CN107406427A - Alkynyl alcohol and its application method - Google Patents

Alkynyl alcohol and its application method Download PDF

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CN107406427A
CN107406427A CN201680011885.2A CN201680011885A CN107406427A CN 107406427 A CN107406427 A CN 107406427A CN 201680011885 A CN201680011885 A CN 201680011885A CN 107406427 A CN107406427 A CN 107406427A
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alkyl
compound
bases
methyl
salt
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N·布拉齐尔
G·卡斯塔涅多
J·A·冯
J·J·克劳福德
W·李
X·林
B·胡
G·吴
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F Hoffmann La Roche AG
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Abstract

The present invention relates to formula (I) compound, wherein Q, A1‑A8、R4And R5As defined herein.Formula (I) compound and its pharmaceutical composition can be used for treatment wherein it was observed that undesirable or excessive activation the disease and obstacle of NF kB signal transductions.

Description

Alkynyl alcohol and its application method
The cross reference of related application
This application according to 35U.S.C. § 119 (a) requirements enjoy in the International Application Serial No. PCT submitted for 25th for 2 months for 2015/ CN2015/077176 rights and interests, this application are herein by reference in its entirety.
Invention field
The present invention relates to the organic compound of the treatment or prevention available for mammal, more particularly to can be used for treating cancer Disease and NF-kB- inducible kinases (NIK) inhibitor of inflammatory conditions.
Background of invention
NF-kB inducible kinases (NIK) are also known as mapk kinase kinases 14 (MAP3K14), and it is serine/threonine kinase Enzyme, it is MAPK family members.It is initially identified as TNF acceptors (TNFR) correlation factor 2 (TRAF2) in double cross screening Binding partners [referring to Malinin, NL, et al., Nature, 1997,385:540-4].NIK overexpressions cause NF-kB to activate, The dominant negative form that NIK lacks kinase activity can be disposed in response to TNF and IL-1 and suppress NF-kB activation.Therefore, NIK Have been previously identified as the important composition of NF-kB signal transduction paths.Scientific research is it has been proved that block the NF- in cancer cell KB signal transduction paths can cause this kind of cell to terminate propagation to death, or become more sensitive to other anticancer therapies.In addition, Research is it has been proved that NF-kB controls participate in the very polygenic expression of inflammation, and NF-kB signal transductions are found in a lot Inflammatory conditions, such as lupus (including systemic loupus erythematosus), rheumatoid arthritis, inflammatory bowel disease, arthritis, sepsis, stomach It is long term activation in scorching and asthma.Therefore, it is possible to suppress NIK and thus suppress, weaken or mitigate NF-kB signal transduction paths Undesirable or excessive activation organic compound can have the not phase for being used to treat and wherein observing this NF-kB signal transductions Prestige or the disease of excessive activation and the treatment benefit of obstacle.
Invention summary
Disclose the alkynyl alcoholic compound as NIK kinase inhibitors, the composition containing these compounds and be used for The method for treating the kinase mediated disorders such as cancers of NIK and inflammatory disease.
In one aspect, there is provided formula (I) compound or its stereoisomer, dynamic isomer, solvate, prodrug or Salt：
Wherein：
Ring A is monocyclic or condensed-bicyclic；
Q is N or C, wherein when Q is N, then A1Key between Q is not double bond and Q and A4Between key be not double bond；
A1It is NR1、N、S、CR1Or CHR1；
A2It is NR2、N、O、S、CR2Or CHR2；
A3It is N or C；
A4It is N；And
A1-A4In one, two or three be N, wherein:
R1It is each independently selected from H, halogen, NRaRb、NHC(O)NRaRb、NHS(O)2CH3、C1-C3Alkyl, C3-C7Cycloalkanes Base, C1-C3Alkoxy and 3-11 circle heterocycles bases, wherein R1Alkyl optionally by F, OH, CN, SH, C1-C3Alkoxy or 3-11 members are miscellaneous Ring group substitutes；R1Cycloalkyl optionally by F, OH, CN, SH, CH3Or CF3Substitution；R1Alkoxy optionally taken by F, OH, CN or SH Generation；And R1Heterocyclic radical optionally by F, OH, CN, SH, CF3Or C1-C3Alkyl substitutes,
R2It is each independently selected from H, NRaRb、C1-C6Alkyl, C3-C7Cycloalkyl, C1-C6Alkoxy, phenyl and 3-11 members are miscellaneous Ring group, wherein R2Optionally by RcSubstitution；Or
R1And R2The atom connected together with them is formed selected from C3-C7Cycloalkyl, phenyl and 3-11 circle heterocycles bases Cyclic group, wherein the cyclic group is optionally by RdSubstitution；
R4Selected from H, C1-C6Alkyl, CH2F and CH2OH；
R5It is 3-11 circle heterocycles bases, optionally by ReOr-C (=O) N (C1-C6Alkyl)2Substitution；Or
R4And R5Formed together optionally by ReSubstituted C3-C11Cycloalkyl or optionally by ReSubstituted 3-11 circle heterocycles bases；
A5-A8One of be N and remaining be CR6Or all CR6；
R6At each occurrence independently selected from H, F, Cl, NH2、NHCH3、N(CH3)2、OH、OCH3、OCHF2、OCH2F、 OCF3、SH、SCH3、SCHF2、SCH2F、CN、CH3、CHF2、CH2F、CH2OH、CF3、NO2And N3；
RaSelected from H and optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substituted C1-C6Alkyl；
RbSelected from H, C1-C6Alkyl, C1-C6Alkoxy, C3-C6Cycloalkyl, C (O) Rg, phenyl and 3-11 circle heterocycles bases, wherein RbCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substitution；
RcAnd RdIt is each independently selected from halogen ,-(X1)0-1-CN、-(X1)0-1-NO2、-(X1)0-1-SF5、-(X1)0-1-OH、- (X1)0-1-NH2、-(X1)0-1-N(H)(R1a)、-(X1)0-1-N(R1b)(R1a)、-(X1)0-1-CF3、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, oxo base ,-(X1)0-1-C1-C6Alkyl ,-(X1)0-1-C3-C10 Cycloalkyl ,-O-C3-C10Cycloalkyl ,-(X1)0-1- 3-11 circle heterocycles base ,-(X1)0-1-C6-C10Aryl ,-C (=O) (X1)1-C3- C10Cycloalkyl ,-C (=O) (X1)1- 3-11 circle heterocycles base ,-(X1)0-1- C (=Y1)N(H)(R1a)、-(X1)0-1- C (=Y1)NH2、- (X1)0-1- C (=Y1)N(R1a)(R1b)、-(X1)0-1- C (=Y1)OR1a、-(X1)0-1- C (=Y1)OH、-(X1)0-1- N (H) C (= Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(H)、-(X1)0-1- N (H) C (=Y1) OR1a、-(X1)0-1-N(R1b) C (=Y1)OR1a、-(X1)0-1-S(O)1-2R1a、-(X1)0-1-N(H)S(O)1-2R1a、-(X1)0-1-N (R1b)S(O)1-2R1a、-(X1)0-1-S(O)0-1N(H)(R1a)、-(X1)0-1-S(O)0-1N(R1b)(R1a)、-(X1)0-1-S(O)0- 1NH2、-(X1)0-1- S (=O) (=NR1b)R1a、-(X1)0-1- C (=Y1)R1a、-(X1)0-1- C (=Y1)H、-(X1)0-1- C (= NOH)R1a、-(X1)0-1- C (=NOR1b)R1a、-(X1)0-1- NHC (=Y1)N(H)(R1a)、-(X1)0-1- NHC (=Y1)NH2、- (X1)0-1- NHC (=Y1)N(R1b)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N(H)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N (R1a)(R1b)、-(X1)0-1-N(R1a) C (=Y1)NH2、-(X1)0-1- OC (=Y1)R1a、-(X1)0-1- OC (=Y1)H、-(X1)0-1- OC (=Y1)OR1a、-(X1)0-1- OP (=Y1)(OR1a)(OR1b)、-(X1)-SC (=Y1)OR1aWith-(X1)-SC (=Y1)N(R1a) (R1b), wherein X1Selected from C1-C6Alkylidene, C1-C6Sub- miscellaneous alkyl, C2-C6Alkenylene, C2-C6Alkynylene, C1-C6Alkylene oxide Base, C3-C7Cycloalkylidene, the sub- heterocyclic radical of 3-11 members and phenylene；R1aAnd R1bIt is each independently selected from C1-C6Alkyl, C1-C6Halogen Substituted alkyl, C1-C6Miscellaneous alkyl, C3-C7Cycloalkyl, (C3-C7Cycloalkylidene) C1-C6Alkyl, 3-11 circle heterocycles base, (3-11 members are sub- miscellaneous Ring group) C1-C6Alkyl, C6Aryl and (C6-C10Arlydene) C1-C6Alkyl, or R1aAnd R1bIt is optional when being connected with identical nitrogen-atoms Combine to be formed comprising the 0-3 other heteroatomic 3-11 circle heterocycles bases selected from N, O and S in ground；Y1It is O, NR1cOr S, wherein R1c It is H or C1-C6Alkyl；Wherein RcOr RdThe arbitrary portion including R of substituent1a、R1bAnd R1cIndependently of one another at each occurrence Further by 0 to 4 RfSubstituent substitutes, described RfSubstituent is selected from halogen, CN, NO2、SF5、OH、NH2、-N(C1-C6Alkane Base)2、-NH(C1-C6Alkyl), oxo base, C1-C6Alkyl ,-(C2-C6Alkynylene)-(3-11 circle heterocycles bases, wherein the heterocycle Base is optionally by ReSubstitution), C1-C6Hydroxy alkyl, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, C3-C7Cycloalkyl, 3-11 circle heterocycles base ,-C (=O) N (H) (C1-C6Alkyl) ,-C (=O) N (C1-C6Alkyl)2,-C (=O) NH2,-C (=O) OC1- C6Alkyl ,-C (=O) OH ,-N (H) C (=O) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) (C1-C6Alkyl) ,-N (H) C (=O) OC1-C6Alkyl ,-N (C1-C6Alkyl) C (=O) OC1-C6(halo) alkyl ,-S (O)1-2C1-C6Alkyl ,-N (H) S (O)1- 2C1-C6Alkyl ,-N (C1-C6Alkyl) S (O)1-2C1-C6Alkyl ,-S (O)0-1N(H)(C1-C6Alkyl) ,-S (O)0-1N(C1-C6Alkane Base)2、-S(O)0-1NH2,-C (=O) C1-C6Alkyl ,-C (=O) C3-C7Cycloalkyl ,-C (=NOH) C1-C6Alkyl ,-C (= NOC1-C6Alkyl) C1-C6Alkyl ,-NHC (=O) N (H) (C1-C6Alkyl) ,-NHC (=O) N (C1-C6Alkyl)2,-NHC (=O) NH2、-N(C1-C6Alkyl) C (=O) N (H) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) NH2,-OC (=O) C1-C6Alkane Base ,-OC (=O) OC1-C6Alkyl ,-OP (=O) (OC1-C6Alkyl)2,-SC (=O) OC1-C6Alkyl and-SC (=O) N (C1-C6 Alkyl)2, wherein RfAny moieties be optionally optionally substituted by halogen；
ReSelected from halogen, OH, C1-C6Alkyl and oxo base；And
RgSelected from C1-C6Alkyl and C3-C6Cycloalkyl, wherein RgCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3 Or CF3Substitution；
Condition is that the compound is not the compound of the compound 1x-199x selected from table 1x.
In some embodiments, Q is C and compound has formula (II):
Its middle ring A, A1、A2、A3、A4、A5、A6、A7、A8、R4And R5As defined in formula (I).
In some embodiments, ring B is substituted phenyl, and Q is C；And compound has formula (III):
Its middle ring A, A1、A2、A3、A4、R4And R5As defined in formula (II), n is 0,1 or 2, and R6It is each independently selected from F、Cl、OCH3、CH3And CF3。
In some embodiments of formula (I), (II) or (III) compound, wherein such as lower part
It is defined as(such as),
Wherein:
A9It is O, NR11Or CR11R12, wherein R11And R12It is each independently selected from H, halogen, OH and C1-C3Alkyl；
R7And R8It is each independently selected from halogen, OH, C1-C6Alkyl, or R7And R8Formation=O together, and
R9And R10It is each independently selected from H and Re, or R9And R10The atom connected together with them is formed optionally by Re Substituted C5-C6Cycloalkyl or optionally by ReSubstituted 5-6 circle heterocycles bases.
On the other hand, the invention provides pharmaceutical composition, comprising formula (I), (II) or (III) compound and pharmaceutically acceptable Carrier, diluent or excipient.
On the other hand, the invention provides the formula used in therapy (I), (II) or (III) compound or its medicine Composition.In another embodiment, the invention provides compound or pharmaceutical composition to prepare for treating inflammatory disease Purposes in the medicament of disease.
On the other hand, the invention provides for treating disease and obstacle including cancer, inflammatory conditions and autoimmunity Formula (I), (II) or (III) compound and its pharmaceutical composition of disease etc..
On the other hand, the invention provides formula (I), (II) or (III) compound or its medicine composite for curing disease With obstacle, the method such as cancer, inflammatory conditions or autoimmune disease (or purposes).
On the other hand, the invention provides the medicine for preparing treating cancer, inflammatory conditions or autoimmune disease etc. Formula (I), (II) or (III) compound of agent.
On the other hand, among the invention provides the compound available for synthesis formula (I), (II) or (III) compound Body.
Detailed description of the invention
The invention provides especially formula (I), (II) or (III) compound and its variant, comprising formula (I), (II) or (III) pharmaceutical composition of compound and treated using this kind of compound and composition with NF-kB signal transduction paths not It is expected or disease and the method for obstacle, such as some cancers and inflammatory conditions that excessive activation is related.
Definition
Term " alkyl " refers to saturated straight chain or branched chain monovalent hydrocarbon group, wherein alkyl group can optionally and independently by One or more substituent substitutions as described herein.In an example, alkyl group has 1 to 18 carbon atom (C1- C18).In another example, alkyl group is C0-C6、C0-C5、C0-C3、C1-C12、C1-C10、C1-C8、C1-C6、C1-C5、C1- C4Or C1-C3。C0Alkyl refers to valence link.The example of alkyl group includes methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), 1- propyl group (n-Pr, n-propyl ,-CH2CH2CH3), 2- propyl group (i-Pr, isopropyl ,-CH (CH3)2), 1- butyl (n-Bu, normal-butyl ,- CH2CH2CH2CH3), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH2CH(CH3)2), 2- butyl (s-Bu, sec-butyl ,-CH (CH3)CH2CH3), 2- methyl-2-propyls (t-Bu, the tert-butyl group ,-C (CH3)3), 1- amyl groups (n-pentyl ,- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), 1- hexyls (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3, 1- heptyl and 1- octyl groups.In some embodiments In, the substituent for " optionally substituted alkyl " includes F, Cl, Br, I, OH, SH, CN, NH2、NO2、N3, COOH, methyl, Ethyl, propyl group, isopropyl, butyl, isobutyl group, cyclopropyl, methoxyl group, ethyoxyl, propoxyl group, oxo base, trifluoromethyl, difluoro Methyl, sulfuryl amino, methane sulfonylamino, SO, SO2, phenyl, piperidyl, piperazinyl (piperizinyl) or pyrimidine radicals 1 to 6 example, wherein its alkyl, aryl and heterocyclic moiety can be optionally substituted.
Term " alkylidene " itself or a part expression divalent group, example as derived from alkane as other substituents There is-CH2CH2CH2CH2-.Generally, alkyl (or alkylidene) group will have 1 to 12 carbon atom, for example, 1-8,1-6 or 1-3 carbon atom." alkenylene " and " alkynylene " refers to the unsaturated form respectively with double or triple bonds of " alkylidene ", generally With 2 to 12 carbon atoms, such as 2-8,2-6 or 2-3 carbon atom." alkylidene ", " alkenylene " and " alkynylene " base Group can optionally be substituted.
Term " miscellaneous alkyl " refers to the carbon atom by specifying number or at most 18 carbon atoms and 1 to 5 if not pointing out The straight or branched monovalent hydrocarbon group of the individual hetero atom composition selected from O, N, Si and S, wherein nitrogen and sulphur atom can be optionally by oxygen Change and nitrogen heteroatom can be optionally quaternary.In some embodiments, hetero atom is selected from O, N and S, and wherein nitrogen and sulphur atom can Can be optionally quaternary with nitrogen heteroatom with optional be oxidized.Hetero atom may be at any interior location of miscellaneous alkyl group, Position (such as-the O-CH being connected including alkyl group with molecule remainder2-CH3).Example includes-CH2-CH2-O-CH3、- CH2-CH2-O-CF3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-S(O)-CH3、-CH2- CH2-S(O)2-CH3、-Si(CH3)3、-CH2- CH=N-OCH3With-OCF3.At most two hetero atoms can be connected, such as-CH2- NH-OCH3With-CH2-O-Si(CH3)3.Miscellaneous alkyl group can be optionally substituted.In some embodiments, it is " optionally substituted Miscellaneous alkyl " substituent include F, Cl, Br, I, OH, SH, CN, NH2、NO2、N3, COOH, methyl, ethyl, propyl group, isopropyl, Butyl, isobutyl group, cyclopropyl, methoxyl group, ethyoxyl, propoxyl group, oxo base, trifluoromethyl, difluoromethyl, sulfuryl amino, Methane sulfonylamino, SO, SO2, phenyl, piperidyl, 1 to 4 example in piperazinyl (piperizinyl) and pyrimidine radicals, its Middle alkyl, aryl and heterocyclic moiety can be optionally substituted.
Term " sub- miscellaneous alkyl " refers to the divalent group derived from miscellaneous alkyl, and the example has-CH2CH2SCH2CH2、- CH2SCH2CH2NHCH3With-OCH2CH3.For sub- miscellaneous alkyl group, hetero atom can also occupy one or two chain end (example Such as alkylidene epoxide, alkylenedioxy group, alkylidene amino, alkylenediamino).Sub- miscellaneous alkyl group can optionally be taken Generation.
