H)。
EXAMPLE 50 Synthesis of Compound 50
First step
Compound 37-1 (130 mg,0.242 mmol) was dissolved in acetonitrile (2 mL) and potassium carbonate (100 mg,0.726 mmol) and TMSCN (trimethylcyanosilane) (36.0 mg, 0.803 mmol) were added sequentially. The reaction mixture was heated to 60℃and stirred overnight. TLC was used to monitor the completion of the reaction, and the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was isolated and purified by reverse direction to give compound 50 (6.00 mg, yield 5.31%).
1H NMR 400MHz,CD 3OD)δ8.43(d,J＝7.5Hz,1H),7.57(s,1H),7.17(d,J＝1.6Hz,1H),7.09(d,J＝1.5Hz,1H),6.46(dd,J＝7.5,2.4Hz,1H),6.32(d,J＝2.3Hz,1H),4.34(q,J＝9.3Hz,2H),4.19(t,J＝7.9Hz,2H),3.94(s,3H),3.80(dd,J＝7.9,5.2Hz,2H),3.70(t,J＝6.2Hz,2H),3.15–3.11(m,1H),3.05(t,J＝6.3Hz,2H),2.89(d,J＝6.8Hz,2H).
MS m/z(ESI):470.2(M+H)。
EXAMPLE 51 Synthesis of Compound 51
First step
Compound 9 (120 mg, 0.255 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (77.0 mg,0.759 mmol) and methanesulfonyl chloride (43.0 mg,0.380 mmol) were added sequentially under ice-bath conditions and nitrogen. The reaction was then stirred at room temperature for 1 hour. LCMS monitored completion of the reaction, the reaction was poured into ice water (10 mL) and extracted with dichloromethane (30 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 51-1 (100 mg, yield 71.4%).
MS m/z(ESI):553.2(M+H)。
Second step
The crude compound 51-1 (100 mg,0.181 mmol) was dissolved in acetonitrile (2 mL) and potassium carbonate (75.0 mg,0.543mmol) and TMSCN (trimethylcyanosilane) (27.0 mg,0.272 mmol) were added sequentially. The reaction was then stirred overnight by raising the temperature to 60 ℃. TLC was used to monitor the completion of the reaction, and the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was isolated and purified by reverse direction to give compound 51 (3.40 mg, yield 3.89%).
1H NMR 400MHz,CD 3OD)δ8.51(d,J＝7.6Hz,1H),7.83(s,1H),7.28(d,J＝1.6Hz,1H),7.18(d,J＝1.6Hz,1H),6.96(dd,J＝7.6,2.4Hz,1H),6.56(d,J＝2.4Hz,1H),4.35(q,J＝9.2Hz,2H),3.95(s,3H),3.85–3.61(m,5H),3.56(d,J＝13.7Hz,1H),3.09(t,J＝6.2Hz,2H),2.82(m,1H),2.75(d,J＝6.8Hz,2H),2.39(m,1H),1.99(m,1H).
MS m/z(ESI):484.2(M+H)。
EXAMPLE 52 Synthesis of Compound 52
Compound 26-3 (100 mg,0.35 mmol), compound A2 (118 mg,0.35 mmol), trimethylacetic acid (36 mg,0.35 mmol), potassium carbonate (146 mg,1.06 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (29 mg,0.035 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 110 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, separating and purifying by a preparation plate (dichloromethane: methanol=10:1) to obtain crude product, and reversely preparing, separating and purifying to obtain compound 52 (30 mg, yield 15.8%).
1H NMR(400MHz,CD 3OD)δ8.35(d,J＝7.8Hz,1H),7.57(s,1H),7.12(d,J＝1.2Hz,1H),7.08(s,0.25H),7.00(s,1H),6.94(dd,J＝7.7,2.6Hz,1H),6.90(s,0.5H),6.77(d,J＝2.5Hz,1H),6.71(s,0.25H),3.92(s,3H),3.36(t,J＝5.1Hz,4H),3.16(q,J＝9.7Hz,2H),2.91–2.82(m,5H),0.86–0.77(m,2H),0.65–0.57(m,2H).
MS m/z(ESI):540.2(M+H)。
EXAMPLE 53 Synthesis of Compound 53
First step
Compound A3-1 (500 mg,2.55 mmol), compound 53-2 (399mg, 2.55 mmol), sodium t-butoxide (730 mg,7.65 mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (201 mg,0.51 mmol), tris (dibenzylideneacetone) dipalladium (233 mg,0.255 mmol) were added to toluene (10 mL) in sequence. The reaction was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 53-3 (480 mg, yield 69.5%).
MS m/z(ESI):272.1(M+H)。
Second step
Compound 53-3 (480 mg,1.77 mmol) was added to a solvent of acetonitrile (10 mL) and N-iodosuccinimide (439 mg,1.95 mmol) was added under nitrogen. The reaction was stirred at room temperature overnight under nitrogen blanket. LCMS monitored reaction was complete. The reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (30 mLx 3). The organic phases were combined, washed with saturated brine (100 ml x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography over silica gel (petroleum ether: ethyl acetate=2:1) to give compound 53-4 (250 mg, yield 35.6%).
MS m/z(ESI):398.1(M+H)。
Third step
1-4 (300 Mg, 0.89mmol), pinacol ester of biboronate (284 mg,1.16 mmol), potassium acetate (262 mg,2.67 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (72.8 mg,0.089 mmol) were added sequentially to anhydrous 1, 4-dioxane (5 mL), and the reaction mixture was heated to 100deg.C under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, the filtrate concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-3:1) to give the target compound 53-5 (260 mg, 75.9% yield).
MS m/z(ESI):386.2(M+H)。
Fourth step
Compound 53-4 (250 mg,0.63 mmol), compound 53-5 (242 mg,0.63 mmol), potassium carbonate (261 mg,1.89 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (52 mg,0.063 mmol) were added sequentially to a mixed solvent of anhydrous 1, 4-dioxane (10 mL) and water (1 mL). The reaction was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, separating and purifying with silica gel column (dichloromethane: methanol=10:1) to obtain crude product, and reversely preparing, separating and purifying to obtain compound 53 (17 mg, yield 5.1%).
1H NMR(400MHz,CD 3OD)δ8.24(s,1H),8.13(d,J＝2.0Hz,1H),7.92(d,J＝9.8Hz,1H),7.40(dd,J＝9.8,2.0Hz,1H),7.20(s,1H),7.14(s,1H),4.33(q,J＝9.2Hz,3H),4.15(d,J＝11.2Hz,1H),3.96(s,3H),3.94–3.85(m,1H),3.71–3.66(m,3H),3.46(d,J＝12.0Hz,1H),3.04(t,J＝6.1Hz,2H),2.94–2.79(m,2H).
MS m/z(ESI):529.2(M+H)。
EXAMPLE 54 Synthesis of Compound 54
First step
Compound A3-2 (150 mg,0.50 mmol) was added to acetonitrile (5 mL). N-iodosuccinimide (123 mg,0.55 mmol) was added slowly under ice-bath and nitrogen protection. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature overnight. LCMS monitored reaction was complete. The reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (30 mLx 3). The organic phases were combined, washed with saturated brine (100 ml x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (ethyl acetate: petroleum ether=0:1-2:1) to give compound 54-2 (120 mg, yield 56.3%).
MS m/z(ESI):429.1(M+H)。
Second step
Compound 54-2 (120 mg,0.28 mmol), compound 53-5 (108 mg,0.28 mmol), potassium carbonate (116 mg,0.84 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (23 mg,0.028 mmol) were added sequentially to a mixed solvent of anhydrous 1, 4-dioxane (10 mL) and water (1 mL). The reaction was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel column separation (methanol: dichloromethane=0:1-10:1) to give compound 54-3 (45 mg, yield 28.7%).
MS m/z(ESI):560.2(M+H)。
Third step
Compound 54-3 (45 mg,0.081 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to give crude compound 54-4 (33 mg, yield 89.2%).
MS m/z(ESI):460.2(M+H)。
Fourth step
The crude compound 54-4 (33 mg,0.072 mmol) was dissolved in acetonitrile (2 mL) and N, N-diisopropylethylamine (28 mg,0.22 mmol) and 2, 2-trifluoroethyl trifluoromethanesulfonate (25 mg,0.11 mmol) were added sequentially. The resulting reaction solution was stirred at room temperature for 2 hours. TLC monitored reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mLx 3). The organic phases were combined, washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by reverse direction preparation to give compound 54 (5 mg, yield 12.8%).
1H NMR(400MHz,CD 3OD)δ8.17(s,1H),7.98(d,J＝2.0Hz,1H),7.81(d,J＝9.7Hz,1H),7.30(dd,J＝9.8,2.1Hz,1H),7.15(d,J＝1.6Hz,1H),7.08(d,J＝1.5Hz,1H),4.31(q,J＝9.3Hz,2H),3.94(s,3H),3.68(t,J＝6.2Hz,2H),3.21–3.09(m,6H),3.02(t,J＝6.2Hz,2H),2.87(dd,J＝6.0,3.6Hz,4H).
MS m/z(ESI):542.2(M+H)。
EXAMPLE 55 Synthesis of Compound 55
First step
Compound 55-1 (360 mg,2.79 mmol) was dissolved in acetonitrile (5 mL) and 26-2 (874 mg,3.63 mmol) and N, N-diisopropylethylamine (1.40 mL,8.37 mmol) were added sequentially under nitrogen. The reaction solution was then heated to 80℃and stirred for 3 hours. LCMS monitored reaction was complete. The reaction solution was cooled and concentrated under reduced pressure to give a crude product, which was purified by silica gel column separation (petroleum ether: ethyl acetate=10:1-2:1) to give compound 55-2 (320 mg, yield 44.0%).