" cycloalkyl " refers to non-aromatic saturation or part unsaturated hydrocarbons cyclic group, and wherein group of naphthene base can be optionally by one Or multiple substituent substitutions as described herein.In an example, group of naphthene base has 3 to 12 carbon atom (C3-C12). In other examples, cycloalkyl is C3-C6、C3-C8、C3-C10Or C5-C10.In other examples, as monocyclic group of naphthene base It is C3-C8、C3-C6Or C5-C6.In another example, it is C as bicyclic group of naphthene base7-C12.In another example, Group of naphthene base as spiral ring system is C5-C12.The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, 1- rings The amyl- 2- alkenyls of amyl- 1- alkenyls, 1- rings, the amyl- 3- alkenyls of 1- rings, cyclohexyl, complete tritiated cyclohexyl, 1- hexamethylene -1- alkenyls, 1- rings Hex- 2- alkenyls, 1- hexamethylene -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl and ring Dodecyl.The exemplary arrangement of bicyclic cycloalkyl with 7 to 12 annular atoms include but is not limited to [4,4], [4,5], [5, 5], [5,6] or [6,6] ring system.It is including but not limited to bicyclic [4.1.0] heptane of exemplary bridging bicyclic cycloalkyl, bicyclic [3.1.1] heptane, bicyclic [2.2.1] heptane, bicyclic [2.2.2] octane, bicyclic [4.1.0] heptane and bicyclic [3.2.2] nonane. The example of spiro cycloalkyl group includes spiral shell [2.2] pentane, spiral shell [2.3] hexane, spiral shell [2.4] heptane, spiral shell [2.5] octane and spiral shell [4.5] last of the ten Heavenly stems Alkane.In some embodiments, the substituent for " optionally substituted cycloalkyl " include F, Cl, Br, I, OH, SH, CN, NH2、NO2、N3, COOH, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, cyclopropyl, methoxyl group, ethyoxyl, propoxyl group, Oxo base, trifluoromethyl, difluoromethyl, sulfuryl amino, methane sulfonylamino, SO, SO2, phenyl, piperidyl, piperazinyl (piperizinyl) 1 to 4 example and in pyrimidine radicals, wherein its alkyl, aryl and heterocyclic moiety can be optionally substituted.
Term " cycloalkylidene " refers to the divalent group derived from group of naphthene base.Cycloalkylene group can optionally be taken Generation.
" heterocyclic group ", " heterocycle shape ", " heterocycle ", " heterocyclic radical " or " heterocycle " used interchangeably, refer to any monocyclic, double Ring or loop coil saturation or unsaturation, aromatics (heteroaryl) or non-aromatic (such as Heterocyclylalkyl) loop system, wherein annular atom is carbon And at least one atom in ring or loop system is the hetero atom selected from nitrogen, sulphur or oxygen.If any annular atom of loop system is Hetero atom, then the system is heterocycle, unrelated with the tie point of the remainder of molecule with the loop system.In an example, it is miscellaneous Ring group includes 3-11 annular atom (" member ", i.e. 3-11 circle heterocycles) and including monocyclic, bicyclic and spiral ring system, wherein the ring Atom is that at least one atom in carbon and ring or loop system is the hetero atom selected from nitrogen, sulphur or oxygen.In an example, it is miscellaneous Ring group includes 1 to 4 hetero atom.In another example, heterocyclic radical is included with one or more selected from the miscellaneous of nitrogen, sulphur or oxygen The 3- of atom is to 7- unit monocycles.In another example, heterocyclic radical is included with one or more miscellaneous originals for being selected from nitrogen, sulphur or oxygen The 4- of son is to 6- unit monocycles.In another example, heterocyclic radical includes 3- unit monocycles.In another example, heterocyclic radical includes 4- unit monocycles.In another example, heterocyclic radical includes 5-6- unit monocycles.In an example, heterocyclic group includes 0 to 3 Double bond.Any nitrogen or sulfur heteroatom can optionally be oxidized (such as NO, SO, SO2) and any nitrogen heteroatom can be optionally by season Change (such as [NR4]+Cl-、[NR4]+OH-).In another example, heterocyclic radical include having it is one or more selected from nitrogen, sulphur or The heteroatomic 3- of oxygen is to 9- member loop coils.The example of heterocycle has Oxyranyle, '-aziridino, thiirane base, azacyclo- Butyl, oxetanylmethoxy, thietanyl, 1,2- dithias cyclobutyl, 1,3- dithias cyclobutyl, pyrrolidinyl, dihydro- 1H- pyrrole radicals, dihydrofuran base, tetrahydrofuran base, dihydro-thiophene base, tetrahydro-thienyl, imidazolidinyl, piperidyl, piperazinyl, Isoquinolyl, tetrahydro isoquinolyl, morpholinyl, thiomorpholine base, 1,1- dioxo-thiomorpholins base, dihydro pyranyl, oxinane Base, hexahydro thiapyran base, hexahydropyrimidine base, oxazepine cyclohexyl, thiazine alkyl, thioxane base, homopiperazine base, high piperidines Base, azacycloheptyl, oxepane base, thia suberyl, oxazepine Zhuo Ji, oxazepine cycloheptyl alkyl, diaza cycloheptyl Alkyl, 1,4- Diazesuberanes base, diazepine base, thiazepine Zhuo Ji, thiazepine cycloheptyl alkyl, tetrahydro thiapyran base, Oxazole alkyl, thiazolidinyl, isothiazole alkyl, 1,1- dioxa isothiazolidines ketone group, oxazolidine ketone group, imidazolidinonyl, 4, 5,6,7- tetrahydrochysenes [2H] indazolyl, Tetrahydrobenzimidazderivative base, 4,5,6,7- tetrahydro benzos [d] imidazole radicals, 1,6- glyoxalidine [4, 5-d] pyrrolo- [2,3-b] pyridine radicals, thiazinyl, oxazinyls, thiadiazine Ji, oxadiazines base, dithiazine base, dioxazines Ji, Evil Thiazinyl, thiophene triazine radical, Evil triazine radicals, two thiadiazine bases, imidazolinyl, dihydro-pyrimidin base, tetrahydro-pyrimidine base, 1- pyrrolins Base, 2- pyrrolinyls, 3- pyrrolinyls, indolinyl, thiapyran base, 2H- pyranoses, 4H- pyranoses, dioxane hexyl, 1,3- dioxolanyls, pyrazoline, pyrazolidinyl, dithiane base, dithiolane base, pyrimidine ketone group, hybar X base, pyrimidine- 2,4- diketos, piperazine ketone group, piperazinedione base, pyrazolidinyl imidazolinyl, 3- azabicyclos [3.1.0] hexyl, 3,6- bis- Azabicyclo [3.1.1] heptyl, 6- azabicyclos [3.1.1] heptyl, 3- azabicyclos [3.1.1] heptyl, 3- azabicyclos [4.1.0] heptyl, azabicyclo [2.2.2] hexyl, 2- azabicyclos [3.2.1] octyl group, 8- azabicyclos [3.2.1] octyl group, 2- azabicyclos [2.2.2] octyl group, 8- azabicyclos [2.2.2] octyl group, 7- oxabicyclos [2.2.1] heptane, azaspiro [3.5] Nonyl, azaspiro [2.5] octyl group, azaspiro [4.5] decane, 1- azaspiros [4.5] decane -2- ketone groups, azaspiro [5.5] 11 Alkyl, tetrahydro indole base, octahydro indyl, tetrahydrochysene isoindolyl, dihydro-indazol base, 1,1- dioxa hexahydro thiapyran bases.Sulfur-bearing Or the example of the 5- circle heterocycles of oxygen atom and one to three nitrogen-atoms has thiazolyl, including thiazol-2-yl and thiazol-2-yl N- oxygen Compound；Thiadiazolyl group, including 1,3,4- thiadiazoles -5- bases and 1,2,4- thiadiazoles -5- bases；Oxazolyl, Li such as oxazole -2- bases； He oxadiazolyls such as 1,3,4- oxadiazoles -5- bases and 1,2,4- oxadiazole -5- bases.5- membered ring heterocyclics containing 2 to 4 nitrogen-atoms Example include imidazole radicals such as imidazoles -2- bases；Triazolyl such as 1,3,4- triazoles -5- bases, 1,2,3- triazole -5- bases, 1,2,4- tri- Azoles -5- bases；With tetrazole radical such as 1H-TETRAZOLE -5- bases.The example of benzo-fused 5- circle heterocycles has benzoxazole -2- bases, benzo thiophene Azoles -2- bases and benzimidazolyl-2 radicals-base.The example of 6- circle heterocycles contains one to three nitrogen-atoms and optional sulphur or oxygen atom, example Such as pyridine radicals, such as pyridine -2- bases, pyridin-3-yl and pyridin-4-yl；Pyrimidine radicals, such as pyrimidine -2-base and pyrimidine-4-yl；Triazine Base, such as 1,3,4- triazine radical -2- bases and 1,3,5-triazines base -4- bases；Pyridazinyl, particularly pyridazine -3- bases；And pyrazinyl.Pyrrole Pyridine N- oxides and pyridazine N-oxide and pyridine radicals, pyrimidine -2-base, pyrimidine-4-yl, pyridazinyl and 1,3,4- pyridazine 2- base bases Group is other examples of heterocyclic group.Heterocycle can be optionally substituted.For example, the substitution for " optionally substituted heterocycle " Base includes F, Cl, Br, I, OH, SH, CN, NH2、NO2、N3, COOH, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, ring Propyl group, methoxyl group, ethyoxyl, propoxyl group, oxo base, trifluoromethyl, difluoromethyl, sulfuryl amino, methane sulfonylamino, SO、SO2, phenyl, piperidyl, 1 to 6 example in piperazinyl (piperizinyl) and pyrimidine radicals, wherein its alkyl, aryl Can optionally it be substituted with heterocyclic moiety.
Term " sub- heterocyclic radical " refers to the divalent group derived from heterocyclic group.Sub- heterocyclyl groups can be optionally substituted.
It is containing 1 to 4 heteroatomic 5- or 6- the member virtue selected from nitrogen, oxygen and sulphur that " heteroaryl ", which refers to wherein at least one ring, Any single-, two- or three ring loop system of race's ring, in an embodiment of illustrating, at least one hetero atom is nitrogen.Referring to example Such as the 13rd edition tables 7-2 [1985] of Lang ' s Handbook of Chemistry (Dean, J.A. are edited).It is included in definition Any one for having in wherein above-mentioned heteroaryl ring be fused to any bicyclic radicals of aryl rings, wherein the aryl rings or heteroaryl Basic ring is connected to the remainder of molecule.In one embodiment, heteroaryl include wherein one or more annular atoms be nitrogen, The 4-6 unit monocycle aromatic groups of sulphur or oxygen.In another embodiment, heteroaryl, which includes wherein one or more annular atoms, is The 5-6 unit monocycle aromatic groups of nitrogen, sulphur or oxygen.The example of heteroaryl groups include thienyl, furyl, imidazole radicals, pyrazolyl, Thiazolyl, isothiazolyl, oxazolyl, isoxazolyls, triazolyl, thiadiazolyl group, oxadiazolyls, tetrazole radical, thiatriazole Ji, Evil tri- Oxazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, tetrazine base, tetrazolo [1,5-b] pyridazinyl, imidazo [1, 2-a] pyrimidine radicals and purine radicals and benzo-fused derivative such as benzoxazolyl, benzofuranyl, benzothiazolyl, benzene And thiadiazolyl group, BTA base, benzimidazolyl and indyl.Heteroaryl groups can be optionally substituted.In some implementations In scheme, the substituent for " optionally substituted heteroaryl " includes F, Cl, Br, I, OH, SH, CN, NH2、NO2、N3、 COOH, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, cyclopropyl, methoxyl group, ethyoxyl, propoxyl group, oxo base, three Methyl fluoride, difluoromethyl, sulfuryl amino, methane sulfonylamino, SO, SO2, phenyl, piperidyl, piperazinyl (piperizinyl) 1 to 6 example and in pyrimidine radicals, wherein its alkyl, aryl and heterocyclic moiety can be optionally substituted.
In specific embodiments, heterocyclic group connects at the carbon atom of heterocyclic group.As an example, bond with carbon is miscellaneous Cyclic group includes following bonding arrangement：2,3,4,5 or 6 of pyridine ring, 3,4,5 or 6 of pyridazine, 2,4, the 5 of pyrimidine ring Or 6,2,3,5 or 6 of pyrazine ring, furans, tetrahydrofuran, sulphur cyclopentadienyl, thiophene, 2,3,4 or the 5 of pyrroles or nafoxidine ring Wei , oxazoles, 2,4 or 5 , isoxazoles of imidazoles or thiazole ring, 3,4 or 5 of pyrazoles or isothiazole ring, the 2 of aziridine ring or 3 Position, 2,3 or 4 of azetidine ring, 2,3,4,5,6,7 or 8 of quinoline ring, or 1,3,4,5,6,7 or the 8 of isoquinolin ring Position.
In some embodiments, heterocyclic group is N- connections.As an example, the heterocyclic radical or heteroaryl base of nitrogen bonding Group includes following bonding arrangement：Aziridine, azetidine, pyrroles, pyrrolidines, 2- pyrrolins, 3- pyrrolins, imidazoles, miaow Oxazolidine, 2- imidazolines, 3- imidazolines, pyrazoles, pyrazoline, 2- pyrazolines, 3- pyrazolines, piperidines, piperazine, indoles, indoline, 2 of 1 of 1H- indazoles, iso-indoles or isoindoline, 4 of morpholine, 9 of carbazole or B-carboline.
Term " alkoxy " refers to the alkyl group being connected via oxygen atom with molecule remainder.Non-limiting example bag Include methoxyl group, ethyoxyl and propoxyl group.Alkoxy base can be optionally substituted, such as be optionally substituted by halogen.
Term " alkyl sulfenyl " refers to the alkyl group being connected via sulphur atom with molecule remainder.Non-limiting example Including-SCH3、-SCH2CH3With-SCH2CH2CH3.Alkylthio group can be optionally substituted, such as be optionally substituted by halogen.
Term " halo " or " halogen " itself refer to fluorine, chlorine, bromine or iodine atom as a part for other substituents, separately have Except instruction.Term " haloalkyl " is intended to include " alkyl " and " haloalkyl " substituent.In addition, term " haloalkyl " is anticipated Monohaloalkyl alkyl to be included and multi-haloalkyl.
Term " oxo base " refers to=O or (=O)2。
Term " aryl " refers to polynary unsaturation, is typically aromatic hydrocarbon cyclic group, and it can be monocyclic or is fused together Polycyclic (up to three rings), there is the aryl ring atom of the number, unless otherwise stated.Aromatic yl group can be optionally substituted.
" phenylene " group refers to the divalent group derived from phenyl group.Phenylene group can be optionally substituted.
It can be unsubstituted or by one or more (such as 0,1,2,3,4 or 5 or more that " optionally substituted ", which refers to group, It is more) substitute for the substituent that the group is listed, wherein the substituent can be with identical or different, unless otherwise stated.That is, appoint The substituted substituent of choosing is independent at each occurrence.In embodiments, optionally substituted group has 1 substitution Base.In a further embodiment, optionally substituted group has 2 substituents.In a further embodiment, optional quilt Substituted group has 3 substituents.In a further embodiment, optionally substituted group has 4 substituents.
Optional substituent for alkyl and cycloalkyl can be various groups, including but not limited to halogen, oxo Base, CN, NO2、N3, OR', perfluor-C1-4It is alkoxy, unsubstituted cycloalkyl, unsubstituted aryl (such as phenyl), unsubstituted Heterocyclic radical, NR'R ", SR', SiR'R " R " ', OC (O) R', C (O) R', CO2R'、CONR'R″、OC(O)NR'R″、NR″C(O) R'、NR″'C(O)NR'R″、NR″C(O)2R'、S(O)2R'、S(O)2NR'R″、NR'S(O)2R″、NR″'S(O)2NR'R ", amidino groups, Guanidine, (CH2)1-4OR'、(CH2)1-4NR'R″、(CH2)1-4SR'、(CH2)1-4SiR'R″R″'、(CH2)1-4OC(O)R'、(CH2)1-4C (O)R'、(CH2)1-4CO2R' and (CH2)1-4CONR'R " or its combination, for quantity for 0 to (2m'+1), wherein m' is in the group The sum of carbon atom.R', R " and R " ' refer to including for example following group independently of one another：Hydrogen；Unsubstituted C1-6Alkyl；Do not take The miscellaneous alkyl in generation；Unsubstituted aryl；Aryl, the unsubstituted C substituted by 1-3 halogen1-C6Alkyl, C1-C6Alkoxy or C1-C6Thio alkoxy group, unsubstituted aryl-C1-C4Alkyl group and unsubstituted heteroaryl.When R' and R " are connected to During identical nitrogen-atoms, they can combine to form 3-, 4-, 5-, 6- or 7- yuan of rings with nitrogen-atoms, and wherein annular atom is optionally by N, O Or S substitutions." refer to for example, NR'R including 1- pyrrolidinyls and 4- morpholinyls.
Similarly, the optional substituent for aryl and heterocyclic group is different.In some embodiments, it is right Substituent for aryl and heterocyclic group is selected from including but not limited to following group：Halogen, OR', OC (O) R', NR'R ", SR'、R'、CN、NO2、CO2R'、CONR'R″、C(O)R'、OC(O)NR'R″、NR″C(O)R'、NR″C(O)2R'、NR'C(O)NR″ R″'、S(O)R'、S(O)2R'、S(O)2NR'R″、NR'S(O)2R″、N3, perfluor-C1-C4Alkoxy, perfluor-C1-C4Alkoxy, (CH2)1-4OR'、(CH2)1-4NR'R″、(CH2)1-4SR'、(CH2)1-4SiR'R″R″'、(CH2)1-4OC(O)R'、(CH2)1-4C(O) R'、(CH2)1-4CO2R'、(CH2)1-4CONR'R " or its combination, quantity are the sum of the opening valence link on 0 to aromatic ring；And its Middle R', R " and R " ' are independently selected from hydrogen, C1-C6Alkyl, C3-C6Cycloalkyl, C2-C6Alkenyl, C2-C6Alkynyl, unsubstituted virtue Base and unsubstituted heteroaryl.Other suitable substituents include being connected to annular atom by the alkylidene chain of 1-4 carbon atom Each above-mentioned aryl substituent.
Term " hetero atom " as used herein is intended to include oxygen (O), nitrogen (N), sulphur (S) and silicon (Si).In some implementations In scheme, hetero atom refers to O, N or S.In some embodiments, hetero atom refers to O or N.
Term " chirality " as used herein refers to the molecule with the nonoverlapping property of mirror image companion, and term " non-hand Property " refer to non-mirror image companion can be overlapping molecule.
Term " stereoisomer " as used herein refers to identical chemical composition but atom or group spatially Arrange different compounds.It is not mutually mirror that " diastereoisomer ", which refers to two or more chiral centres and its molecule, The stereoisomer of picture.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity. The mixture of diastereoisomer can be operated such as electrophoresis and chromatography by high resolution analysis to be separated.
" enantiomter " refers to two kinds of stereoisomers of the compound of mirror image non-overlapping each other.
Stereochemical definitions used herein and agreement generally follow S.P.Parker and edited, McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill BookCompany, New York；And Eliel, E. and Wilen, S., " Stereochemistry of OrganicCompounds ", John Wiley＆Sons, Inc., New York, 1994.The compound of the present invention can contain asymmetric or chiral centre, therefore exist with different stereoisomeric forms in any ratio.The present invention Compound all stereoisomeric forms in any ratio, include but is not limited to diastereoisomer, enantiomter and atropisomer with And their mixture such as racemic mixture is intended to form the part of the present invention.Many organic compounds are with optical active forms In the presence of that is, they have the ability of the plane of Plane of rotation polarised light.When describing optically active compound, prefix D and L are used Or R and S represents absolute configuration of the molecule on its (one or more) chiral centre.Prefix d and l or (+) and (-) use Make the symbol of linearly polarized light rotation in appointed compound, wherein (-) or l represent that compound is left-handed.Prefix be (+) or Person d compound is dextrorotation.For given chemical constitution, in addition to mirror image each other, these stereoisomers are phases With.Specific stereoisomer is alternatively referred to as enantiomter, and the mixture of this isomers is commonly referred to as enantiomter Mixture.The 50 of enantiomter:50 mixtures are referred to as racemic mixture or racemate, and they are when in chemical reaction or side Do not have to be likely to occur when stereoselectivity or stereocpecificity in method.Term " racemic mixture " and " racemate " refer to two kinds The equimolar mixture of enantiomerism material, it does not have optical activity.
Term " dynamic isomer " as used herein or " tautomeric form " refer to can build mutual inversion of phases by low energy Constitutional isomer with different-energy.For example, proton tautomer (also referred to as prototropic tautomeric body) includes leading to Cross the mutual inversion of phases of proton migration, such as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body includes logical Cross the mutual inversion of phases that the restructuring of some bonding electrons is carried out.
In structure shown in this article, when not indicating the spatial chemistry of any specific chiral atom, then pay close attention to and wrap Include compound of all stereoisomers as the present invention.When the solid wedge or dotted line by representing particular configuration illustrate to stand During body chemistry, then the stereoisomer be so indicate and definition.Unless otherwise indicated, when use solid wedge or During dotted line, then indicated with respect to stereoisomer.As exist between fruit structure and title it is inconsistent if, be defined by structure.
Term " solvate " as used herein refers to one or more solvent molecules and the association of the compound of the present invention Thing or compound.The example for forming the solvent of solvate includes but is not limited to water, isopropanol, ethanol, methanol, DMSO, acetic acid Ethyl ester, acetic acid and monoethanolamine.Term " hydrate " refers to the compound that wherein solvent molecule is water.
Term " protection group " as used herein, which refers to, to be generally used for blocking or protects taking for the particular functional group in compound Dai Ji.For example, " amino protecting group " is the substituent for the blocking or amido functional group in protection compound being connected with amino.It is suitable Suitable amino protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), benzyloxycarbonyl group (CBz) and 9- fluorenes methoxy carbonyls Base (Fmoc).Similarly, " hydroxyl protecting group " is the blocking of hydroxyl or the substituent for protecting hydroxy functional group.Suitable protection group Including acetyl group and silicyl." carboxyl-protecting group " refers to the blocking of carboxyl or protects the substituent of carboxyl functional group.Common Carboxyl-protecting group includes phenylsulfonylethyl, cyano ethyl, 2- (trimethyl silyl) ethyl, 2- (trimethyl silyls Base) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenyl sulfinyl) ethyl, 2- (diphenylphosphino)- Ethyl, nitro-ethyl etc..For protection group and its universal description used, referring to P.G.M.Wuts and T.W.Greene, Greene ' s Protective Groups in Organic Synthesis, the 4th edition, Wiley-Interscience, knob About, 2006.
Term " mammal " as used herein include but is not limited to people, mouse, rat, cavy, monkey, dog, cat, Horse, ox, pig and sheep.
" object ", " individual " or " patient " is vertebrate.In some embodiments, vertebrate is mammal. Object, individual or patient can need the compound of the present invention.
Term " officinal salt " as used herein is intended to include (being depended on as described herein with the acid or alkali of relative nontoxic The specific substituent found in compound) prepare reactive compound salt.When the compound of the present invention contain it is relatively acid During functional group, by making the neutral form of the compound be connect with enough expection alkali under net terms or in suitable inert solvent Base addition salts can be obtained by touching.As derived from pharmaceutically acceptable inorganic base the example of salt include aluminium, ammonium, calcium, copper, ferric iron, ferrous iron, Lithium, magnesium, manganic, bivalent manganese, potassium, sodium, zinc etc..As derived from pharmaceutically acceptable organic base salt include primary amine, secondary amine and tertiary amine including The salt of substituted amine, cyclammonium, naturally occurring amine etc., such as arginine, glycine betaine, caffeine, choline, N, N'- dibenzyl Ethylene diamine, diethylamine, 2- DEAE diethylaminoethanols, DMAE, monoethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, aminoglucose, Glucosamine, histidine, Kazakhstan amine (hydrabamine), isopropylamine, lysine, methyl Amine, morpholine, piperazine, piperidines, polyamino resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethamine Deng.When the compound of the present invention contains relatively alkaline functional group, by making under net terms or in suitable inert solvent The neutral form of the compound contacts with enough expected acid can obtain acid-addition salts.The example of pharmaceutically acceptable acid addition salts includes By those of inorganic acids, the inorganic acid for example hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, a hydrogen carbonic acid, phosphoric acid, a hydrogen phosphoric acid, Dihydrogen phosphoric acid, sulfuric acid, a hydrosulphuric acid, hydroiodic acid or phosphorous acid etc., and the salt as derived from the organic acid of relative nontoxic, it is described to have Machine acid such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, butanedioic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzene Sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid etc..Also include salt such as arginine salt of amino acid etc. and organic acid such as Glucuronic acid or galacturonic acid (galactunoric acids) etc. salt (see, for example, Berge, S.M. et al., “Pharmaceutical Salts”,J.Pharm.Sci.,1977,66,1-19).Some specific compounds of the present invention contain Both alkalescence and acidic functionality, this allows compound to be converted into alkali or acid-addition salts.
The neutral form of compound can by by salt and alkali or acid contact and separate in a usual manner parent compound and Regeneration.The difference of the parent fo of compound and various salt forms in some physical properties, it is for example molten in polar solvent Xie Du, but salt and the parent fo of compound are equivalent for the purposes of the present invention.
Except salt form, present invention also offers the compound of prodrug forms.Term " prodrug " as used herein refers to Under physiological condition easily after chemical change with provide the present invention compound those compounds.In addition, prodrug ring in vitro The compound of the present invention can be converted into border by chemistry or biochemical method.For example, tried when being placed in suitable enzyme or chemistry When in the transdermal patch reservoir of agent, prodrug can slowly be converted into the compound of the present invention.
The prodrug of the present invention includes wherein amino acid residue or has two or more (such as two, three or four) The polypeptide chain of amino acid residue is covalently attached to free amine group, hydroxyl or the carboxylic acid of the compound of the present invention via acid amides or ester bond The compound of group.Amino acid residue includes but is not limited to generally by 3 letter characters 20 kinds of naturally occurring ammonia naming Base acid, and also include phosphoserine, phosphothreonine, phosphotyrosine, 4- hydroxy-prolines, oxylysine, chain Rely ammonia plain (demosine), isodesmosine (isodemosine), gamma carboxyglutamate, hippuric acid, octahydro indoles -2- Formic acid, statine, 1,2,3,4- tetrahydroisoquinoline -3- formic acid, penicillamine, ornithine, 3-Methyl histidine, norvaline, β - Alanine, γ-aminobutyric acid, citrulling, homocysteine, homoserine, methyl-alanine, to benzoyl phenylalanine, Phenylglycine, propargylglycine, methyl amimoacetic acid, methionine sulfone and t-butylglycine.
It further comprises the other type of prodrug.Turned to for example, the free carboxyl groups of the compound of the present invention can derive Acid amides or Arrcostab.As other example, the compound of the invention comprising free hydroxyl radicals can derive as follows to be turned to Prodrug：Oh group is converted into such as, but not limited to phosphate, hemisuccinic acid ester, dimethylaminoacetate or phosphoryl oxygen The group of ylmethyl Epoxide carbonyl group, such as Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by use of Prodrugs Advanced Drug Delivery Reviews,19:As outlined in 115.Also include the mephenesin Carbamate prodrug of hydroxyl and amino group, such as oh group Carbonate prodrug, sulphonic acid ester and sulfuric ester are such.Also include oh group derivative and turn to (acyloxy) methyl and (acyloxy) second Base ether, wherein the carboxyl groups can be optionally by group, the alkyl that including but not limited to ether, amine and carboxylic acid functional substitute Ester, or wherein carboxyl groups is amino-acid ester as described above.The prodrug of the type is recorded in J.Med.Chem., (1996), 39:In 10.The hydrogen atom that example particularly includes alcohol groups is replaced by such as following group：(C1-C6) alkanoyl epoxide first Base, 1- ((C1-C6) alkanoyl epoxide) ethyl, 1- methyl isophthalic acids-((C1-C6) alkanoyl epoxide) ethyl, (C1-C6) alkoxy carbonyl Epoxide methyl, N- (C1-C6) alkoxycarbonyl amino methyl, succinyl group, (C1-C6) alkanoyl, alpha-amido (C1-4) alkanoyl, Aryl-acyl and alpha-amido acyl group or alpha-amido acyl-alpha-aminoacyl, wherein alpha-amido carboxyl groups are each independently selected from Naturally occurring l-amino acid, P (O) (OH)2、-P(O)(O(C1-6) alkyl)2Or glycosyl is (from the hemiacetal form of carbohydrate Remove group caused by oh group).
The other example of prodrug derivant is edited see, for example, a) Design of Prodrugs, H.Bundgaard (Elsevier, 1985) and Methods in Enzymology, volume 42, the 309-396 pages, K.Widder et al. is edited (Academic Press,1985)；b)A Textbook of Drug Design and Development,Krogsgaard- Larsen and H.Bundgaard are edited, the 5th chapter " Design and Application of Prodrugs ", H.Bundgaard, the 113-191 pages (1991)；c)H.Bundgaard,Advanced Drug Delivery Reviews,8: 1-38(1992)；D) H.Bundgaard et al., Journal of Pharmaceutical Sciences, 77:285(1988)； And e) N.Kakeya, et al., Chem.Pharm.Bull., 32:692 (1984), each document are specifically incorporated herein by referring to.
In addition, the invention provides the metabolin of the compound of the present invention." metabolin " refers in vivo as used herein Pass through product caused by the metabolism of specific compound or its salt.This kind of product can result from applied compound such as oxidation, Reduction, hydrolysis, amidatioon, desamidization, esterification, de- ester, enzymatic lysis etc..
Generally, metabolite is carried out as follows discriminating：Prepare the present invention compound radio-labeled (such as14C or3H it is) same Position element, it is applied to animal such as rat, mouse, cavy, monkey or people with detectable dosage (such as greater than about 0.5mg/kg), permitted Permitted to be enough the time (normally about 30 seconds to 30 hours) being metabolized, its turn is separated from urine, blood or other biological samples Change product.These products are easily separated because they marked it is (other to be deposited by using be incorporated in metabolin The antibody of epitope separate).Metabolite structures determine in a usual manner, such as are analyzed by MS, LC/MS or NMR.It is logical Often, metabolite analysis is carried out in a manner of with conventional drug metabolism well known to those skilled in the art research identical.Metabolite Available for the diagnostic analysis of the therapeutic administratp of the compound of the present invention, as long as not finding them in vivo.
Some compounds of the present invention can exist with nonsolvated forms and solvation form including hydrated form. The compound of the present invention may have a variety of crystallizations or amorphous form.Generally, all physical forms are intended to cover in this hair In bright scope.
The compound of the present invention is at the one or more atoms for forming this kind of compound also containing unnatural proportions Atom isotope.For example, present invention additionally comprises the variant of the isotope marks of the present invention, they and those described herein phase Together, but one or more atoms are by with the different atom matter of the advantage atomic mass naturally found from nature or mass number The atom of amount or mass number is replaced.The institute of described any specific atom or element is paid close attention in the range of the compound of the present invention There is isotope.Can be impregnated in the present invention compound Exemplary isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine and The isotope of iodine, respectively for example2H(D)、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I With125I.The compound of the invention of some isotope marks (such as marked3H and14Those of C) it can be used for compound or bottom Thing tissue distribution assays.Tritiated (3H) and carbon-14 (14C) isotope is because they are easily prepared and detectable but useful.And And with heavier isotope such as deuterium (i.e.2H some treatment benefits for resulting from higher metabolic stability can be provided by) replacing (such as Half-life in vivo increase or volume requirements reduce), therefore be preferable in some cases.Launch the same position of positive electron Element is such as15O、13N、11C and18F can be used for positron emission computerized tomography (PET) research to be occupied with detection substrate acceptor.Isotope mark The compound of the invention of note generally can according to this paper flows and embodiment disclosed in those similar methods, by using The reagents of isotope marks replaces the reagents of non-isotope marks to prepare.One non-limiting reality of the part of isotope substitution Under such as：
Unless otherwise directed, otherwise term " compound of the invention " etc. include formula (I), (II) or (III) compound and Its stereoisomer (including atropisomer), geometric isomer, dynamic isomer, solvate, metabolin, isotope, salt (such as officinal salt) and prodrug.In some embodiments, solvate, metabolin, isotope or prodrug or its any group Conjunction is left out.
" treatment " (and its variant such as " disposal ") refers to the natural process that clinical intervention disposes individual or cell to change, can For preventing or being carried out during clinical condition.Expected therapeutic effect includes preventing the generation of disease or recurrence, alleviates disease Shape, any direct or indirect pathological consequence to eliminate a disease, (do not deteriorate) morbid state stably, mitigate disease process speed If rate, improvement relax morbid state, extend survival and exemption compared with the expected survival for not receiving to treat or improve pre- Afterwards.In some embodiments, compound of the invention be used for postpone disease or obstacle development or for slow down disease or The process of obstacle.Need those treated to include suffering from those of illness or obstacle and there is tendency to suffer from illness or obstacle Those (such as passing through genetic mutation) or wherein intend to prevent illness or obstacle those.In some embodiments, from Prevention is excluded in the definition of " treatment ".
Phrase " therapeutically effective amount " or " effective dose " refer to the following amount of the compound of the present invention：(i) treat or prevent special Determine disease, illness or obstacle, (ii) alleviation, the one or more symptoms for improving or eliminating specified disease, illness or obstacle, or (iii) prevent or postpone specified disease as described herein, the breaking-out of one or more symptoms of illness or obstacle.For cancer Therapy, effect can be determined for example by assessing disease developing time (TTP) or measure response rate (RR).In amynologic disease In, therapeutically effective amount is to be enough to reduce or relief allergic obstacle, autoimmunity or inflammatory conditions (such as psoriasis or inflammatory bowel Disease) symptom or acute inflammatory response (such as asthma) symptom amount.In some embodiments, therapeutically effective amount is this Chemical entities described in text are enough the amount for significantly reducing B- cytoactives or quantity.
Any variant of term " suppression " and " reduction " or these terms includes any measurable reduction or complete inhibition To obtain expected results.For example, compared with normal, can reduce about, at most about or at least about 5%, 10%, 15%, 20%, 25%th, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more or the activity (such as NIK activity) of any range that can wherein derive reduce.
Term " bioavilability " refers to system availability (the i.e. blood/plasma water for being administered to the specified rate medicine of patient It is flat).Bioavilability is to indicate that medicine reaches the time (speed) of systemic circulation and the degree of total amount (degree) from institute's form of administration The absolute terms of amount.
" inflammatory conditions ", which refer to wherein excessive or out of control inflammatory responses, as used herein causes excessive inflammatory symptoms, host Any disease, obstacle or the symptom that tissue damage or function of organization lose.
" inflammation " refers to histologic lesion or topical protective response caused by destroying as used herein, and it is used to destroying, is dilute Release or divest (separation) harmful substance and damaged tissues.Inflammation is especially flowed into leucocyte or neutrophil chemotactic Property.Inflammation can result from Pathogenic organisms and virus infection and result from non-inflammatory means such as wound or miocardial infarction or in Reperfu- sion, the immune response of exogenous antigen and autoimmune response after wind.
Term " cancer " and " cancer " are related to or described the usual characterized by cell growth or proliferation out of control of mammal Physiological status." tumour " includes one or more cancer cells.The example of cancer includes but is not limited to cancer, lymthoma, blastocyte Knurl, sarcoma and leukaemia or lymphoid malignant disease.
" autoimmune disease " refers to wherein tissue damage and body fluid or cell-mediated to body itself as used herein The arbitrary collection of the obstacle of the response correlation of component.
It is especially envisaged that, can be used for appointing for the present invention for any limitation that one embodiment of the invention is discussed Anticipate other embodiments.Moreover, any compound or composition of the present invention can be used for any means of the present invention, and this hair Bright any means can be used for production or any compound or composition using the present invention.
Although the open definition for supporting only to refer to material for the election and "and/or", the use of term "or" be used to representing " and/ Or ", represent to be only that for the election or material for the election is mutually exclusive unless specifically indicated.
In the application in the whole text, term " about " is used for the standard for stating device or method of the numerical value including being used to determine the numerical value Error.
It is as used herein "one", " one kind " or entity refer to/kind or multiple/kind, except clearly indicating herein. As used herein " other " refer at least second/kind or more/kind.
Title used herein is only for organized.