MS m/z(ESI):262.1(M+H)。
Second step
Compound 55-2 (320 mg,1.23 mmol), sodium bicarbonate (207 mg,2.46 mmol), 40% aqueous chloroacetaldehyde (1.45 g,7.38 mmol) was added sequentially to ethanol (5 mL). The reaction solution was heated to 90℃under nitrogen protection and stirred for 2 hours. LCMS monitored reaction was complete. The reaction solution was cooled, concentrated under reduced pressure to give a crude product, and purified by silica gel column separation (dichloromethane: methanol=1:0-10:1) to give compound 55-3 (200 mg, yield 56.2%).
MS m/z(ESI):286.1(M+H)。
Third step
Compound 55-3 (200 mg,0.70 mmol) was dissolved in acetonitrile (5 mL) and N-bromosuccinimide (137 mg,0.77 mmol) was added slowly under ice-bath. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography over silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 55-4 (40 mg, yield 15.7%).
MS m/z(ESI):364.0(M+H)。
Fourth step
Compound 55-4 (40 mg,0.11 mmol), compound 53-5 (63.6 mg,0.17 mmol), potassium carbonate (46 mg,0.33 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (9 mg,0.01 mmol) were added sequentially to a mixed solvent of anhydrous 1, 4-dioxane (5 mL) and water (1 mL). The reaction was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, separating and purifying with silica gel plate (dichloromethane: methanol=1:0-10:1) to obtain crude product, and reversely preparing, separating and purifying to obtain compound 55 (12 mg, yield 20.1%).
1H NMR(400MHz,CDCl 3)δ8.30(d,J＝7.8Hz,1H),7.58(s,1H),6.95(d,J＝1.6Hz,1H),6.87(d,J＝1.5Hz,1H),6.48(d,J＝7.8Hz,1H),4.30–4.17(m,2H),3.96(s,3H),3.81(t,J＝5.0Hz,4H),3.67(t,J＝6.2Hz,2H),3.10–2.98(m,4H),2.79(t,J＝5.0Hz,4H).
MS m/z(ESI):543.2(M+H)。
EXAMPLE 56 Synthesis of Compound 56
First step
Compound 54-4 (100 mg,0.22 mmol) was dissolved in acetonitrile (3 mL) and cesium carbonate (142 mg,0.44 mmol) and bromoacetonitrile (52 mg,0.44 mmol) were added sequentially. The reaction was then stirred at room temperature overnight. TLC monitored reaction was complete. The reaction mixture was poured into water (30 mL), and extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (100 ml x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by reverse direction preparation to give compound 56 (17 mg, yield 13.6%).
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),8.01(d,J＝2.0Hz,1H),7.72(d,J＝9.7Hz,1H),7.15(dd,J＝9.7,2.1Hz,1H),7.07(d,J＝1.5Hz,1H),6.98(d,J＝1.5Hz,1H),4.23(q,J＝9.0Hz,2H),4.00(s,3H),3.66(t,J＝6.2Hz,2H),3.62(s,2H),3.19(t,J＝4.8Hz,4H),3.03(t,J＝6.2Hz,2H),2.82(t,J＝4.9Hz,4H).
MS m/z(ESI):499.2(M+H)。
EXAMPLE 57 Synthesis of Compound 57
First step
Compound 39-1 (300 mg,1.23 mmol) was added to methanol (100 mL). 42% sodium methoxide methanol solution (470 mg,3.09 mmol) was slowly added under ice bath and nitrogen protection. After the addition was completed, the ice bath was removed, and the temperature was raised to 60℃and the reaction was continued with stirring for 2 hours. LCMS monitored reaction was complete. The reaction solution was poured into ice water (300 mL), ph=4 to 5 was adjusted with 1mol/L of diluted hydrochloric acid, extraction was performed with ethyl acetate (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 57-1 (362 mg).
MS m/z(ESI):256.1(M+H)。
Second step
Compound 57-1 (360 mg,1.41 mmol), pinacol biborate (460 mg,1.84 mmol), potassium acetate (418 mg,4.23 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (115 mg,0.14 mmol) were added sequentially to anhydrous 1, 4-dioxane (8 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and separating and purifying by silica gel column (petroleum ether: ethyl acetate=1:0-2:1) to obtain compound 57-2 (320 mg, two-step yield 85.8%).
MS m/z(ESI):304.1(M+H)。
Third step
Compound 57-2 (100 mg,0.33 mmol), compound 41-3 (100 mg,0.26 mmol), potassium carbonate (109 mg,0.79 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (22 mg,0.026 mmol) were added sequentially to a mixed solvent of anhydrous 1, 4-dioxane (5 mL) and water (1 mL). The reaction was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was purified by silica gel plate separation (dichloromethane: methanol=10:1) to give compound 57-4 (54 mg, yield 52.5%).
MS m/z(ESI):478.2(M+H)。
Fourth step
Compound 57-4 (54 mg) was dissolved in methylene chloride (2 mL), and trifluoroacetic acid (1 mL) was slowly added under ice-bath conditions. After the addition was completed, the ice bath was removed, and the reaction solution was stirred at room temperature for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 57-5 (50 mg).