NIK inhibitor
One aspect of the present invention provide formula (I) compound or its stereoisomer, dynamic isomer, solvate, Prodrug or salt：
Wherein:
Ring A is monocyclic or condensed-bicyclic；
Q is N or C, wherein when Q is N, then A1Key between Q is not double bond and Q and A4Between key be not double bond；
A1It is NR1、N、S、CR1Or CHR1；
A2It is NR2、N、O、S、CR2Or CHR2；
A3It is N or C；
A4It is N；And
A1-A4In one, two or three be N, wherein:
R1It is each independently selected from H, halogen, NRaRb、NHC(O)NRaRb、NHS(O)2CH3、C1-C3Alkyl, C3-C7Cycloalkanes Base, C1-C3Alkoxy and 3-11 circle heterocycles bases, wherein R1Alkyl optionally by F, OH, CN, SH, C1-C3Alkoxy or 3-11 members are miscellaneous Ring group substitutes；R1Cycloalkyl optionally by F, OH, CN, SH, CH3Or CF3Substitution；R1Alkoxy optionally taken by F, OH, CN or SH Generation；And R1Heterocyclic radical optionally by F, OH, CN, SH, CF3Or C1-C3Alkyl substitutes,
R2It is each independently selected from H, NRaRb、C1-C6Alkyl, C3-C7Cycloalkyl, C1-C6Alkoxy, phenyl and 3-11 members are miscellaneous Ring group, wherein R2Optionally by RcSubstitution；Or
R1And R2The atom connected together with them is formed selected from C3-C7Cycloalkyl, phenyl and 3-11 circle heterocycles bases Cyclic group, wherein the cyclic group is optionally by RdSubstitution；
R4Selected from H, C1-C6Alkyl, CH2F and CH2OH；
R5It is optionally by ReSubstituted 3-11 circle heterocycles or-C (=O) N (C1-C6Alkyl)2；Or
R4And R5Formed together optionally by ReSubstituted C3-C11Cycloalkyl or optionally by ReSubstituted 3-11 circle heterocycles bases；
A5-A8One of be N and remaining be CR6Or all CR6；
R6At each occurrence independently selected from H, F, Cl, NH2、NHCH3、N(CH3)2、OH、OCH3、OCHF2、OCH2F、 OCF3、SH、SCH3、SCHF2、SCH2F、CN、CH3、CHF2、CH2F、CH2OH、CF3、NO2And N3；
RaSelected from H and optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substituted C1-C6Alkyl；
RbSelected from H, C1-C6Alkyl, C1-C6Alkoxy, C3-C6Cycloalkyl, C (O) Rg, phenyl and 3-11 circle heterocycles bases, wherein RbCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substitution；
RcAnd RdIt is each independently selected from halogen ,-(X1)0-1-CN、-(X1)0-1-NO2、-(X1)0-1-SF5、-(X1)0-1-OH、- (X1)0-1-NH2、-(X1)0-1-N(H)(R1a)、-(X1)0-1-N(R1b)(R1a)、-(X1)0-1-CF3、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, oxo base ,-(X1)0-1-C1-C6Alkyl ,-(X1)0-1-C3-C10Ring Alkyl ,-O-C3-C10Cycloalkyl ,-(X1)0-1- 3-11 circle heterocycles base ,-(X1)0-1-C6-C10Aryl ,-C (=O) (X1)1-C3-C10Ring Alkyl ,-C (=O) (X1)1- 3-11 circle heterocycles base ,-(X1)0-1- C (=Y1)N(H)(R1a)、-(X1)0-1- C (=Y1)NH2、- (X1)0-1- C (=Y1)N(R1a)(R1b)、-(X1)0-1- C (=Y1)OR1a、-(X1)0-1- C (=Y1)OH、-(X1)0-1- N (H) C (= Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(H)、-(X1)0-1- N (H) C (=Y1) OR1a、-(X1)0-1-N(R1b) C (=Y1)OR1a、-(X1)0-1-S(O)1-2R1a、-(X1)0-1-N(H)S(O)1-2R1a、-(X1)0-1-N (R1b)S(O)1-2R1a、-(X1)0-1-S(O)0-1N(H)(R1a)、-(X1)0-1-S(O)0-1N(R1b)(R1a)、-(X1)0-1-S(O)0- 1NH2、-(X1)0-1- S (=O) (=NR1b)R1a、-(X1)0-1- C (=Y1)R1a、-(X1)0-1- C (=Y1)H、-(X1)0-1- C (= NOH)R1a、-(X1)0-1- C (=NOR1b)R1a、-(X1)0-1- NHC (=Y1)N(H)(R1a)、-(X1)0-1- NHC (=Y1)NH2、- (X1)0-1- NHC (=Y1)N(R1b)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N(H)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N (R1a)(R1b)、-(X1)0-1-N(R1a) C (=Y1)NH2、-(X1)0-1- OC (=Y1)R1a、-(X1)0-1- OC (=Y1)H、-(X1)0-1- OC (=Y1)OR1a、-(X1)0-1- OP (=Y1)(OR1a)(OR1b)、-(X1)-SC (=Y1)OR1aWith-(X1)-SC (=Y1)N(R1a) (R1b), wherein X1Selected from C1-C6Alkylidene, C1-C6Sub- miscellaneous alkyl, C2-C6Alkenylene, C2-C6Alkynylene, C1-C6Alkylene oxide Base, C3-C7Cycloalkylidene, the sub- heterocyclic radical of 3-11 members and phenylene；R1aAnd R1bIt is each independently selected from C1-C6Alkyl, C1-C6Halo Alkyl, C1-C6Miscellaneous alkyl, C3-C7Cycloalkyl, (C3-C7Cycloalkylidene) C1-C6Alkyl, 3-11 circle heterocycles base, (the sub- heterocycle of 3-11 members Base) C1-C6Alkyl, C6Aryl and (C6-C10Arlydene) C1-C6Alkyl, or R1aAnd R1bWhen being connected with identical nitrogen-atoms optionally Combination is formed comprising the 0-3 other heteroatomic 3-11 circle heterocycles bases selected from N, O and S；Y1It is O, NR1cOr S, wherein R1cIt is H or C1-C6Alkyl；Wherein RcOr RdThe arbitrary portion including R of substituent1a、R1bAnd R1cEnter independently of one another at each occurrence One step is by 0 to 4 RfSubstituent substitutes, the RfSubstituent is selected from halogen, CN, NO2、SF5、OH、NH2、-N(C1-C6Alkyl)2、- NH(C1-C6Alkyl), oxo base, C1-C6Alkyl ,-(C2-C6Alkynylene)-(3-11 circle heterocycles bases, wherein the heterocyclic radical is optional By ReSubstitution), C1-C6Hydroxy alkyl, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, C3-C7Cycloalkyl, 3-11 members Heterocyclic radical ,-C (=O) N (H) (C1-C6Alkyl) ,-C (=O) N (C1-C6Alkyl)2,-C (=O) NH2,-C (=O) OC1-C6Alkane Base ,-C (=O) OH ,-N (H) C (=O) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) (C1-C6Alkyl) ,-N (H) C (=O) OC1-C6Alkyl ,-N (C1-C6Alkyl) C (=O) OC1-C6(halo) alkyl ,-S (O)1-2C1-C6Alkyl ,-N (H) S (O)1-2C1-C6 Alkyl ,-N (C1-C6Alkyl) S (O)1-2C1-C6Alkyl ,-S (O)0-1N(H)(C1-C6Alkyl) ,-S (O)0-1N(C1-C6Alkyl)2、-S (O)0-1NH2,-C (=O) C1-C6Alkyl ,-C (=O) C3-C7Cycloalkyl ,-C (=NOH) C1-C6Alkyl ,-C (=NOC1-C6Alkane Base) C1-C6Alkyl ,-NHC (=O) N (H) (C1-C6Alkyl) ,-NHC (=O) N (C1-C6Alkyl)2,-NHC (=O) NH2、-N(C1- C6Alkyl) C (=O) N (H) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) NH2,-OC (=O) C1-C6Alkyl ,-OC (=O) OC1-C6Alkyl ,-OP (=O) (OC1-C6Alkyl)2,-SC (=O) OC1-C6Alkyl and-SC (=O) N (C1-C6Alkyl)2, wherein Rf Any moieties be optionally optionally substituted by halogen；
ReSelected from halogen, OH, C1-C6Alkyl and oxo base；And
RgSelected from C1-C6Alkyl and C3-C6Cycloalkyl, wherein RgCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3 Or CF3Substitution.
In some embodiments, formula (I) compound is not in the PCT/EP2014/ submitted on the 22nd of August in 2014 Compound 1-199 or wherein disclosed intermediates in 067872.In some embodiments, formula (I) compound is not selected from The compound of compound 1x-199x in table 1x.
Table 1x
In some embodiments, compound has formula (I), and wherein Q is C.In some embodiments, compound has Formula (I), wherein Q are C, and condition is that compound is not the compound selected from compound 1x-146x and 148x-199x.
In some embodiments, formula (I) compound is further defined as formula (II) compound：
Or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein:
Ring A is monocyclic or condensed-bicyclic；
A1It is NR1、N、S、CR1Or CHR1；
A2It is NR2、N、O、S、CR2Or CHR2；
A3It is N or C；
A4It is N；And
A1-A4In one, two or three be N, wherein:
R1It is each independently selected from H, halogen, NRaRb、NHC(O)NRaRb、NHS(O)2CH3、C1-C3Alkyl, C3-C7Cycloalkanes Base, C1-C3Alkoxy and 3-11 circle heterocycles bases, wherein R1Alkyl optionally by F, OH, CN, SH, C1-C3Alkoxy or 3-11 members are miscellaneous Ring group substitutes；R1Cycloalkyl optionally by F, OH, CN, SH, CH3Or CF3Substitution；R1Alkoxy optionally taken by F, OH, CN or SH Generation；And R1Heterocyclic radical optionally by F, OH, CN, SH, CF3Or C1-C3Alkyl substitutes,
R2It is each independently selected from H, NRaRb、C1-C6Alkyl, C3-C7Cycloalkyl, C1-C6Alkoxy, phenyl and 3-11 members are miscellaneous Ring group, wherein R2Optionally by RcSubstitution；Or
R1And R2The atom connected together with them is formed selected from C3-C7Cycloalkyl, phenyl and 3-11 circle heterocycles bases Cyclic group, wherein the cyclic group is optionally by RdSubstitution；
R4Selected from H, C1-C6Alkyl, CH2F and CH2OH；
R5It is 3-11 circle heterocycles bases, optionally by ReOr-C (=O) N (C1-C6Alkyl)2Substitution；Or
R4And R5Formed together optionally by ReSubstituted C3-C11Cycloalkyl or optionally by ReSubstituted 3-11 circle heterocycles bases；
A5-A8One of be N and remaining be CR6Or all CR6；
R6At each occurrence independently selected from H, F, Cl, NH2、NHCH3、N(CH3)2、OH、OCH3、OCHF2、OCH2F、 OCF3、SH、SCH3、SCHF2、SCH2F、CN、CH3、CHF2、CH2F、CH2OH、CF3、NO2And N3；
RaSelected from H and optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substituted C1-C6Alkyl；
RbSelected from H, C1-C6Alkyl, C1-C6Alkoxy, C3-C6Cycloalkyl, C (O) Rg, phenyl and 3-11 circle heterocycles bases, wherein RbCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substitution；
RcAnd RdIt is each independently selected from halogen ,-(X1)0-1-CN、-(X1)0-1-NO2、-(X1)0-1-SF5、-(X1)0-1-OH、- (X1)0-1-NH2、-(X1)0-1-N(H)(R1a)、-(X1)0-1-N(R1b)(R1a)、-(X1)0-1-CF3、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, oxo base ,-(X1)0-1-C1-C6Alkyl ,-(X1)0-1-C3-C10Ring Alkyl ,-O-C3-C10Cycloalkyl ,-(X1)0-1- 3-11 circle heterocycles base ,-(X1)0-1-C6-C10Aryl ,-C (=O) (X1)1-C3-C10Ring Alkyl ,-C (=O) (X1)1- 3-11 circle heterocycles base ,-(X1)0-1- C (=Y1)N(H)(R1a)、-(X1)0-1- C (=Y1)NH2、- (X1)0-1- C (=Y1)N(R1a)(R1b)、-(X1)0-1- C (=Y1)OR1a、-(X1)0-1- C (=Y1)OH、-(X1)0-1- N (H) C (= Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(H)、-(X1)0-1- N (H) C (=Y1) OR1a、-(X1)0-1-N(R1b) C (=Y1)OR1a、-(X1)0-1-S(O)1-2R1a、-(X1)0-1-N(H)S(O)1-2R1a、-(X1)0-1-N (R1b)S(O)1-2R1a、-(X1)0-1-S(O)0-1N(H)(R1a)、-(X1)0-1-S(O)0-1N(R1b)(R1a)、-(X1)0-1-S(O)0- 1NH2、-(X1)0-1- S (=O) (=NR1b)R1a、-(X1)0-1- C (=Y1)R1a、-(X1)0-1- C (=Y1)H、-(X1)0-1- C (= NOH)R1a、-(X1)0-1- C (=NOR1b)R1a、-(X1)0-1- NHC (=Y1)N(H)(R1a)、-(X1)0-1- NHC (=Y1)NH2、- (X1)0-1- NHC (=Y1)N(R1b)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N(H)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N (R1a)(R1b)、-(X1)0-1-N(R1a) C (=Y1)NH2、-(X1)0-1- OC (=Y1)R1a、-(X1)0-1- OC (=Y1)H、-(X1)0-1- OC (=Y1)OR1a、-(X1)0-1- OP (=Y1)(OR1a)(OR1b)、-(X1)-SC (=Y1)OR1aWith-(X1)-SC (=Y1)N(R1a) (R1b), wherein X1Selected from C1-C6Alkylidene, C1-C6Sub- miscellaneous alkyl, C2-C6Alkenylene, C2-C6Alkynylene, C1-C6Alkylene oxide Base, C3-C7Cycloalkylidene, the sub- heterocyclic radical of 3-11 members and phenylene；R1aAnd R1bIt is each independently selected from C1-C6Alkyl, C1-C6Halo Alkyl, C1-C6Miscellaneous alkyl, C3-C7Cycloalkyl, (C3-C7Cycloalkylidene) C1-C6Alkyl, 3-11 circle heterocycles base, (the sub- heterocycle of 3-11 members Base) C1-C6Alkyl, C6Aryl and (C6-C10Arlydene) C1-C6Alkyl, or R1aAnd R1bWhen being connected with identical nitrogen-atoms optionally Combination is formed comprising the 0-3 other heteroatomic 3-11 circle heterocycles bases selected from N, O and S；Y1It is O, NR1cOr S, wherein R1cIt is H or C1-C6Alkyl；Wherein RcOr RdThe arbitrary portion including R of substituent1a、R1bAnd R1cEnter independently of one another at each occurrence One step is by 0 to 4 RfSubstituent substitutes, the RfSubstituent is selected from halogen, CN, NO2、SF5、OH、NH2、-N(C1-C6Alkyl)2、- NH(C1-C6Alkyl), oxo base, C1-C6Alkyl ,-(C2-C6Alkynylene)-(3-11 circle heterocycles bases, wherein the heterocyclic radical is optional By ReSubstitution), C1-C6Hydroxy alkyl, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, C3-C7Cycloalkyl, 3-11 members Heterocyclic radical ,-C (=O) N (H) (C1-C6Alkyl) ,-C (=O) N (C1-C6Alkyl)2,-C (=O) NH2,-C (=O) OC1-C6Alkane Base ,-C (=O) OH ,-N (H) C (=O) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) (C1-C6Alkyl) ,-N (H) C (=O) OC1-C6Alkyl ,-N (C1-C6Alkyl) C (=O) OC1-C6(halo) alkyl ,-S (O)1-2C1-C6Alkyl ,-N (H) S (O)1-2C1-C6 Alkyl ,-N (C1-C6Alkyl) S (O)1-2C1-C6Alkyl ,-S (O)0-1N(H)(C1-C6Alkyl) ,-S (O)0-1N(C1-C6Alkyl)2、-S (O)0-1NH2,-C (=O) C1-C6Alkyl ,-C (=O) C3-C7Cycloalkyl ,-C (=NOH) C1-C6Alkyl ,-C (=NOC1-C6Alkane Base) C1-C6Alkyl ,-NHC (=O) N (H) (C1-C6Alkyl) ,-NHC (=O) N (C1-C6Alkyl)2,-NHC (=O) NH2、-N(C1- C6Alkyl) C (=O) N (H) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) NH2,-OC (=O) C1-C6Alkyl ,-OC (=O) OC1-C6Alkyl ,-OP (=O) (OC1-C6Alkyl)2,-SC (=O) OC1-C6Alkyl and-SC (=O) N (C1-C6Alkyl)2, wherein Rf Any moieties be optionally optionally substituted by halogen；
ReSelected from halogen, OH, C1-C6Alkyl and oxo base；And
RgSelected from C1-C6Alkyl and C3-C6Cycloalkyl, wherein RgCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3 Or CF3Substitution.
In some embodiments, compound has formula (II), and condition is that compound is not to be selected from compound 1x-146x With 148x-199x compound.
In some embodiments, ring A is monocyclic.A1It is N or CHR1.In some embodiments, A1It is N.In some realities Apply in scheme, A1It is N, A2It is S, and A3It is C.In some embodiments, A2It is N, O or CHR2.In some embodiments, A2 It is N.In some embodiments, A1It is S, A2It is N and A3It is C.In some embodiments, A2It is O, A1It is CR1、A2It is O and A3 It is C.
In some embodiments, A1It is CHR1And A2It is CHR2It is non-aromatic heterocyclic with ring A.In some embodiments, A1It is CHR1And A2It is CHR2It is non-aromatic monocyclic heterocycle with ring A.In some embodiments, A1It is CHR1And A2It is CHR2With ring A It is condensed-bicyclic non-aromatic heterocyclic.In some embodiments, A1It is CHR1；A2It is CHR2；And R1And R2Connected together with them Atom formed together optionally by RdSubstituted C3-C7Cycloalkyl or optionally by RdSubstituted 3-11 circle heterocycles bases.In some implementations In scheme, R1And R2Following cyclic group is formed together, and wherein asterisk represents that ring is fused to ring A point, and cyclic group is each Optionally by RdSubstitution:
In some embodiments, R1And R2The atom connected together with them forms the part with following structure：It is optionally by RdSubstitution, wherein asterisk represent that ring is fused to ring A point.
In some embodiments, A1It is CR1, wherein R1Selected from NHC (O) NRaRb；
NHS(O)2CH3；By C1-C3Alkoxy or the C of 3-11 circle heterocycles base substitution1-C3Alkyl；With by C1-C3Alkyl substitutes 3-11 circle heterocycles bases.In some embodiments, A1It is CR1, wherein R1It is NHC (O) NRaRb.In some these embodiments In, RaAnd RbIndependently selected from H and C1-C6Alkyl.
In some embodiments, A1It is CR1, wherein R1It is NHS (O)2CH3.In some embodiments, A1It is CR1, its Middle R1It is by C1-C3Alkyl-substituted 3-11 circle heterocycles base.In some embodiments, A1It is CR1, wherein R1It is by C1-C3Alcoxyl Base or the C of 3-11 circle heterocycles base substitution1-C3Alkyl.
In some embodiments, A1It is CR1, wherein R1It is selected from：
Wherein wave represents R1Tie point in formula (I) or (II).
In formula (I) or some embodiments of (II), A1It is NR1, S or CR1；And A2It is NR2, S or CR2.In some realities Apply in scheme, A is monocyclic.
In some embodiments, A1It is NR1.In some embodiments, A1It is NR1、A2It is CR2And A3It is C.At some In these embodiments, R1It is H or C1-C3Alkyl.In some embodiments, A1It is CR1.In some embodiments, A1It is CR1、A2It is CR2And A3It is N.In some embodiments, A1It is CR1And A6It is CR6.In some these embodiments, A2It is CR2, wherein R2It is H or-OCH3。
In some embodiments, A1It is CR1、A2It is S and A3It is C.In some these embodiments, R1It is not -NH2 Or-CH3。
In some embodiments, R1It is H, F or Cl.
In some embodiments, R1It is NRaRb.In some these embodiments, RaIt is H or C1-C6Alkyl.At some In these embodiments, RbIt is H；Optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substituted C1-C6Alkyl；Or appoint Choosing is by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substituted 3-11 circle heterocycles bases.In some these embodiments, RbIt is C(O)Rg.In some embodiments, RgIt is the C optionally substituted by F3-C6Cycloalkyl.
In some embodiments, R1It is optionally by F, OH, CN, SH, C1-C3What alkoxy or 3-11 circle heterocycles base substituted C1-C3Alkyl；Optionally by F, OH, CN, SH, CH3Or CF3Substituted C3-C7Cycloalkyl；Or C1-C3Alkoxy.
In some embodiments, R1It is optionally by F, OH, CN, SH, CF3Or C1-C3Alkyl-substituted 3-11 circle heterocycles Base.
In some embodiments, R1It is optionally by F, OH, CN, SH, CF3Or C1-C3Alkyl-substituted 5-6 unit's heteroaryls.
In some embodiments, R1It is selected from：
H、-CH3、-CH2CH3、
Wherein wave represents R1Tie point in formula (I) or (II).
In some embodiments, A1It is S.In some embodiments, A1It is S, A2It is CR2And A3It is C.In some implementations In scheme, R2It is H.In some embodiments,
In some embodiments, A1It is NR1Or CR1；And A2It is NR2Or CR2。
In some embodiments, A1It is NR1Or CR1；A2It is NR2Or CR2；And R1And R2The atom connected together with them Formed together optionally by RdSubstituted C3-C7Cycloalkyl, or optionally by RdSubstituted 3-11 circle heterocycles bases.At some, these are implemented In scheme, R1And R2The atom connected together with them is formed selected from following part：
Wherein asterisk represents that ring is fused to ring A point.
In some embodiments, A7It is CR6, wherein R6It is H.In some embodiments, A8It is CR6, wherein R6Be H or F.In some embodiments, A5It is CR6, wherein R6It is H.In some embodiments, A6It is CR6, wherein R6Selected from H, F, OCH3And CH3.In some embodiments, A5、A6、A7And A8It is CR independently of one another6, wherein R6At each occurrence independently Selected from H, F, OCH3And CH3, and n is 0.
In some embodiments, formula (I) compound is further defined as formula (III) compound:
Its middle ring A, A1、A2、A3、A4、R4And R5As defined in formula (II) or any variants detailed in this article, n It is 0,1 or 2, and R6It is each independently selected from F, Cl, OCH3、CH3And CF3.In some embodiments, compound has formula (III), condition is, compound be not compound 1x-3x, 12x-14x in table 1x, 16x, 18x-50x, 53x, 57x, 67x-70x, 73x-77x, 84x-140x, 143x-164x and 167x-199x compound.
In some embodiments of formula (I), (II) or (III) compound, R4And R5Shape together with the carbon connected with them Into optionally by ReSubstituted C8-C10Cycloalkyl.In some embodiments, R4And R5Formed and appointed together with the carbon connected with them Choosing is by ReSubstituted 4-9 circle heterocycles bases.
In some embodiments of formula (I), (II) or (III) compound, wherein such as lower part:
It is defined as
Wherein:
A9It is O, NR11Or CR11R12, wherein R11And R12It is each independently selected from H, halogen, OH and C1-C3Alkyl；
R7And R8It is each independently selected from halogen, OH, C1-C6Alkyl, or R7And R8Formation=O together, and
R9And R10It is each independently selected from H and Re, or R9And R10The atom connected together with them is formed optionally by Re Substituted C5-C6Cycloalkyl or optionally by ReSubstituted 5-6 circle heterocycles bases.
In some these embodiments, R7And R8Formation=O together；R9And R10Individually H；And A9It is NR11, wherein R11 It is C1-C3Alkyl.
In some embodiments, partIt is selected from：
In some embodiments, partIt is
Intend and understand, to the A described in formula (I), (II) or (III)1-A4Each and each variants, when can Using when include R1And R2Variants can with to the A described in formula (I), (II) or (III)5-A8Each and each accommodation Form and with to the R described in formula (I), (II) or (III)4And R5Each and each variants merge, as each and every kind of Combination is recorded like that by independent.For example, in some embodiments, ring A is monocyclic, A1It is NR1, A5、A6、A7And A8It is each independent Ground is CR6, and-C (R4)(R5) OH part be 3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases.In some embodiments, Ring A is monocyclic, A1It is CR1, wherein R1It is not -NH2Or-CH3, A2It is S, A3It is C, A5、A6、A7And A8It is CR independently of one another6, And-C (R4)(R5) OH part be 3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases.In some embodiments, ring A is single Ring, A1It is CR1, A2It is CR2, A3It is N, A6It is CR6, and-C (R4)(R5) OH part be 3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- bases.
In some embodiments, formula (I), (II) or (III) compound, its middle ring A is monocyclic；A1It is NR1, S or CR1； And A2It is NR2, S or CR2.In some embodiments, formula (I), (II) or (III) compound, its middle ring A is monocyclic；A1It is NR1, S or CR1；And A2It is NR2, S or CR2；Condition is, compound be not selected from compound 55x, 78x-83x, 89x, 195x and 197x compound.
In some embodiments, compound has formula (I), (II) or (III), wherein-C (R4)(R5) OH part be 3- Hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases.In some embodiments, compound has formula (I), (II) or (III), its In-C (R4)(R5) OH part be 3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases；Condition is that compound is not to be selected from chemical combination Thing 1x-25x, 30x-59x, 61x-66x, 68x-71x, 73x-81x, 83x-114x, 119x-124x, 129x-133x, 136x- 162x, 164x-169x, 173x-180x, 182x-184x, 186x, 188x-199x compound.
In some embodiments, A1-A4One of be N.In some embodiments, A4It is N.In some embodiments, A1-A4In two be N.For example, in some embodiments, A1And A4Individually N.In other embodiments, A3And A4Respectively N naturally.In any this kind of embodiment, ring B can be phenyl or independently by one or two R6Substituted phenyl.At some In embodiment, A1It is CR1, A2It is CR2, A3It is N, and A4It is N.
In some embodiments, R1Selected from H, F and Cl.In some embodiments, R2Selected from H, NH2、CH3With ring third Base.In other embodiments, R2It is C3-C11Heterocyclylalkyl.In some embodiments, R1And R2Following ring-type is formed together Group, wherein asterisk represent that ring is fused to ring A point, and each cyclic group is optionally by RdSubstitution:
In some embodiments, R1And R2Following cyclic group is formed together, and wherein asterisk represents that ring is fused to ring A's Point, and each cyclic group is optionally by RdSubstitution:
In some embodiments, R1And R2Unsubstituted cyclic group is formed together.
In some embodiments, RdSelected from OH, CN, F, C1-C3Alkoxy ,-O-C1-C3Alkyl-phenyl, NRaRb、4-6 Circle heterocycles base, C (O) Rg、C(O)2RgThe C optionally substituted by OH, CN or 4-6 circle heterocycles base1-C6Alkyl.
In some embodiments, ring B is phenyl.
In some embodiments, RcAnd RdIt is each independently selected from halogen ,-(X1)0-1-CN、-(X1)0-1-NO2、- (X1)0-1-SF5、-(X1)0-1-OH、-(X1)0-1-NH2、-(X1)0-1-N(H)(R1a)、-(X1)0-1-N(R1b)(R1a)、-(X1)0-1- CF3、C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, oxo base ,-(X1)0-1- C1-C6Alkyl ,-(X1)0-1-C3-C7Cycloalkyl ,-(X1)0-1- 3-11 circle heterocycles base (such as 4-7 circle heterocycles alkyl or 5-6 member heteroaryls Base) ,-(X1)0-1-C6-C10Aryl ,-C (=O) (X1)1-C3-C7Cycloalkyl ,-C (=O) (X1)1- 3-11 circle heterocycles base ,- (X1)0-1- C (=Y1)N(H)(R1a)、-(X1)0-1- C (=Y1)NH2、-(X1)0-1- C (=Y1)N(R1a)(R1b)、-(X1)0-1- C (= Y1)OR1a、-(X1)0-1- C (=Y1)OH、-(X1)0-1- N (H) C (=Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(R1a)、- (X1)0-1-N(R1b) C (=Y1)(H)、-(X1)0-1- N (H) C (=Y1)OR1a、-(X1)0-1-N(R1b) C (=Y1)OR1a、-(X1)0-1- S(O)1-2R1a、-(X1)0-1-N(H)S(O)1-2R1a、-(X1)0-1-N(R1b)S(O)1-2R1a、-(X1)0-1-S(O)0-1N(H)(R1a)、- (X1)0-1-S(O)0-1N(R1b)(R1a)、-(X1)0-1-S(O)0-1NH2、-(X1)0-1- S (=O) (=NR1b)R1a、-(X1)0-1- C (= Y1)R1aWith-(X1)0-1- C (=Y1) H, wherein X1Selected from C1-C6Alkylidene, C1-C6Sub- miscellaneous alkyl, C2-C6Alkenylene, C2-C6Sub- alkynes Base, C1-C6Alkylidene epoxide, C3-C7Cycloalkylidene, the sub- heterocyclic radical of 3-11 members and phenylene；R1aAnd R1bIt is each independently selected from C1-C6Alkyl, C1-C6Haloalkyl, C1-C6Miscellaneous alkyl, C3-C7Cycloalkyl, 3-11 circle heterocycles base and phenyl, or R1aAnd R1bWhen with Optionally combine to be formed comprising the 0-3 other heteroatomic 3-11 circle heterocycles bases selected from N, O and S during identical nitrogen-atoms connection (such as 4-7 circle heterocycles alkyl or 5-6 unit's heteroaryls)；Y1It is O, NR1cOr S, wherein R1cIt is H or C1-C6Alkyl；Wherein RcOr Rd The arbitrary portion including R of substituent1a、R1bAnd R1cAt each occurrence independently of one another further by 0 to 4 RfSubstituent takes Generation, the RfSubstituent is selected from halogen, CN, NO2、OH、NH2、-N(C1-C6Alkyl)2、-NH(C1-C6Alkyl), oxo base, C1-C6 Alkyl, C1-C6Haloalkyl, C1-C6Hydroxy alkyl, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, C3-C7Cycloalkanes Base, or 3-11 circle heterocycles base (such as 4-7 circle heterocycles alkyl or 5-6 unit's heteroaryls).
In some embodiments, heterocyclic group contain one to three nitrogen-atoms, an oxygen atom or a sulphur atom or It is combined.
In some embodiments, compound of the invention is defined as following one or more：
Some embodiments provide compound and pharmaceutical acceptable carrier comprising the present invention, the medicine of diluent or excipient Composition.Compound or pharmaceutical composition as described herein can be used for therapy, such as inflammatory conditions (such as lupus, such as system Property lupus erythematosus, the outer lupus of kidney or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, Dermatitis, endometriosis and graft rejection) treatment.Compound or pharmaceutical composition as described herein is additionally provided to make Be ready for use on treatment inflammatory conditions (such as lupus, for example, the outer lupus of systemic loupus erythematosus, kidney or lupus nephritis, COPD, rhinitis, Multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and graft rejection) medicament in Purposes.
The method for treating inflammatory conditions in patients is additionally provided, this method is included to patient using effective dose as herein Described compound or pharmaceutical composition.Inflammatory conditions can be selected from lupus or lupus outside lupus such as systemic loupus erythematosus, kidney Ephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplanting Repel.
Additionally provide the method for preparing formula (I) compound：
Wherein Q, A1、A2、A3、A4、A5、A6、A7、A8、R4And R5As hereinbefore defined, in (a) (i) palladium (0) catalyst or (a) in the presence of (ii) copper catalyst and (b) alkali, formula (A) compound is made under Suzuki reaction conditions：
Wherein X is Cl, Br or I,
Contacted with formula (B) compound,
Wherein [M] is boric acid, borate or trifluoroborate,
Obtain formula (I) compound.
Reagent employed in the known Suzuki reactions of those skilled in the art and this kind of reaction.See, for example, Suzuki, J.Organometallic Chem.,576:147-168(1999).The non-limiting examples of palladium catalyst include Pd (PPh3)4、 Pd(OAc)2With Pd (PPh3)2Cl2.The non-limiting examples of copper catalyst are copper acetate (II).The non-limiting examples of alkali include Sodium carbonate, potassium carbonate and cesium carbonate or its mixture.In some embodiments, acetic acid is used under Chan-Lam coupling conditions Copper (II) and the pyridine as alkali, as known in the art.For example, the carbonnitrogen bond in indazole or azaindazole can use Chan-Lam coupling conditions are formed.Can use a variety of organic solvents, including toluene, THF, dioxanes, 1,2- dichloroethanes, DMF, DMSO and acetonitrile.Reaction temperature is different according to condition, but usually room temperature is to 150 DEG C.
In some embodiments, the invention provides table 1A and table 1B compound：
Table 1A
Table 1B
In some embodiments, the invention provides the compound of embodiment.
In some embodiments, compound is selected from compound 1-69 and its salt.In some embodiments, compound is selected From compound 4,5,12,16,20,26,37,43,49,52,55,65 and 67 and its salt.
The synthesis of NIK inhibitor
Prepare the intermediate of the present invention and the method for compound provides in following examples part.Those skilled in the art It will be understood that other route of synthesis can be used for the compound of the synthesis present invention.Although specific raw material and reagent are described on stream And be discussed below, other raw materials and reagent are readily replaceable to provide a variety of derivatives or reaction condition.In addition, In the compound prepared by process described below it is most of can in view of present disclosure, using known to those skilled in the art Conventional chemical be further modified.
Raw material is generally available from commercial source such as Aldrich Chemicals (Milwaukee, Wis.) or using this Method known to art personnel easily prepares that (such as prepared by method by being summarized in documents below：Louis F.Fieser and Mary Fieser, Reagents for OrganicSynthesis, the 1-23 volumes, Wiley, N.Y. (1967- 2006 editors), or Beilsteins Handbuchder organischen Chemie, 4, Aufl. edit, Springer- Verlag, Berlin, including supplementary issue, it is included via Beilstein online databases).
In preparation formula (I), (II) or (III) compound, the distal end functional group (such as primary amine or secondary amine) of intermediate Protection is probably necessary.The demand of this kind of protection changes the property according to distal end functional group and the condition of preparation method. The demand of this kind of protection is easily determined by by those skilled in the art.There is provided herein exemplary protection group.For protection group General description and application thereof, referring to T.W.Greene, Protective Groups in Organic Synthesis, John Wiley＆Sons, New York, 1991.
Diastereomeric mixtures can according to their physical chemical differences, pass through side well known to those skilled in the art Method is separated into their independent diastereoisomer, such as passes through chromatography or Steppecd crystallization.Enantiomter can be as follows Separated：Will by being reacted with appropriate activity of optically active compounds (such as chiral auxiliary such as chiral alcohol or Mosher's acyl chlorides) Enantiomeric mixture is converted into diastereomeric mixtures, separates diastereoisomer, and independent diastereoisomer is turned It is corresponding pure enantiomter to change (such as hydrolysis).Equally, some in compound of the invention can be atropisomer (such as substituted biaryl), and be considered as the part of the present invention.Enantiomter can also be by using chirality HPLC column or supercritical fluid chromatography are separated.
Independent stereoisomer, such as enantiomter substantially free of its stereoisomer can be by using such as adopting The method formed with the diastereoisomer of the resolution reagent with optically active is split racemic mixture to obtain (Eliel, E. and WileN, S., Stereochemistry of Organic Compound, John Wiley＆Sons, Inc., New York, 1994；Lochmuller,C.H.,J.Chromatogr.,113(3):283-302(1975)).The chiralityization of the present invention The racemic mixture of compound can be separated or separated by the method for any suitable, including：(1) formed with chipal compounds Nonionic diastereo-isomerism salt and separated by fractional crystallization or other methods；(2) formed with chiral derivatizing reagents Diastereomeric compounds, separate diastereoisomer and be converted into pure stereoisomer；(3) under chiral conditions directly Separate stereoisomer that is substantially pure or being rich in.Referring to：Drug Stereochemistry,Analytical Methods And Pharmacology, Irving W.Wainer are edited, Marcel Dekker, Inc., New York (1993).
Diastereo-isomerism salt can by the chiral base of enantiomer-pure for example brucine, quinine, ephedrine, strychnine, The reaction with the asymmetric compound with acidic functionality such as carboxylic acid and sulfonic acid such as Alpha-Methyl-beta-phenyl ethylamine (amphetamine) To be formed.Diastereo-isomerism salt can be introduced to be separated by fractional crystallization or the chromatography of ions.For amino-compound Optical isomer separation, the addition of chiral carboxylic acids or sulfonic acid such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can cause shape Into diastereo-isomerism salt.
Or a kind of enantiomerism precursor reactant of substrate to be dissolved and chipal compounds is set to form a pair of diastereo-isomerisms Body to (Eliel, E. and Wilen, S., Stereochemistry of Organic Compound, John Wiley＆Sons, Inc., New York, page 1994,322).Diastereomeric compounds can be by making asymmetric compound and enantiomeric pure Chiral derivatizing agent such as menthyl derivatives reaction and then separation diastereoisomer and hydrolysis to obtain pure or be rich in Enantiomter is formed.Determine that the method for polarimetry purity is related to prepare the chiral ester such as peppermint base ester of racemic mixture and such as exist (-) chloro-carbonic acid peppermint base ester or Mosher esters, acetic acid α-methoxyl group-α-(trifluoromethyl) phenylester in the presence of alkali (Jacob,J.Org.Chem.47:4165 (1982)) and hindered for two kinds and turn the enantiomter or diastereoisomer of isomery Presence analysis H NMR spectroscopy.Resistance turn isocompound suitable diastereoisomer can by positive and RP chromatography, after The method (WO 96/15111) of naphthyl-isoquinoline compound that isomery is turned with separation resistance separated and separated.The side of passing through Method (3), the racemic mixture of two kinds of enantiomters can separate (Chiral by using the chromatography of chiral stationary phase Liquid Chromatography W.J.Lough, editor, Chapman and Hall, New York, (1989)；Okamoto,J.of Chromatogr.513:375-378(1990)).The enantiomter for being rich in or purifying can be by other having for distinguishing The method of the chiral molecules of asymmetric carbon atom is distinguished, such as optical activity and circular dichroism.Chiral centre and enantiomter Absolute stereochemical can be determined by X-ray crystallography.
Formula (I), (II) or (III) compound can be observed by characterizing method such as NMR and analytic type HPLC and is used for Synthesize the position isomer such as E of their intermediate and Z-shaped formula.For wherein exchanging the sufficiently high some compounds of energy barrier For, it can separate, E and Z isomers is for example separated by preparation HPLC.
Pharmaceutical composition and administration
Present invention compound of interest is NIK kinase inhibitors, available for treating a variety of disorders such as cancers or inflammatory disease Disease.
Present invention also offers comprising formula detailed in this article (I), (II), (III) compound or its any variant and at least The composition and medicament of a kind of pharmaceutical acceptable carrier, diluent or excipient.The composition of the present invention can be used in mammal (example Such as people patient) in suppress NF-kB signaling activities, such as by suppress NIK activity.
" pharmaceutically acceptable " refers to carrier, diluent or excipient must be compatible with other compositions of preparation, and to its recipient It is harmless.
In an embodiment, the invention provides comprising formula detailed in this article (I), (II), (III) compound or its Any variant and pharmaceutical acceptable carrier, the pharmaceutical composition (or medicament) of diluent or excipient.In another embodiment, this Invention provides the composition (or medicament) for preparing the compound comprising the present invention.In another embodiment, the present invention carries Supplied to need its mammal (such as people patient) apply formula detailed in this article (I), (II), (III) compound or its Meaning variant and the composition for including formula detailed in this article (I), (II), (III) compound or its any variant.