MS m/z(ESI):378.2(M+H)。
Fifth step
The crude compound 57-5 (50 mg,0.13 mmol) was dissolved in acetonitrile (2 mL). N, N-diisopropylethylamine (52 mg,0.40 mmol) and 2, 2-trifluoroethyl trifluoromethane sulfonate (37 mg,0.16 mmol) were added sequentially. The reaction was then stirred at room temperature overnight. LCMS monitored reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was isolated and purified by a silica gel plate (dichloromethane: methanol=10:1), and then compound 57 (10 mg, two-step yield 15.2%) was obtained by reverse preparation, isolation and purification.
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),8.01(d,J＝2.0Hz,1H),7.72(d,J＝9.7Hz,1H),7.14(dd,J＝9.7,2.1Hz,1H),7.07(d,J＝1.5Hz,1H),7.01(d,J＝1.5Hz,1H),6.10(s,1H),4.00(s,3H),3.53–3.44(m,2H),3.21–3.13(m,4H),3.07(q,J＝9.5Hz,2H),2.99(t,J＝6.3Hz,2H),2.93–2.86(m,4H).
MS m/z(ESI):460.2(M+H)。
EXAMPLE 58 Synthesis of Compound 58
First step
Compound 57 (160 mg,0.35 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL). 60% sodium hydrogen (28 mg,0.70 mmol) was slowly added to the reaction solution under ice bath and nitrogen protection. After the addition was completed, the reaction was stirred under ice bath for 30 minutes, and then bromoacetonitrile (84 mg,0.70 mmol) was slowly added. After the addition was completed, the ice bath was removed, and the reaction was stirred at room temperature overnight. TLC monitored reaction was complete. The reaction mixture was poured into ice water (30 mL) and extracted with ethyl acetate (20 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was purified by reverse direction preparation to give compound 58 (25 mg, yield 14.4%).
1H NMR(400MHz,CDCl 3)δ8.08(s,1H),8.00(d,J＝2.0Hz,1H),7.71(d,J＝9.6Hz,1H),7.15(dd,J＝9.7,2.1Hz,1H),7.06(d,J＝1.5Hz,1H),6.98(s,1H),4.58(s,2H),3.99(s,3H),3.67(t,J＝6.3Hz,2H),3.25–3.12(m,4H),3.12–3.01(m,4H),2.93–2.83(m,4H).
MS m/z(ESI):499.2(M+H)。
EXAMPLE 59 Synthesis of Compound 59
First step
Compounds 1-4 (720 mg,2.51 mmol) were dissolved in acetonitrile (10 mL) and water (10 mL), potassium hydroxide (1.00 g,25.1 mmol) was slowly added under ice-bath and nitrogen protection, the ice-bath was removed, and the reaction was stirred at room temperature for an additional 1 hour. Diethyl (bromodifluoromethyl) phosphonate (1.00 g,3.77 mmol) was then added slowly under ice bath, the reaction was allowed to warm slowly to room temperature and stirred for 4 hours. LCMS monitored completion of the reaction, the reaction was poured into ice water (50 mL) and extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:0-2:1) to give compound 59-1 (750 mg, yield 80.1%).
MS m/z(ESI):374.0(M+H)。
Second step
Compound 59-1 (750 mg,2.01 mmol), pinacol biborate (803 mg,2.41 mmol), potassium acetate (591 mg,6.03 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (164 mg,0.201 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored completion of the reaction, the reaction was filtered and the filtrate concentrated under reduced pressure to give crude compound 59-2 (1.30 g).
Third step
Crude compound 59-2 (380 mg,1.01 mmol), compound 41-3 (1.30 g,2.01 mmol), potassium carbonate (418 mg,3.03 mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (82.6 mg,0.101 mmol) were added sequentially to anhydrous 1, 4-dioxane (10 mL) and water (1 mL). The reaction mixture was heated to 100 ℃ under nitrogen and stirred overnight. LCMS monitored reaction was complete, the reaction was filtered, and the filtrate concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane: methanol=10:1) to give compound 59-3 (230 mg, yield 38.3%).
MS m/z(ESI):596.2(M+H)。
Fourth step
Compound 59-3 (230 mg,0.387 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL) was slowly added under ice-bath conditions. The reaction solution was warmed to room temperature and stirred for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give crude compound 59-4 (210 mg).
MS m/z(ESI):496.2(M+H)。
Fifth step
Compound 59-4 was dissolved in acetonitrile (5 mL), and N, N-diisopropylethylamine (164 mg,1.27 mmol) and 2-bromoacetonitrile (76 mg,0.64 mmol) were added sequentially. The reaction was stirred at room temperature overnight. TLC was used to monitor the completion of the reaction, and the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give crude product, which was then reversely prepared for isolation and purification to give compound 59 (35 mg, two-step yield 16.9%).
1H NMR(400MHz,DMSO-d 6)δ8.41(s,1H),8.19(d,J＝2.1Hz,1H),7.96(d,J＝9.8Hz,1H),7.59(d,J＝1.7Hz,1H),7.47(dd,J＝9.8,2.1Hz,1H),7.39(d,J＝1.6Hz,1H),7.32(s,0.25H),7.13(s,0.5H),6.94(s,0.25H),4.36(q,J＝9.5Hz,2H),3.82(s,2H),3.67(t,J＝6.3Hz,2H),3.24–3.15(m,4H),3.06(t,J＝6.1Hz,2H),2.72–2.63(m,4H).