It can be prepared, quantified and using composition in a manner of consistent with good medical practice.Consider herein because Element includes the specific obstacle treated, the specific mammal treated, the clinical condition of individual patient, the cause of disease, medicine delivery Position, application process, application program and other factorses known to medical practitioner.The effective dose of compound to be administered will be by this kind of Consideration is determined that it is prevention or treats undesirable disease or obstacle such as such as neurodegeneration, amyloidosis, nerve fibril NIK required by (neurofibrillary tangle) formation or the undesirable cell growth (such as growth of cancer cells) of tangling Minimum needed for activity suppression.For example, the amount can be less than integrally has virose amount to normal cell or mammal.
In an example, the therapeutically effective amount of the compound of the invention of parenteral administration will for each dosage It is about 0.01-100mg/kg weight in patients daily or about such as 0.1 to 20mg/kg weight in patients, such as 0.3 to 15mg/kg/ My god.Daily dose is given as single daily dose or twice a day given in separate doses to six times in some embodiments, Or given in sustained release forms.For 70kg adults, total daily dose generally would be about 7mg to about Isosorbide-5-Nitrae 00mg.It can adjust Save the dosage and responded with providing optimal treatment.Compound can with the scheme of daily 1 to 4 time, preferably once a day or It is administered twice.
The compound of the present invention can be with any conventional administration form such as tablet, powder agent, capsule, solution, scattered Agent, supensoid agent, syrup, spray, suppository, gel, emulsion, patch etc. are applied.This based composition can contain pharmaceutical preparation In conventional constituents, such as diluent, carrier, pH adjusting agent, sweetener, filler and other activating agents.
The compound of the present invention can be applied in a manner of any suitable, the mode include it is oral, local (including it is buccal and It is sublingual), rectum, vagina, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and Epidural cavity and intranasal administration, such as Fruit is needed if being used for local treatment, in addition to is applied in damage.Parenteral infusions include intramuscular, intravenous, intra-arterial, peritonaeum Interior or subcutaneous administration.
Composition comprising formula detailed in this article (I), (II), (III) compound or its any variant is generally according to standard Medicinal practice is configured to pharmaceutical composition.Typical preparation is by by the compound of the present invention and diluent, carrier or excipient Mix to prepare.Suitable diluent, carrier and excipient is well known by persons skilled in the art, and is recorded in detail for example Ansel, Howard C. et al., Ansel ' s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia:Lippincott,Williams&Wilkins,2004；Gennaro, Alfonso R. et al., Remington:Science and Practice of Pharmacy. Philadelphia:Lippincott,Williams&Wilkins, 2000；And Rowe, Raymond C.Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press,2005.Preparation can also include one or more buffers, stabilizer, surfactant, profit Humectant, lubricant, emulsifying agent, suspending agent, preservative, antioxidant, opacifier, glidant, processing aid, colouring agent, sweet tea Taste agent, flavouring agent, flavouring, diluent and other known additive are to provide medicine (compound i.e. of the invention or its medicine Compositions) cosmetic elegance or help prepare drug products (i.e. medicament).
Suitable carrier, diluent or excipient is well known by persons skilled in the art, including such as carbohydrate, The material of wax, water solubility or swellable polymer, hydrophily or hydrophobic material, gelatin, oil, solvent, water etc..Used is specific Carrier, diluent or excipient are by depending on the mode and purpose using compound of the invention.Solvent is typically based on this area The solvent that technical staff is known as the safety (GRAS) for being applied to mammal selects.Generally, safe solvent It is nontoxic aqueous solvent such as water and to be dissolved in water or miscible other innoxious solvents in water.Suitable aqueous solvent includes water, second Alcohol, propane diols, polyethylene glycol (such as PEG 400, PEG 300) etc. and its mixture.Preparation can also include one or more It is buffer, stabilizer, surfactant, wetting agent, lubricant, emulsifying agent, suspending agent, preservative, antioxidant, light tight Agent, glidant, processing aid, colouring agent, sweetener, flavouring agent, flavouring and other known additive are to provide medicine (i.e. The present invention compound or its pharmaceutical composition) cosmetic elegance or help prepare drug products (i.e. medicament).
Acceptable diluent, carrier, excipient and stabilizer are in the dosage and concentration applied for recipient It is nontoxic, it includes buffer such as phosphate, citrate and other organic acids；Antioxidant including ascorbic acid and first Methyllanthionine；Preservative (such as stearyl dimethyl benzyl ammonium chloride；Chloor-hexaviet；Benzalkonium chloride, benzethonium chloride；Phenol, Butyl or benzyl alcohol；Nipalgin Arrcostab such as methyl hydroxybenzoate or propyl ester；Catechol；Resorcino；Cyclohexanol；3- amylalcohols；With Metacresol)；Low molecule amount (being below about 10 residues) polypeptide；Protein, such as seralbumin, gelatin or immunoglobulin； Hydrophilic polymer, such as polyvinylpyrrolidone；Amino acid, such as glycine, glutamine, asparagine, histidine, smart ammonia Acid or lysine；Monose, disaccharides and other carbohydrate including glucose, mannose or dextrin；Chelating agent, such as EDTA； Sugar, such as sucrose, mannitol, trehalose or sorbierite；Salt forms counter ion counterionsl gegenions, such as sodium；Metal complex (such as Zn- albumen Matter complex compound)；Or nonionic surface active agent such as TWEENTM、PLURONICSTMOr polyethylene glycol (PEG).The work of the present invention Property drug ingedient (such as formula detailed in this article (I), (II), (III) compound or its any variant) can also be encapsulated in made Standby micro-capsule (such as by condensation technique or pass through interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsule and poly- respectively (methyl methacrylate) micro-capsule), colloid drug delivery systems (such as liposome, albumin microsphere, micro emulsion, nanoparticle and Nanocapsule) or thick emulsion in.This kind of technology is disclosed in Remington:Science and Practice of Pharmacy: Remington Science and Practice of Pharmacy (2005) the 21st edition, Lippincott Williams＆ Wilkins, Philadelphia, PA.
The sustained release preparation of the compound of the present invention can be prepared.The Sutable examples of sustained release preparation are included containing detailed in this article Formula (I), (II), (III) compound or its any variant solid hydrophobic polymers semipermeable matrices, the matrix is into The form of shape article, such as film or micro-capsule.The example of sustained-release matrix includes polyester, hydrogel (such as poly- (2- hydroxyethyls-first Base acrylate) or it is poly- (vinyl alcohol)), polyactide (U.S. Patent number 3,773,919), Pidolidone and- Pidolidone second The copolymer of base ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-ethanol copolymer such as LUPRON DEPOTTM(by The Injectable microspheres of lactic acid-ethanol copolymer and acetic acid leuproside composition) and poly- D- (-) -3-hydroxybutyrate.
Preparation includes those suitable for route of administration detailed in this article.Preparation can easily be presented on unit dosage form In, and can be prepared by any means known to pharmaceutical field.Technology and preparation are typically found at Remington: Science and Practice of Pharmacy:Remington Science and Practice of Pharmacy (2005) the 21st editions, Lippincott Williams＆Wilkins, Philadelphia, PA.This method includes making active component with forming one The carrier in combination of kind or a variety of auxiliary elements.
Generally, preparation is made as follows：Active component and liquid-carrier, diluent or excipient or the solid of subdivision are carried Body, diluent or excipient or both uniformly mixing closely, then if necessary shape product.Typical preparation passes through The compound and carrier of the present invention, diluent or excipient are mixed to prepare.Preparation can use conventional dissolution and mixing Operate to prepare.For example, by drug substance raw material (the i.e. present invention in the presence of one or more as described above excipient The stable form of compound or compound (such as with cyclodextrine derivatives or the complex compound of other known complexing agent) is dissolved in suitable Solvent in.The compound of the present invention is generally prepared into pharmaceutical dosage forms to provide easily controllable drug dose and make trouble Person is complied with the scheme issued.
In an example, formula (I), (II) or (III) compound can by ambient temperature, under appropriate pH Mixed with desired purity with physiologically acceptable carrier to prepare.The pH of preparation depends primarily on particular use and chemical combination Thing concentration, but typically about 3 to about 8.In an example, formula (I) detailed in this article, (II), (III) compound or its Meaning variant is formulated in pH5 acetate buffer.In a further embodiment, formula (I), (II) or (III) compound It is sterile.Compound can be used as such as solid or unformed composition, freeze-dried preparation or aqueous solution storage.
The preparation of compound of the invention suitable for orally administering can be prepared into discrete unit such as piller, capsule, sachet Agent or tablet, each compound of the invention containing scheduled volume.
Compressed tablets can by suitable tablet press machine will optionally with adhesive, lubricant, inert diluent, anti-corrosion The active component of the free-flowing form of agent, surfactant or dispersant such as powder or particle is suppressed to prepare. Molded tablet can be by moulding the powder active ingredient soaked with inert liquid diluent to prepare in suitable machine.Piece Agent can be optionally coated or indentation, and is optionally prepared to provide the active component of sustained release or controlled release.
Tablet, tablet, lozenge, water-based or Oil suspensions, dispersible powder or particle, emulsion, hard or soft can be prepared Capsule such as gelatine capsule, syrup or elixir are used for oral use.It is intended for the preparation of the compound of the invention of oral use It can be prepared according to any means known in the art for being used to prepare pharmaceutical composition, said composition can contain one or more Material including sweetener, flavouring, colouring agent and preservative are to provide agreeable to the taste preparation.Containing with suitable for preparing the non-of tablet The tablet of the active component of toxicity pharmaceutically acceptable excipient mixing is acceptable.These excipient can be such as inert diluent Such as calcium carbonate or sodium, lactose, calcium phosphate or sodium；Granulation agent and disintegrant such as cornstarch or alginic acid；Adhesive such as starch, bright Glue or Arabic gum；With lubricant such as magnesium stearate, stearic acid or talcum powder.Tablet can be uncoated or can pass through Known technology including microencapsulation are coated to postpone disintegration in intestines and stomach and absorption and thus provide after the long period Slow releasing function.It is, for example, possible to use time delay material glycerin monostearate for example alone or in combination with a wax or distearyl Acid glyceride.
The example of suitable oral application forms have containing with about 5-30mg Lactis Anhydrouses, about 5-40mg crosslinking carboxylic first fiber Plain sodium, about 5-30mg polyvinylpyrrolidone (PVP) K30 and about 1-10mg magnesium stearate mixing about 1mg, 5mg, 10mg, The tablet of the compound of 25mg, 30mg, 50mg, 80mg, 100mg, 150mg, 250mg, 300mg and 500mg present invention.First will Powder ingredients mix, and are then mixed with PVP solution.Mixed by resulting composition drying, granulation, with magnesium stearate, Utilize the tabletted form of conventional equipment.The example of aerosol formulation can by by the present invention compound, such as 5- 400mg compounds are dissolved in such as phosphate buffer neutralization of suitable cushioning liquid and add tonicity agent if desired (tonicifier) as prepared by salt such as sodium chloride.Solution can be filtered, such as using 0.2 micron membrane filter by solution mistake Filter, to remove impurity and pollutant.
Treatment for eye or other outside organizations such as mouth and skin, preparation is preferably as containing such as 0.075 to 20% The topical ointment or emulsifiable paste of the active component of w/w amounts are applied.When prepare in ointment when, active component can with it is Paraffinic Or water-miscible ointment base is applied.Or active component can be prepared in the emulsifiable paste with oil-in-water type emulsifiable paste matrix In.
If desired, the aqueous phase of emulsifiable paste matrix may include polyalcohol, the i.e. alcohol with two or more hydroxyls such as Propane diols, butane 1,3- glycol, mannitol, sorbierite, glycerine and polyethylene glycol (including PEG 400) and its mixture.It is local Preparation may desirably include promoting compound of the active component via absorption or the infiltration of skin or other affected areas.It is this kind of The example of epidermal penetration accelerator includes dimethyl sulfoxide and related analogs.
The oil phase of the emulsion of the present invention can be made up of in known manner known composition.Although mutually can be only containing emulsification Agent, but be also desirable that comprising at least one emulsifying agent and both oily or fatty and oily mixtures of fat.Preferably, hydrophily Emulsifying agent with the lipophilic emulsifier of used as stabilizers with being included together.Further preferably include both oil ＆ fats.Have or Emulsifying agent without stabilizer forms so-called emulsifying wax together, and wax forms so-called emulsifying ointment base together with oil ＆ fat Matter, the latter form the oiliness dispersed phase of cream preparation.Include suitable for the emulsifying agent and emulsion stabilisers of the preparation of the present invention60、80th, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerin monostearate and Sodium Laurylsulfate.
The aqueous suspension of the compound of the present invention contains the activity mixed with suitable for preparing the excipient of aqueous suspension Material.This kind of excipient includes suspending agent such as sodium carboxymethylcellulose, Croscarmellose, PVP, methylcellulose, hydroxyl Propyl methocel, sodium alginate, polyvinylpyrrolidone, gum tragacanth and Arabic gum and scattered or wetting agent are for example natural Existing phosphatide (such as lecithin), the condensation product (such as Myrj 45) of alkylene oxide and aliphatic acid, second The condensation product of olefinic oxide and long-chain fatty alcohol (such as 17 carbon ethyleneoxy hexadecanol (heptadecaethyleneoxyc Etanol)), condensation product (such as the polyoxyethylene mountain of ethylene oxide and the part ester as derived from aliphatic acid and hexitan The smooth monoleate of pears).Aqueous suspension can also contain one or more preservatives such as P-hydroxybenzoic acid ethyl ester or n-propyl Ester, one or more colouring agents, one or more flavourings and one or more sweeteners such as sucrose or saccharin.
The preparation of the compound of the present invention can be the form of sterile injectable preparation, such as sterile injectable is water-based or oily Property supensoid agent.The supensoid agent can according to known technique, using the suitable scattered or wetting agent of those already mentioned above and Suspending agent is prepared.Sterile injectable preparation can also be in the parenteral acceptable diluent of non-toxic or solvent Sterile injectable solution or suspension, such as the solution in 1,3-BDO, or be prepared into freeze-dried powder.Can be with The acceptable solvent and solvent used has water, Ringer's solution and isotonic sodium chloride solution.Furthermore it is possible to easily use Sterile fixed oil is as solvent or suspension medium.For the purpose, any mixing fixing oil can be used, includes the glycerine of synthesis Monoesters or diester.In addition, aliphatic acid such as oleic acid can be equally used in the preparation of injectable agent.
Can be combined to produce with carrier mass the amount of the active component of single dose form by according to the host treated and Specific method of application and it is different.For example, the time delivery formulations for being intended for being administered orally to people contain about 1 to 1000mg's The active material mixed with the carrier mass of appropriate and convenient amount, carrier mass can account for about 5 to about 95% (weights of total composition Amount:Weight).Pharmaceutical composition can be prepared to provide the amount of application that can easily determine.For example, for the water-soluble of intravenous infusion Liquid phase can contain about 3 to 500 μ g active components for every milliliter of solution, so as to carry out the suitable of about 30mL/hr speed The infusion of suitable volume.
Preparation suitable for parenteral administration includes water-based and non-aqueous sterile injection solution, its can contain antioxidant, Buffer, bacteriostatic agent and make the preparation solute isotonic with the blood of expected recipient；With water-based and non-aqueous sterile suspensions, its Suspending agent and thickener can be included.
Preparation suitable for being locally applied to eye also includes eye drops, and wherein active component is dissolved in or be suspended in suitable load Body, in particular in the aqueous solvent of active component.Active component preferably with about 0.5 to 20%w/w, e.g., from about 0.5 to 10%w/w, e.g., from about 1.5%w/w concentration are present in said preparation.
Preparation suitable for the local application in mouth includes lozenge, and it is included in flavored base, is typically sucrose and Arab Active component in glue or tragacanth；Pastille, it is included in inert base such as gelatin and glycerine or sucrose and Arab Active component in glue；And collutory, it is included in the active component in suitable liquid carrier.
Preparation for rectal administration can be rendered as containing the bolt comprising such as cocoa butter or salicylic appropriate substrate Agent.
There is such as 0.1 to 500 micrometer range (including 0.1 with micrometer increments suitable for the preparation of intrapulmonary or nasal administration To the granularity of 500 micrometer ranges, such as 0.5,1,30 micron, 35 microns etc.) granularity, it passes through the quick suction via nasal passage Enter or be administered by the suction via mouth to reach alveolar sac.The water-based or oiliness that suitable preparation includes active component is molten Liquid.The preparation applied suitable for aerosol or dry powder can be prepared conventionally, and can be with other therapeutic agents as used It is delivered together in the compound for treating following obstacles.
Preparation suitable for vaginal application can be rendered as pesseulum, tampon, creme, gel, paste, foaming agent or spraying system Agent, it is in addition to active component also containing all appropriate carriers as known in the art.
Preparation can be packaged in single dose or multi-dose container such as closed ampoule and bottle, and can be stored in and only needed Adding before use in freeze-drying (lyophilized) condition of sterile liquid carrier such as water for injection.By the aseptic powder of aforesaid kind End, particle and tablet prepare Extemporaneous injection solutions and supensoid agent.Preferable unit dose formulations are containing day as indicated above Those of dosage or the active component of sub- daily dose unit or its appropriate part.
Idicatio and treatment method
Formula (I), (II) or (III) compound suppresses NIK activity.Therefore, in additional aspects of the present invention, change of the invention Compound can be used for treating disease and obstacle in mammal, such as people patient, and the NIK wherein in patient suppresses be that treatment has Effect.For example, the compound of the present invention can be used for treating via such as NIK excessive activations in mammal (such as people patient) The disease related to hyperactive or undesirable NF-kB signal transductions or obstacle.In one embodiment, it is of the invention During compound is used to suppress NIK activity, such as analysis is set in vitro, by changing formula detailed in this article (I), (II), (III) Compound or its any variant are contacted with NIK to carry out.For example, formula (I), (II) or (III) compound can in vitro be analyzed and set It is used as control compound in putting.
In a further embodiment, compound of the invention is used to suppress undesirable NF-kB signal transductions, such as In analysis of cell proliferation, by formula (I), (II), (III) compound or its any variant that detailed description is incorporated herein into cell. In a further embodiment, the invention provides the treatment in the mammal (such as people patient) and hyperactive or not phase The method of the related disease of the NF-kB signal transductions of prestige or obstacle (such as cancer, inflammatory disease etc.), methods described need including giving Its mammal (such as people patient) is wanted to apply the compound of the invention of therapeutically effective amount.
The disease and obstacle that the method treatment of the present invention can be used include cancer, inflammatory conditions, autoimmune disease and medical treatment Caused propagation after operation (such as caused cell increases after arthritis, graft rejection, inflammatory bowel disease, surgery vascular plasty Grow).In one embodiment, the compound and pharmaceutical acceptable carrier, adjuvant of mammal (such as people patient) present invention Or excipient is treated, wherein described compound of the invention via such as, but not limited to NIK to suppress to suppress NF-kB The amount of signal transduction is present.
In one embodiment, compound of the invention can be used for treating cell proliferation disorder.
In one embodiment of the invention, can be selected from the cancer of formula (I), (II) and (III) compounds for treating Lung cancer (bronchiogenic cancer (non-small cell lung cancer)；The cancer of stomach and intestine-rectum, colorectum and colon；Genitourinary tract-kidney Cancer (Papillary Renal Cell Carcinoma)；With skin-head and neck squamous cell carcinoma.
In one embodiment, formula (I), (II) and (III) compound can be used for treatment to be selected from following cancer：Head and Neck squamous cell carcinoma, histocytic lymphoma, adenocarcinoma of lung, ED-SCLC, non-small cell lung cancer, cancer of pancreas, mamillary kidney are thin Born of the same parents' cancer, liver cancer, stomach cancer, colon cancer, leukaemia, lymthoma, Huppert's disease, spongioblastoma and breast cancer.
In one embodiment, formula (I), (II) and (III) compound can be used for treatment to be selected from following cancer：Tissue Cell lymphoma, adenocarcinoma of lung, ED-SCLC, cancer of pancreas, liver cancer, stomach cancer, colon cancer, leukaemia, lymthoma, multiple marrow Knurl, spongioblastoma and breast cancer.
In one embodiment, formula (I), (II) and (III) compound can be used for treatment to be selected from following cancer：Lymph Knurl, leukaemia and Huppert's disease.
In an embodiment, the invention provides for treating lymthoma, leukaemia or the medicine of Huppert's disease The preparation of agent, the medicament include formula detailed in this article (I), (II), (III) compound or its any variant.
In an embodiment, the invention provides the treatment of lymthoma, leukaemia or Huppert's disease, this method Formula detailed in this article (I), (II), (III) compound or its any variant including applying effective dose.
In one embodiment, compound of the invention can be used for treatment inflammatory disease and illness, include but is not limited to Lupus (including lupus and lupus nephritis outside systemic loupus erythematosus, kidney), asthma, COPD, rhinitis, multiple sclerosis, IBD, pass Save inflammation, gastritis, rheumatoid arthritis, dermatitis, endometriosis, graft rejection, miocardial infarction, Alzheimer disease, Type ii diabetes, inflammatory bowel disease, sepsis and atherosclerosis.
In an embodiment, the invention provides formula detailed in this article (I), (II), (III) compound or its is any Purposes of the variant in inflammatory conditions are treated.
In an embodiment, the invention provides formula detailed in this article (I), (II), (III) compound or its is any Variant is preparing the purposes in being used to treat the medicament of inflammatory conditions.
In an embodiment, the invention provides the formula detailed in this article (I) for treating inflammatory conditions, (II), (III) compound or its any variant.
In an embodiment, the invention provides the method for treating inflammatory conditions, this method is included to needs Its patient applies formula detailed in this article (I), (II), (III) compound or its any variant of effective dose.
In an embodiment, the invention provides the treatment of inflammatory conditions, the inflammatory conditions be selected from lupus (including The outer lupus of systemic loupus erythematosus, kidney and lupus nephritis), COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid close Save inflammation, dermatitis, endometriosis and graft rejection, this method include applying the formula detailed in this article (I) of effective dose, (II), (III) compound or its any variant.
Combination
Formula (I), (II) and (III) compound can be used alone or make with being combined for other therapeutic agents for the treatment of With.In one embodiment, compound of the invention can be used alone or be used with chemotherapeutic combination.At one In embodiment, compound of the invention can be used alone or is applied in combination with antiinflammatory.The compound of the present invention can be with Other medicine, such as anti-inflammatory compound or the anticancer compound to be worked with one or more by the different mechanisms of action, which combines, to be made With.Second of compound of medicine composition or dosage regimen preferably has the activity complementary with the compound of the present invention, with Just they can not adversely influence each other.This quasi-molecule for the effective amount of expected purpose suitably to be present in combination.Change Compound can together be applied with single medicine composition or applied respectively, and when applying respectively, this can be simultaneously or with any order Order occurs.This is sequentially applied and can approached in time or remote in time.
In some embodiments, formula (I) detailed in this article, (II), (III) compound or its any variant are in medicine group Close in preparation or combined in dosage regimen as combined therapy with second of therapeutic compounds, second of therapeutic compounds tool There are anti-inflammatory or anticancer property or available for treatment inflammation, immune response obstacle or hyperproliferation disorder (such as cancer).Second Kind therapeutic agent can be NSAID (NSAIDs) or other anti-inflammatory agents.Second of therapeutic agent can be chemotherapeutant. In one embodiment, pharmaceutical composition of the invention include combined with therapeutic agent such as NSAID formula detailed in this article (I), (II), (III) compound or its any variant.
Embodiment
Although having described and explained the present invention with certain exact level, it will be appreciated that only by way of example Mode has carried out the disclosure, and those skilled in the art can carry out various change joint and each several part arrangement without departing from such as The purpose and scope of the invention defined in claim.
The chemical reaction in the embodiment can be easily adjusted to prepare various other compounds of the invention, used It is considered as within the scope of the invention in the alternatives for the compound for preparing the present invention.For example, the change of the invention do not illustrated The synthesis of compound can successfully be carried out by clear accommodation to those skilled in the art, such as by suitably protecting Shield interference group, by using be not it is described those other Suitable agents known in the art or by being carried out to reaction condition It is conventional flexible.Or other reactions disclosed herein or known in the art will be deemed applicable to prepare other present invention Compound.
Universal method A：SNAr
To containing nitrogen nucleophile (1 equivalent) and cesium carbonate (3.0 equivalent) in N,N-dimethylformamide (2mL/mmol) Solution in add 2- halogenated heterocyclics (1.1 equivalent).Reactant is heated to 100 DEG C, stirs 2 hours at such a temperature.Then will Reactant is cooled to room temperature, and pH=1 is acidified to the 10%HCl aqueous solution if product contains formic acid, or if neutral If be diluted with water.Solution is extracted twice with dichloromethane.Merge organic layer, dried with sodium sulphate, is concentrated in vacuo.Thick material is straight Connect for subsequent reaction or pass through purified by flash chromatography.
Universal method B：The acid amides carried out by heterocyclic carboxylic acid synthesizes
Aromatics or non-aromatic heterocyclic sour (1 equivalent) and HATU (1.2 equivalent) are weighed, are transferred in bottle, successively to small DMF and DIPEA (3-5 equivalents) is added in bottle.Added later into reactant mixture as free alkali or the amine of HCl salt (HNRR), reactant is in room temperature or 50 DEG C of stirring 2-18 hours.Reaction conversion is monitored by LCMS.After the completion of, reactant is cold But, crude product is developed via addition water, is collected by filtration or is extracted with saturated ammonium chloride and DCM.Develop or pure through chromatography Change, obtain acid amides.
Universal method C：Chan-Lam cross-couplings
The nitrogenous nucleophilic examination added into bottle in N,N-dimethylformamide (2mL/mmol) and pyridine (3.0 equivalent) Agent (1 equivalent), aryl boric acid (1.5 equivalent), copper acetate (II) monohydrate (0.3 equivalent).By reactant under oxygen atmosphere Stirred 6 hours in 90 DEG C.Then reactant is cooled to room temperature, diluted with saturated sodium bicarbonate aqueous solution, by aqueous phase dichloro Methane extracts 3 times.Merge organic phase, it is dried over sodium sulfate with salt water washing, it is concentrated in vacuo.Thick material is pure through flash chromatography Change.
Universal method D：Hydrolysis of the nitrile to primary amide
Hydrogenation is added into solution of the aryl nitrile (1 equivalent) in ethanol (0.8mL/mmol) and water (0.04mL/mmol) (dimethyl phosphonous acid-kp) [hydrogen is double (dimethyl phosphino--kp)] platinum (II) (hydrido (dimethylphosphinous Acid-kp) [hydrogenbis (dimethyl phosphinito-kp)] platinum (II)) (0.05 equivalent).Reactant Stirred 2 hours under air in 90 DEG C.Then solution is cooled to room temperature, be extracted twice with ethyl acetate or dichloromethane.Close And organic layer, it is dried over sodium sulfate, it is concentrated in vacuo.Thick material is directly used in subsequent reaction or passes through purified by flash chromatography.
The general operation of aryl-halide (ArX) terminad alkynes cross-coupling：
Universal method E：Weigh aryl halide, be transferred in sealing test tube, bring acetonitrile (3mL/mmol) and triethylamine into In (3mL/mmol).Solution is deaerated with nitrogen, and (0.1 works as addition copper(I) iodide (I) (0.05 equivalent) and double (triphenyl phasphine) palladium bichlorides (II) Amount).Then DMF (3mL/mmol) is added, alkynes (2-3 equivalents) is then added dropwise.Reactant mixture heats 3-18 hours in 80 DEG C, The consumption of raw material is monitored by LCMS.After the completion of, reactant is cooled down, the added water of crude product is developed, and is collected by filtration, or Person's saturated ammonium chloride and DCM extractions, now dry organic layer, filtering, are concentrated to dryness.Crude product carries out reverse HPLC-purified.
Universal method F：Weigh aryl halide (wherein X=bromines) (1 equivalent), copper(I) iodide (I) (0.06 equivalent), three tertiary fourths Base phosphorus tetrafluoroborate (0.2 equivalent) and double (phenyl cyanide) palladiums (0.1 equivalent) of dichloro, are transferred in microwave tube.Add After DMSO (3mL/mmol), by reactant mixture subsequent degassifying, alkynes (3 equivalent) is now added dropwise at diisopropylamine (3 equivalent) In solution.Reactant mixture is closed the lid, in 80 DEG C of heating, the consumption of raw material is monitored by LCMS.Post processing and operation E In it is identical.
Universal method G：Weigh aryl halide (wherein X=bromines), be transferred in sealed tube, bring DMSO or DMF into In (3mL/mmol) and triethylamine (3mL/mmol).Solution is deaerated with nitrogen, adds double (triphenyl phasphine) palladium bichlorides (II) (0.2 equivalent) With alkynes (2-3 equivalents) (" not cupric " condition).Reactant mixture heats 2-18 hours in 80 DEG C, and raw material is monitored by LCMS Consumption.Post processing is identical with aforesaid operations E.
Universal method H：Conversion with the ester that sodium methoxide/formamide is carried out to acid amides：
Formamide (10 equivalent) is added into solution of the heterocyclic ester in DMF, sodium methoxide is then added dropwise (3 equivalent).Mixture is stirred at room temperature or be heated to 40 DEG C, is monitored and completed by LC-MS.Via addition saturated ammonium chloride pair Crude product mixture developed or the non-fragmentation of product wherein in the case of extracted with dichloromethane.This is intermediate wherein In the case of, thick material is directly used in subsequent reaction.
Universal method I：With the conversion of the ester carried out in ammonium hydroxide dioxanes to acid amides：
The ammonium hydroxide (25% material) in water is added in solution into heterocyclic ester dioxanes (10mL/mmol) (50 equivalents, 14mmol).Reactant mixture is monitored complete in 40 DEG C of stirrings by LC-MS.Crude product mixture is concentrated into It is dry, by reverse HPLC-purified, obtain product.
Universal method J：Ester saponification：
To heterocyclic ester 1:Lithium hydroxide monohydrate (3-10 equivalents) is added in solution in 1 tetrahydrofuran/water.Reaction Thing is stirred at room temperature or is heated to 50 DEG C, is monitored by LC-MS complete.Then tetrahydrofuran is evaporated, water-based crude reaction is mixed The pH of thing is adjusted to 3, and now product ruptures and separated, or in the case where product does not rupture by water layer dichloromethane or Ethyl acetate extracts.In the case that this is intermediate wherein, thick material is directly used in subsequent reaction.
Universal method K：Ketone/aldehyde reduction：
Sodium borohydride (1-3 equivalents) is added into the solution of heterocyclic ketone/aldehyde in methyl alcohol.Reactant stirs in 0 DEG C or room temperature Mix until bubbling is reduced, by LC-MS monitorings completely.Reactant mixture dichloromethane and saturated ammonium chloride extraction, now do Dry organic layer, filtering and concentration, obtain thick heterocycle alcohol intermediate, are directly used in subsequent reaction.
Universal method L：Fluorination reaction
The diethylamino that 4 equivalents are added into the solution of alcohol, aldehydes or ketones in dichloromethane or dichloroethanes is borontrifluoride Sulphur (DAST) or double (2- methoxy ethyls) amino sulfur trifluoride (Deoxo-Fluor).Reactant is stirred at room temperature or is heated to 45 DEG C, monitored by LC-MS complete.Reactant mixture is concentrated to dryness, and thick intermediate is developed via addition water, by it not Through being further purified for subsequent reaction.
Universal method M：The Suzuki of boric acid or borate and aryl halide is coupled
By aryl halide, four (triphenyl phasphine) palladiums or double (triphenyl phasphine) palladium chlorides (II) (0.05 equivalent) and boric acid or frequency Which alcohol ester (1.2 equivalent) is weighed into microwave tube or sealed tube.Add acetonitrile (3mL/mmol) and 1M aqueous sodium carbonates (3 Equivalent).Bottle is closed the lid, 3-18 hours are heated in 100 DEG C.After the completion of, reactant is cooled down, by crude product via addition Water is developed, and is collected by filtration, or is extracted with saturated ammonium chloride and DCM.If crude product is intermediate, in most of feelings In progress or without lower carry out next step is further purified under condition, or progress reversed-phase HPLC is pure when it is end-product Change.
Universal method N：The reduction amination of aryl aldehyde.
Molecular sieve is added in containing solution of the aryl aldehyde (1 equivalent) in the 10%DMF solution (6mL/mmol) of acetic acid (1 equivalent weight), amine (HNRR, 4 equivalents) and sodium cyanoborohydride (1.2 equivalent).Reactant stirs in 45 DEG C of heating or in room temperature Mix.After the completion of, reactant is extracted with DCM and saturated ammonium chloride.Organic layer is dried with magnesium sulfate, is filtered and is concentrated, is slightly produced Thing, it not purified is used for next step.
Universal method O：The carbonylation methanol solution of aryl halide
The solution rinsed to nitrogen of the aryl iodide in TEA (3mL/mmol), DMF (3mL/mmol) and MeOH (3mL/mmol) Middle addition acid chloride (II) (0.03 equivalent) and Xantphos (0.06 equivalent).Reactant mixture is rinsed with CO gas Several minutes, connected CO air sac sealings are then used, are heated to 60 DEG C up to 3 hours.After the completion of, reactant is cooled to room temperature, Crude product is developed and is collected by filtration via addition water.By thick intermediate carry out/without being further purified in the case of For next step.
Universal method P：The carbonylation amidatioon carried out with HMDS
Double (triphenyl phasphines) two are added into nitrogen de gassed solution of the non-exclusive aryl iodide (Ar-I) in DMF (170 equivalent) Palladium bichloride (II) (0.05 equivalent) and hexamethyldisilane base amine (6 equivalent).Reactant mixture is rinsed with CO gas Several minutes, connected CO air sac sealings are then used, are heated to 70 DEG C up to 18 hours.After the completion of, reactant is cooled to room temperature, Crude product is developed and is collected by filtration via addition water.By thick intermediate carry out/without being further purified in the case of use In next step.
Universal method S：Conversion using the ester that ammonia in methyl alcohol is carried out to acid amides
Into the agitating solution of ester (1 equivalent) in methyl alcohol with methyl alcohol saturated ammonia (>20 equivalents) processing.Will mixing Thing is stirred at room temperature or is heated to 40 DEG C, is monitored and reacted by LC-MS.Crude product mixture is concentrated, it is pure by reversed-phase HPLC Change.
Universal method T：The SEM carried out with HCl is deprotected
By the 4.0M solution (17.0 equivalent) in the protected amine of SEM- or alcohol and hydrogen chloride dioxanes in ethanol Merge in (4.0mL/mmol), stirred 2 hours in 50 DEG C.Then sample is concentrated in vacuo, is directly used in subsequent reaction or logical Cross purified by flash chromatography.
The general operation that the Suzuki carried out with aryl trifluoroborate is coupled：
Universal method U：The solution of aryl chlorine bromine (1 equivalent) and aryl trifluoroborate (1 equivalent) in ethanol will be contained Test tube pour nitrogen, then add Pd (OAc)2(0.06 equivalent), RuPhos (0.12 equivalent) and sodium carbonate (2 equivalent).Will Test tube is sealed with the lid for being lined with disposable Teflon film, and 12-20 hours are heated in 85 DEG C.Reactant mixture is set to be cooled to room Temperature, filtered through diatomite, be then directly used in reverse HPLC-purified or extracted with dichloromethane and saturated ammonium chloride solution, then Dry, evaporation, carry out anti-phase purifying or not purified be used for subsequent step.
Universal method V：By aryl chlorine bromine (1 equivalent) and aryl trifluoroborate (1 equivalent) in the 20% dioxane aqueous solution Solution degassing in (0.28M), then adds cesium carbonate (3 equivalent) and four (triphenyl phasphine) palladiums (0) (0.05 equivalent).Reaction mixing Thing heats 1 hour in 100 DEG C, is subsequently cooled to room temperature.Post processing is identical with universal method U.
Universal method W：By aryl chlorine bromine (1 equivalent) and aryl trifluoroborate (1 equivalent) in acetonitrile (0.25M) Solution deaerates, and then adds four (triphenyl phasphine) palladiums (0) (0.05 equivalent) and 1M sodium carbonate (2 equivalent) and 1M potassium acetates (2 equivalent) 1:1 mixture.Reaction is carried out in 5mL biotage microwave tubes, is heated to 140 DEG C and is reached 20-40 minutes, is subsequently cooled to room Temperature.Post processing is identical with universal method U.
Universal method X：The synthesis of the protected tetrahydrochysene indazoles of SEM-
Step 1：Solution of the diisopropylamine (1.7 equivalent) in THF (4.6mL/mmol) is cooled to -78 DEG C, then The solution (1.6M, 1.5 equivalents) of n-BuLi in hexane is added dropwise.After stirring 5 minutes, the mixture is added into diazonium through sleeve pipe In -78 DEG C of solution of ethyl (1.6 equivalent) and naphthenic one (1.0 equivalent) in THF (4.6mL/mmol).Mixture Stirred 1 hour in -78 DEG C, then by adding NH4Cl saturated aqueous solutions are quenched.Mixture is diluted with water, and is extracted with EtOAc Take (2 times).The organic extract of merging dries (MgSO4), it is concentrated in vacuo.Pass through CombiFlash (heptane:EtOAc) purify, Expected product is provided.
Step 2：Added into solution of the product (1.0 equivalent) in pyridine (4.6mL/mmol) from abovementioned steps POCl3(4.35 equivalent), mixture is set to be stirred at room temperature overnight.After vacuum concentration, mixture is poured on ice, Ran Houyong EtOAc extracts (3 times).The organic extract of merging dries (MgSO4) and be concentrated in vacuo.By residue octane (2.1mL/ Mmol) dilute, heated 2 hours in 110 DEG C.After vacuum concentration, pass through CombiFlash (heptane:EtOAc) purify, there is provided it is expected that Product.