MS m/z(ESI):535.3(M+H)。
EXAMPLE 60 Synthesis of Compound 60
First step
Compound A3-1 (200 mg,1.01 mmol), compound 60-1 (304 mg,1.52 mmol), sodium t-butoxide (293 mg,3.03 mmol), 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl (80 mg,0.20 mmol), tris (dibenzylideneacetone) dipalladium (91 mg,0.10 mmol) were added to anhydrous toluene (5 mL) sequentially under nitrogen. The reaction mixture was heated to 100 ℃ and stirred overnight. LCMS monitored reaction was complete. Cooling, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by silica gel column (dichloromethane: methanol=1:0-20:1) to obtain compound 60-2 (102 mg, yield 32.1%).
MS m/z(ESI):317.2(M+H)。
Second step
To a solvent of Compound 60-2 (102 mg,0.32 mmol) in anhydrous DMF (5 mL) was added NBS (63 mg,0.36 mmol) under nitrogen protection at-65 ℃. After the addition was completed, the reaction was continued with stirring at this temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was poured into ice water (10 mL), extracted with ethyl acetate (10 mL x 3), washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and purified by silica gel column separation (petroleum ether: ethyl acetate=2:1) to give compound 60-3 (113 mg, yield 88.9%).
MS m/z(ESI):395.1(M+H)。
Third step
A mixed solution of compound 60-3 (113 mg,0.29 mmol), compound 53-5 (166 mg,0.43 mmol), potassium carbonate (99 mg,0.72 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (24 mg,0.029 mmol) in 1, 4-dioxane (10 mL) and water (1 mL) was heated to 100deg.C under nitrogen and stirred for reaction overnight. LCMS monitored reaction was complete. Cooled, filtered, and the filtrate concentrated under reduced pressure and purified by silica gel column (dichloromethane: methanol=10:1) to give compound 60-4 (125 mg, yield 75.8%).
MS m/z(ESI):574.2(M+H)。
Fourth step
Trifluoroacetic acid (1 mL) was slowly added dropwise to a solution of compound 60-4 (125 mg,0.22 mmol) in dichloromethane (3 mL) under ice-bath conditions. After the completion of the dropwise addition, the reaction solution was warmed to room temperature and reacted with stirring for 1 hour. LCMS monitored completion of the reaction and the reaction concentrated under reduced pressure to give compound 60-5 (125 mg).
MS m/z(ESI):474.2(M+H)。
Fifth step
To a solution of compound 60-5 (125 mg,0.26 mmol), cesium carbonate (258 mg,0.80 mmol) in acetonitrile (2 mL) under nitrogen protection was added bromoacetonitrile (63 mg,0.53 mmol). The resulting reaction solution was stirred at room temperature for 2 hours. LCMS monitored reaction was complete. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mL x 3), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product, which was then subjected to reverse production, separation and purification to give compound 60 (40 mg, yield 29.6%).
MS m/z(ESI):513.2(M+H)。
1H NMR(400MHz,CDCl 3)δ8.08(s,1H),8.00(d,J＝2.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.07(s,1H),6.98(s,1H),4.22(q,J＝8.0Hz,2H),3.99(s,3H),3.91(d,J＝17.5Hz,1H),3.66(t,J＝6.2Hz,2H),3.54(d,J＝17.5Hz,1H),3.49–3.37(m,2H),3.02(t,J＝6.2Hz,2H),2.94–2.76(m,4H),2.55(t,J＝10.7Hz,1H),1.18(d,J＝6.2Hz,3H).
EXAMPLE 61 Synthesis of Compound 61
Compound 54-4 (115 mg,0.251 mmol) was dissolved in acetonitrile (2 mL) and cesium carbonate (245 mg,0.750 mmol) and 2-bromopropionitrile (67.0 mg,0.502 mmol) were added sequentially. The reaction was then stirred at room temperature for 2 hours. LCMS monitored completion of the reaction, the reaction was poured into water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phases combined, washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave crude product, which was then subjected to reverse direction preparation, separation and purification to give compound 61 (8.40 mg, yield 6.50%).
MS m/z(ESI):513.2(M+H)。
1H NMR(400MHz,CDCl 3)δ8.12-8.02(m,2H),7.72(d,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),7.07(s,1H),6.98(s,1H),4.23(q,J＝8.0Hz,2H),4.02(s,3H),3.76-3.65(m,3H),3.42(brs,2H),3.22(brs,2H),3.09–2.90(m,4H),2.70(brs,2H),1.53(d,J＝4.0Hz,3H).
Biological evaluation
Test examples SIK2 kinase Activity test experiments
The test compounds were dissolved in DMSO to 10mM stock solution and stored at-20℃until use. Initial concentration of compound was 20 μm,1% dmso, 5-fold dilution, 10 concentrations, double-multiplexed wells; 25mM Tris pH 7.5,5mM MgCl 2, 0.01% Triton X-100,0.5mM EGTA,2.5mM DTT was used as a reaction buffer to prepare a 2.5 XSIK 2-AMARA mixture, and a 2.5 XATP working solution, and the final 5. Mu.L reaction was performed in 384 well plates (Corning, 4512) containing 0.0625 ng/. Mu.L SIK2 (ThermoFisherScientific, PV 4792), 45. Mu.M AMARA (SignalCjem, A11-58), 5. Mu.M ATP; the negative control wells contained no SIK2 protein and no compound, and the positive control wells contained no compound. After 2 hours of reaction at room temperature, 5. Mu.L of ADP-Glo Reagent (Promega, V912B), the mixture was centrifuged briefly, and after 40 minutes of incubation at room temperature, 10. Mu. L Kinase Detection Reagent (Promega, V913B+V 914B) was added to each well, centrifuged briefly, and after 30 minutes of incubation at room temperature, the mixture was detected by a microplate reader (Lumineancence). The concentration-effect curve was fitted with GRAPHPAD PRISM software and the compound concentration for 50% inhibition, i.e. IC 50, was calculated.
Example Compounds SIK2 IC 50(nM)
Compound 1 36
Compounds 1-P1 40
Compounds 1-P2 57
Compound 2 50
Compound 2-P1 36
Compound 2-P2 51
Compound 4 31
Compound 5 17
Compound 6 53
Compound 7 16
Compound 10 66
Compound 11 11
Compound 12 29
Compound 14 21
Compound 15 3
Compound 16 22
Compound 17 13
Compound 24 17
Compound 25 10
Compound 26 29
Compound 27 24
Compound 28 41
Compound 29 12
Compound 30 23
Compound 31 52
Compound 32 75
Compound 33 6
Compound 34 37
Compound 35 9
Compound 36 99
Compound 37 9
Compound 38 16
Compound 39 107
Compound 40 298
Compound 43 25
Compound 44 73
Compound 45 159
Compound 46 24
Compound 47 36
Compound 48 23
Compound 49 19
Compound 50 71
Compound 51 295
Compound 52 13
Compound 53 110
Compound 54 27
Compound 56 12
Compound 57 9
Compound 58 12
Compound 59 25
Compound 60 19
Compound 61 3
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

  1. A compound of formula I, racemates, stereoisomers, tautomers, isotopic labels, solvates, pharmaceutically acceptable salts or prodrugs thereof;
    Wherein X and Y are N or C, and X and Y are not both N or C;
    z is N or CH, and X and Z are not both N;
    T is selected from N or CR 3;
    E is selected from NHR 4a or NR 4b when E is NR 4b where the N atom and R 2 together with the atom to which they are attached form a 5-14 membered heterocyclic ring;
    A is selected from 3-14 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-14 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
    Each R 1, identical or different, is independently selected from H, OH, halogen, CN, oxo (＝O)、-(CH 2) mNR 5aR 5b、-C(O)NR 6、-S(O) nR 7、-(CH 2) mOR 8、-NH(CH 2) pR 9、-C(O)R 10、, the following groups, unsubstituted or optionally substituted with 1,2 or more R groups: c 1-20 alkyl; m is a positive integer from 0 to 5 (e.g., 0,1,2,3,4, 5); n is a positive integer from 0 to 2 (e.g., 0,1, 2); p is a positive integer from 0 to 5 (e.g., 0,1,2,3,4, 5);
    Each R is the same or different and is selected from OH, CN, halogen, NH 2、-S(O) 2R 7、OR 8、NR 5aR 5b, 4-6 membered heterocyclic groups;
    R 2 is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-20 alkyl, C 1-20 alkoxy;
    R 3 is selected from H, halogen, hydroxy, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-20 alkyl, C 1-20 alkoxy;
    R 4a and R 4b are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-20 alkyl, C 3-20 cycloalkyl, 3-14 membered heterocyclyl;
    Rx is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-20 alkoxy;
    R 5a、R 5b、R 6、R 7 are identical or different and are selected, independently of one another, from H, radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-20 alkyl, C 3-20 cycloalkyl;
    R 8、R 9 and R 10 are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1,2 or more OH, CN, halogen, NH 2、-S(O) 2R 7、C 1-20 alkyl, C 1-20 alkoxy: c 1-20 alkyl, 3-14 membered heterocyclyl, C 3-20 cycloalkyl;
    preferably, the compound of formula I is a compound of formula II:
    Wherein X and Y are N or C, and X and Y are not both N or C;
    T is selected from N or CR 3;
    E is selected from NHR 4a or NR 4b when E is NR 4b where the N atom and R 2 together with the atom to which they are attached form a 5-14 membered heterocyclic ring;
    A is selected from 3-14 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-14 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
    Each R 1, identical or different, is independently selected from H, OH, halogen, CN, oxo (＝O)、-(CH 2) mNR 5aR 5b、-C(O)NR 6、-S(O) nR 7、-(CH 2) mOR 8、-NH(CH 2) pR 9、-C(O)R 10、, the following groups, unsubstituted or optionally substituted with 1,2 or more R groups: c 1-20 alkyl; m is a positive integer from 0 to 5 (e.g., 0,1,2,3,4, 5); n is a positive integer from 0 to 2 (e.g., 0,1, 2); p is a positive integer from 0 to 5 (e.g., 0,1,2,3,4, 5);
    Each R is the same or different and is selected from OH, CN, halogen, NH 2、-S(O) 2R 7、OR 8、NR 5aR 5b, 4-6 membered heterocyclic groups;
    r 2 is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1,2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-20 alkoxy;
    R 3 is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1,2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-20 alkoxy;
    R 4a and R 4b are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-20 alkyl, C 3-20 cycloalkyl, 3-14 membered heterocyclyl;
    Rx is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-20 alkoxy;
    R 5a、R 5b、R 6、R 7 are identical or different and are selected, independently of one another, from H, radicals which are unsubstituted or optionally substituted by 1, 2 or more halogen radicals, OH, CN, NH 2: c 1-20 alkyl, C 3-20 cycloalkyl;
    R 8、R 9 and R 10 are identical or different and are selected, independently of one another, from H, the following radicals which are unsubstituted or optionally substituted by 1, 2 or more OH, CN, halogen, NH 2、-S(O) 2R 7、C 1-20 alkyl: c 1-20 alkyl, 3-14 membered heterocyclyl, C 3-20 cycloalkyl.
  2. The compound of claim 1, wherein when X is N, Y is C and Z is CH; when X is C, Y is N, Z is N or CH;
    Preferably, T is selected from N or CR 3;
    Preferably, E is selected from NHR 4a or NR 4b when E is NR 4b where the N atom and R 2 together with the atom to which they are attached form a 5-8 membered heterocyclic ring;
    Preferably, a is selected from 3-8 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-8 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
    Preferably, each R 1, identical or different, is independently selected from H, OH, halogen, CN, oxo (＝O)、-(CH 2) mNR 5aR 5b、-C(O)NR 6、-S(O) nR 7、-(CH 2) mOR 8、-NH(CH 2) pR 9、-C(O)R 10、, the following groups, unsubstituted or optionally substituted with 1,2 or more R groups: c 1-12 alkyl; m is a positive integer from 0 to 5; n is a positive integer from 0 to 2; p is a positive integer from 0 to 5;
    Preferably, each R is the same or different and is independently selected from OH, CN, halogen, NH 2、-S(O) 2R 7、OR 8、NR 5aR 5b, 4-6 membered heterocyclyl;
    Preferably, R 2 is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-12 alkyl, C 1-12 alkoxy;
    Preferably, R 3 is selected from H, halogen, hydroxy, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2, deuterium: c 1-12 alkyl, C 1-12 alkoxy;
    Preferably, R 4a and R 4b are identical or different and are independently selected from H, the following groups which are unsubstituted or optionally substituted by 1, 2 or more halogen, OH, CN, NH 2: c 1-12 alkyl, C 3-12 cycloalkyl, 3-8 membered heterocyclyl;
    Preferably, rx is selected from H, halogen, the following groups unsubstituted or optionally substituted with 1, 2 or more halogen, OH, NH 2: c 1-20 alkyl, C 1-12 alkoxy;
    Preferably, R 5a、R 5b、R 6、R 7, identical or different, are independently from each other selected from H, radicals unsubstituted or optionally substituted by 1, 2 or more halogen, OH, CN, NH 2: c 1-12 alkyl, C 3-12 cycloalkyl;
    Preferably, R 8、R 9 and R 10 are identical or different and are independently selected from H, the following groups which are unsubstituted or optionally substituted by 1,2 or more OH, CN, halogen, NH 2、-S(O) 2R 7、C 1-12 alkyl, C 1-12 alkoxy: c 1-12 alkyl, 3-8 membered heterocyclyl, C 3-12 cycloalkyl.
  3. A compound according to claim 1 or 2, wherein when X is N, Y is C and Z is CH; when X is C, Y is N, Z is N or CH;
    T is selected from CR 3;
    Preferably, E is selected from NHR 4a or NR 4b when E is NR 4b where the N atom and R 2 together with the atom to which they are attached form a 5-8 membered heterocyclic ring;
    Preferably, a is selected from 3-8 membered heterocyclyl optionally substituted with 1,2 or more R 1; the 3-8 membered heterocyclic group at least contains one N atom, and one N atom is connected with the mother nucleus;
    Preferably, each R 1 is the same or different and is independently selected from H, OH, halogen, oxo (=o), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, OH substituted C 1-6 alkyl, OH substituted C 1-6 alkoxy, di (C 1-6 alkyl) amino, di (C 1-6 alkyl) amino-C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 alkoxy C 1- 6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl;
    Preferably, R 2 is selected from C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, deuterated C 1-6 alkoxy, haloalkyl;
    Preferably, R 3 is selected from C 1-6 alkoxy, hydroxy, halogen, deuterated C 1-6 alkoxy, halogenated C 1-6 alkoxy;
    Preferably, R 4a may be selected from halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl;
    Preferably, R 4b can be selected from H, halo C 1-6 alkyl, cyano C 1-6 alkyl, C 3-6 cycloalkyl;
    Preferably, rx is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy.
  4. A compound according to any one of claims 1 to 3 wherein when X is N, Y is C and Z is CH; when X is C, Y is N, Z is N or CH;
    Preferably, T is selected from CR 3;R 3 selected from methoxy, hydroxy, halogen, deuterated methoxy, CHF 2 O-;
    Preferably, E is selected from NHR 4a or NR 4b, when E is NR 4b, wherein the N atom and R 2 together with the atom to which they are attached form a piperidine ring;
    Preferably, A is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1,2 or more R 1,
    Preferably, each R 1 is identical or different and is selected, independently of one another, from H, OH, F, oxo (=O), methyl, isopropyl, methoxy, acetyl, hydroxymethyl, hydroxyethyl, hydroxyethoxy, methoxymethyl, methylaminomethyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, trifluoromethyl, CF 3CH 2-、CNCH 2 -,
    Preferably, R 2 is selected from methoxy, tridentate methoxy, difluoromethoxy, difluoromethylene;
    Preferably, R 3 may be selected from methoxy, tridentate methoxy, difluoromethoxy;
    Preferably, R 4a is selected from CF 3CH 2 -, cyclopropyl;
    Preferably, R 4b is selected from H, CF 3CH 2-、CN-CH 2 -;
    Preferably, rx may be selected from H, F.
  5. A compound according to any one of claims 1 to 4 wherein a is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1, 2 or more R 1, R 1 can replace H on heterocyclic NH; each R 1, which may be the same or different, is independently selected from H, OH, halogen, oxo (=O), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl C (O) -, C 1-6 alkoxy-C 1-6 alkyl C (O) -, OH-substituted C 1-6 alkyl, OH-substituted C 1-6 alkoxy, N (C 1-6 alkyl) 2、(C 1- 6 alkyl) 2N-C 1-6 alkyl, NH (C 1-6 alkyl), C 1-6 alkyl-NH-C 1-6 alkyl, C 1-6 alkoxyc 1-6 alkyl, halo C 1-6 alkyl, cyano C 1-6 alkyl;
    preferably, a is selected from:
  6. a compound according to any one of claims 1 to 5, wherein the compound has a structure according to formula Ia or formula Ib:
    Wherein X, Y, Z, T, R x、R 4a、R 4b and a independently of each other have the definition as defined in any one of claims 1 to 5;
    preferably, the compound has a structure represented by formula IIa or formula IIb:
    Wherein X, Y, T, R x、R 4a、R 4b and A independently of one another have the meanings given in any of claims 1 to 5.
  7. A compound according to any one of claims 1 to 6, wherein the compound has the structure:
    Preferably, the compound has the following structure:
  8. A process for the preparation of a compound as claimed in any one of claims 1 to 7 comprising the steps of: the compound a and the compound b undergo a coupling reaction to obtain a compound shown in a formula I;
    Wherein X, Y, Z, T, E, R x、R 2 and a independently of each other have the definition as defined in any one of claims 1 to 7; w is selected from Cl, br or I;
    Preferably, the reaction is carried out in the presence of a catalyst and/or a base;
    Preferably, the catalyst is a palladium catalyst, such as at least one of Pa (dppf) Cl 2、Pa 2(dba) 3、Pd(OAc) 2;
    preferably, the base is selected from at least one of sodium carbonate, potassium acetate, triethylamine and pyridine.
  9. Use of at least one of the compounds of any one of claims 1-7, racemates, stereoisomers, tautomers, isotopic labels, solvates, pharmaceutically acceptable salts or prodrug compounds thereof, for the manufacture of a medicament; the drug is preferably a SIK inhibitor, more preferably a SIK2 inhibitor;
    Preferably, the medicament is for the treatment and/or prophylaxis of inflammatory diseases, auto-inflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, diseases involving impairment of bone turnover, diseases associated with hypersecretion of tnfα, interferon, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases and/or diseases associated with abnormal angiogenesis; also for example psoriasis, inflammatory Bowel Disease (IBD), rheumatoid Arthritis (RA), primary sjogren's syndrome, ankylosing spondylitis, cold-related periodic syndrome (CAPS);
    Preferably, the inflammatory disease is selected from rheumatoid arthritis, osteoarthritis, allergic airway diseases (e.g. asthma), chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel diseases (e.g. crohn's disease, ulcerative colitis). More particularly, the inflammatory diseases refer to rheumatoid arthritis, chronic Obstructive Pulmonary Disease (COPD) and inflammatory bowel disease (e.g. crohn's disease, ulcerative colitis).
  10. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1-7, racemates, stereoisomers, tautomers, isotopic labels, solvates, pharmaceutically acceptable salts, or prodrug compounds thereof.
CN202280064115.XA 2021-10-18 2022-10-17 SIK inhibitor and composition, preparation method and application thereof Pending CN118119619A (en)

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