Step 3：Solution of the product (1.0 equivalent) in THF (20mL/mmol) from abovementioned steps is cooled to 0 DEG C, Then sodium hydride (60%, 3.0 equivalents) is added.After stirring 1 hour, SEMCl (1.2 equivalent) is added, mixture is warmed to room Temperature is overnight.After hydride by adding 0 DEG C of sterilized amount of water quenching, mixture is extracted into (3 times) with EtOAc, organic extract is done Dry (MgSO4) and be concentrated in vacuo.Pass through CombiFlash (heptane:EtOAc) purify, there is provided expected to contain ester products.By the ester Diluted with THF (5.4mL/mmol), acetonitrile (5.4mL/mmol) and water (5.4mL/mmol), add lithium hydroxide monohydrate (7.0 equivalent), mixture is stirred overnight.Mixture is diluted with water, and is acidified to pH 3 with 1N HCl (aq), uses Et2O (1 time) and 10%MeOH/CH2Cl2(3 times) extractions.The organic extract of merging dries (MgSO4) and be concentrated in vacuo, there is provided have and be enough The expection carboxylic acid of the purity directly used.
Universal method Y：The protected tetrahydrochysene indazoles of SEM- synthesize for choosing
Step 1：Solution of the naphthenic one (1.0 equivalent) in EtOH (0.5mL/mmol) is cooled to 0 DEG C, then added Caustic alcohol (the 21%wt solution in EtOH, 1.1 equivalents).Diethyl oxalate (1.0 equivalent) is added into the mixture, is made Mixture is warmed to room temperature overnight.It is concentrated under vacuum, there is provided there is expection product (the yield vacation for the purity for being enough directly to use It is set to quantitative).
Step 2：Solution of the product (1.0 equivalent) in glacial acetic acid (0.5mL/mmol) from abovementioned steps is cooled to 0 DEG C, then add hydrazine hydrate (1.1 equivalent).After warming to room temperature, stir the mixture for 1 hour, then use NaHCO3Saturation water Solution dilutes, and uses 10%MeOH/CH2Cl2Extraction.Organic extract is dried into (MgSO4), it is concentrated in vacuo.Pass through CombiFlash (heptane:EtOAc) purify, obtain expected tetrahydrochysene indazole -3- formic acid esters.
Step 3：Carried out in a manner of similar to universal method X steps 3.
In some cases, stereoisomer is separated, obtains single enantiomer or as independent unknown stereoisomer Diastereoisomer, it is arbitrarily plotted as individual isomer.When in place, separation method and elution time and order are provided Information.
Embodiment 1
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (1- first Base -1H- pyrazoles -4- bases) thiazole -4-carboxamide
Step 1：Synthesize 2- amino -5- diuril azoles -4- carboxylates
2- amino -1,3- 4-thiazolecarboxylic acids ethyl esters (3g, 17.421mmol, 1.00 equivalent) and N- chlorine succinyl is sub- Solution of the amine (2.783g, 20.841mmol, 1.20 equivalent) in acetonitrile (50mL) stirs 2 hours in 80 DEG C.Resulting solution is true Sky concentration, residue is through silica gel column chromatography methylene chloride/methanol (30:1) be purified by flash, obtain title compound (2g, 56%), it is light yellow solid.LC-MS(ES,m/z):207[M+H]+。
Step 2：Synthesize the bromo- 5- diurils azoles -4- carboxylates of 2-
By the chloro- 1,3- 4-thiazolecarboxylic acids ethyl esters of 2- amino -5- (2.00g, 9.678mmol, 1.00 equivalent), the tert-butyl group Nitrile (1.20g, 11.637mmol, 1.20 equivalent), copper bromide (2.59g, 11.596mmol, 1.20 equivalent) are in acetonitrile (50mL) Solution in 80 DEG C stir 2 hours.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography methylene chloride/methanol (40:1) it is purified by flash, obtains title compound (1.2g, 46%), is white solid.LC-MS(ES,m/z):270[M+H]+。
Step 3：Synthesize (R) -5- chloro- 2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) 4-thiazolecarboxylic acid ethyl ester
Similar to the operation described in universal method U, the bromo- 5- diurils azoles -4- carboxylates of 2- and (R)-trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtain title compound (180mg, 40%), it is light yellow solid.LC-MS(ES,m/z):376[M+H]+。
Step 4：Synthesize (R) -5- chloro- 2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) thiazole -4-carboxamide
Similar to the operation described in universal method S, the chloro- 2- of (R) -5- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Alkane -3- bases) acetenyl) phenyl) 4-thiazolecarboxylic acid ethyl ester and ammonia reacts, title compound (150mg, 90%) is obtained, to be shallow Yellow solid.LC-MS(ES,m/z):376[M+H]+。
Step 5：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (1- methyl isophthalic acid H- pyrazoles -4- bases) thiazole -4-carboxamide
Similar to the operation described in universal method M, the chloro- 2- of (R) -5- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Alkane -3- bases) acetenyl) phenyl) (4,4,5,5- tetramethyl -1,3,2- dioxa boron is miscellaneous with 1- methyl -4- for thiazole -4-carboxamide Pentamethylene -2- bases) reaction of -1H- pyrazoles, title compound (33.1mg, 27%) is obtained, is white solid.LC-MS(ES,m/ z):422[M+H]+.1H NMR(400MHz,CD3OD):δ8.38(s,1H),8.14(s,1H),8.03-8.00(m,1H),7.89 (s,1H),7.59-7.57(m,1H),7.52-7.49(m,1H),3.96(s,3H),3.53-3.47(m,2H),2.96(s,3H), 2.65-2.59(m,1H),2.38-2.31(m,1H)。
Embodiment 2
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (1- first Base -1H- pyrazoles -5- bases amino) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -5- bases) amino] -1H- pyrazoles -3- first Acid
Under nitrogen, by the bromo- 1- of 4- (3- methoxyphenyls) -1H- pyrazoles -3- carboxylic acid methyl esters (600mg, 1.928mmol, 1.00 equivalents), 1- methyl isophthalic acid H- pyrazoles -5- amine (563mg, 5.797mmol, 1.00 equivalent), t-BuXPhos (82mg, 0.193mmol, 0.10 equivalent), third generation t-BuXPhos pre-catalysts (154mg, 0.194mmol, 0.10 equivalent), t-BuONa The solution microwave irradiation of (279mg, 2.903mmol, 1.50 equivalent) in 1,4- dioxanes (12mL) irradiates 90 points in 90 DEG C Clock.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography methylene chloride/methanol (1:1) it is purified by flash, obtains title Compound (425mg, 70%), it is yellow solid.LC-MS(ES,m/z):314[M+H]+。
Step 2：Synthesize 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -5- bases) amino] -1H- pyrazoles -3- first Acid amides
Similar to the operation described in universal method B, 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -5- bases) Amino] -1H- pyrazoles -3- formic acid and ammonium chloride reacts, obtains title compound (350mg, 88%), be yellow solid.LC-MS (ES,m/z):313[M+H]+。
Step 3：Synthesize 1- (3- hydroxy phenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -5- bases) amino] -1H- pyrazoles -3- formyls Amine
To 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -5- bases) amino] -1H- pyrazole-3-formamides Tribromo borine is added dropwise in 0 DEG C under agitation in the solution of (340mg, 1.089mmol, 1.00 equivalent) in dichloromethane (20mL) (818mg, 3.265mmol, 3.00 equivalent).Resulting solution is stirred at room temperature 2 hours.Reactant is quenched by methanol.Gained mixes Compound is concentrated in vacuo, and residue is through silica gel column chromatography methylene chloride/methanol (3:1) it is purified by flash, obtains title compound (290mg, 89%), it is yellow solid.LC-MS(ES,m/z):299[M+H]+。
Step 4：Synthesis
1- (3- hydroxy phenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -5- bases) amino] -1H- pyrazole-3-formamides (280mg, 0.939mmol, 1.00 equivalents), fluoro- N- phenyl-N- (fluoroform) the sulfonyls Methanesulfomides of 1,1,1- tri- (669mg, 1.873mmol, 2.00 equivalents) and solution of the triethylamine (5mL) in dichloromethane (50mL) be stirred at room temperature 14 hours.Will be molten The pH of liquid is adjusted to 8, and mixture is extracted with dichloromethane.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.It is remaining Thing is through silica gel column chromatography ethyl methylene chloride/methanol (10:1) it is purified by flash, obtains title compound (350mg, 87%), For yellow solid.LC-MS(ES,m/z):431[M+H]+。
Step 5：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (1- methyl isophthalic acid H- pyrazoles -5- bases amino) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, trifluoromethayl sulfonic acid 3- [3- carbamyls -4- [(1- methyl isophthalic acids H- Pyrazoles -5- bases) amino] -1H- pyrazol-1-yls] phenylester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- ketone it is anti- Should, title compound (50.8mg, 35%) is obtained, is pale solid.
LC-MS(ES,m/z):420[M+H]+。
1H NMR(400MHz,CD3OD):δ8.14(s,1H),8.04(s,1H),7.93-7.91(m,1H),7.53-7.49 (m,1H),7.45-7.40(m,2H),6.15(s,1H),3.78(s,3H),3.52-3.49(m,2H),2.96(s,3H),2.61- 2.60(m,1H),2.38-2.32(m,1H)。
Embodiment 3
Synthesize 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases] acetenyl] phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method M, the bromo- 1H- pyrazoles -3- carboxylic acid methyl esters of 4- and 1,3- dimethyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) -1H- pyrazoles reacts, and obtains title compound (200mg, 20%), it is yellow oil.LC-MS(ES,m/z):221[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylic acid methyls Ester
Similar to the operation described in universal method C, 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1H- pyrazoles -3- first Acid methyl ester reacts with 3- bromophenylboronic acids, obtains title compound (200mg, 27%), is yellow oil.LC-MS(ES,m/z): 375[M+H]+。
Step 3：Synthesize 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (1,3- dimethyl -1H- pyrazoles -4- bases) - 1H- pyrazoles -3- carboxylic acid methyl esters and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound Thing (150mg, 65%), it is yellow oil.LC-MS(ES,m/z):434[M+H]+。
Step 4：Synthesize 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- (1,3- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylic acid methyl esters and ammonia it is anti- Should, title compound (20.4mg, 14%) is obtained, is white solid.LC-MS(ES,m/z):419[M+H]+.1H NMR (300MHz,CD3OD):δ8.37(s,1H),8.06(s,1H),7.96-7.93(m,1H),7.84(s,1H),7.55-7.45(m, 2H),3.85(s,3H),3.55-3.48(m,2H),2.94(s,3H),2.65-2.57(m,1H),2.37-2.32(m,1H), 2.29(s,3H)。
Embodiment 4
Synthesize 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -4- [(first Base carbamyl) amino] -1H- pyrazole-3-formamides
Step 1：Synthesize 4- amino -1- (3- bromophenyls) -1H- pyrazole-3-formamides
By 1- (3- bromophenyls) -4- acetylaminohydroxyphenylarsonic acid 1H- pyrazole-3-formamides (200mg, 0.619mmol, 1.00 equivalent) Solution in methanol (10mL) and hydrochloric acid (5mL) is stirred at room temperature overnight.The pH of solution is adjusted with sodium hydrate aqueous solution To 7, mixture is extracted with dichloromethane.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silicagel column Chromatography methylene chloride/methanol (10:1) it is purified by flash, obtains title compound (115mg, 63%), is white solid.LC- MS(ES,m/z):281[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- [(methylcarbamoyl) amino] -1H- pyrazole-3-formamides
By 4- amino -1- (3- bromophenyls) -1H- pyrazole-3-formamides (130mg, 0.462mmol, 1.00 equivalent), N- first The solution of base carbamyl chloride (129.5mg, 1.385mmol, 3.00 equivalent) and triethylamine (6mL) in dichloromethane (12mL) in It is stirred at room temperature 2 hours.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography methylene chloride/methanol (10:1) elute Purifying, obtains title compound (140mg, 89%), is white solid.LC-MS(ES,m/z):338[M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- [(methylcarbamoyl) amino] -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [(methylcarbamoyl) amino] -1H- pyrroles Azoles -3- formamides and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (23.4mg, 13%), it is white solid.LC-MS(ES,m/z):397[M+H]+.1H NMR(300MHz,CD3OD):δ8.42(s,1H), 7.86-7.85(m,1H),7.74-7.73(m,1H),7.41-7.30(m,2H),3.40-3.36(m,2H),2.83(s,3H), 2.69(s,3H),2.53-2.46(m,1H),2.26-2.17(m,1H)。
Embodiment 5
Synthesis (R) -1'- ethyls -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) - 4,4'- joins (1H- pyrazoles) -3- formamides
Step 1：Synthesize 1'- ethyls -4,4'- connection (1H- pyrazoles) -3- carboxylates
Similar to the operation described in universal method M, the iodo- 1H- pyrazoles -3- carboxylates of 4- and 1- ethyl -1H- pyrroles Azoles -4- ylboronic acids react, and obtain title compound (343mg, 27%), are yellow oil.LC-MS(ES,m/z):235[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -1'- ethyls -4,4'- connection (1H- pyrazoles) -3- carboxylates
Similar to the operation described in universal method C, 1'- ethyls -4,4'- connection (1H- pyrazoles) -3- carboxylates and 3- Bromophenylboronic acid reacts, and obtains title compound (311mg, 57%), is white solid.LC-MS(ES,m/z):389[M+H]+。
Step 3：Synthesize (R) -1'- ethyls -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) Phenyl) -4,4'- connection (1H- pyrazoles) -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -1'- ethyls -4,4'- connection (1H- pyrazoles) -3- Carboxylate and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (215mg, 62%), it is yellow oil.LC-MS(ES,m/z):448[M+H]+。
Step 4：Synthesize (R) -1'- ethyls -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) Phenyl) -4,4'- connection (1H- pyrazoles) -3- formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylates and ammonia reacts, marked Compound (19.6mg, 9%) is inscribed, is white solid.LC-MS(ES,m/z):419[M+H]+.1H NMR(300MHz,CD3OD):δ 8.64(s,1H),8.24(s,1H),8.06(s,1H),7.95-7.94(m,2H),7.62-7.45(m,2H),4.25-4.18(m, 2H), 3.55-3.47 (m, 2H), 2.94 (s, 3H), 2.65-2.57 (m, 1H), 2.38-2.28 (m, 1H), 1.50 (t, J= 7.2Hz,3H)。
Embodiment 6
Synthesize (R) -4- (ethylamino) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- (N- ethylacetamidos) -1H- pyrazoles -3- carboxylates
By 1- (3- bromophenyls) -4- acetylaminohydroxyphenylarsonic acid 1H- pyrazoles -3- carboxylates, (1g, 2.839mmol, 1.00 work as Amount), sodium hydride (340mg, 14.168mmol, 4.99 equivalent) and iodoethane (886mg, 5.681mmol, 2.001 equivalent) in N, Solution in dinethylformamide (130mL) stirs 1 hour in 0 DEG C.Reactant mixture is diluted with water, and is extracted with ethyl acetate Take.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue through silica gel column chromatography purify and with dichloromethane/ Methanol (10:1) elute, obtain title compound (800mg, 74%), be red solid.LC-MS(ES,m/z):380[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (N- ethylacetamidos) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- bromophenyls) -4- (N- ethylacetamidos) -1H- pyrazoles - 3- carboxylates react with ammonia, obtain title compound (650mg, 88%), are yellow solid.LC-MS(ES,m/z):351 [M+H]+。
Step 3：Synthesize 1- (3- bromophenyls) -4- (ethylamino) -1H- pyrazole-3-formamides
By 1- (3- bromophenyls) -4- (N- ethylacetamidos) -1H- pyrazole-3-formamides (650mg, 1.851mmol, 1.00 equivalents) solution in methanol (10mL) and hydrochloric acid (5mL) be stirred at room temperature overnight.After the completion of, it is water-soluble with sodium hydroxide Solution is adjusted pH to 7 by liquid, is extracted with dichloromethane.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue Purified through silica gel column chromatography and with methylene chloride/methanol (10:1) elute, obtain title compound (150mg, 26%), for Huang Color solid.LC-MS(ES,m/z):309[M+H]+。
Step 4：Synthesize 4- (ethylamino) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] Acetenyl] phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (ethylamino) -1H- pyrazoles -3- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (52.5mg, 32%), are White solid.LC-MS(ES,m/z):368[M+H]+.1H NMR(300MHz,CD3OD):δ7.85(s,1H),7.85-7.84(m, 1H),7.73-7.69(m,1H),7.38-7.29(m,1H),7.28-7.26(m,1H),3.40-3.37(m,2H),3.22-3.20 (m,2H),3.06-2.98(m,3H),2.53-2.51(m,1H),2.46-2.45(m,1H),2.26-2.20(m,3H)。
Embodiment 7
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (fluoroforms Base) thiazole -4-carboxamide
Step 1：Synthesize 2- amino -5- iodine 4-thiazolecarboxylic acid ethyl esters
2- amino -1,3- 4-thiazolecarboxylic acids ethyl esters (3g, 17.421mmol, 1.00 equivalent) and N- iodine succinyl is sub- Solution of the amine (4.689g, 20.841mmol, 1.20 equivalent) in acetonitrile (50mL) stirs 2 hours in 80 DEG C.Resulting solution is true Sky concentration, residue is through silica gel column chromatography methylene chloride/methanol (30:1) be purified by flash, obtain title compound (3.5g, 67%), it is light yellow solid.LC-MS(ES,m/z):299[M+H]+。
Step 2：Synthesize the chloro- 5- iodine 4-thiazolecarboxylic acid ethyl esters of 2-
By 2- amino -5- iodine 4-thiazolecarboxylic acids ethyl esters (3g, 10.067mmol, 1.00 equivalent), tert-butyl group nitrile (1.24g, 12.080mmol, 1.20 equivalent), stannous chloride (1.19g, 12.080mmol, 1.20 equivalent) are in acetonitrile (50mL) Solution in 80 DEG C stir 2 hours.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography methylene chloride/methanol (40:1) it is purified by flash, obtains title compound (1.8g, 56%), is white solid.LC-MS(ES,m/z):318[M+H]+。
Step 3：Synthesize 2- chloro- 5- (trifluoromethyl) 4-thiazolecarboxylic acid ethyl ester
By the chloro- 5- iodine 4-thiazolecarboxylic acid ethyl esters of 2- (1.05g, 3.295mmol, 1.00 equivalent), the fluoro- 2- (fluorine of 2,2- bis- Sulfonyl) acetoxymethyl ester (948.21mg, 4.936mmol, 1.50 equivalent), cuprous iodide (938.74mg, 4.929mmol, 1.50 equivalents) solution in N,N-dimethylformamide (20mL) stirs 12 hours in 70 DEG C.Solution is diluted with water, and uses acetic acid Ethyl ester extracts.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue through silica gel column chromatography with ethyl acetate/ Petroleum ether (1:10) it is purified by flash, obtains title compound (260mg, 32%), is colorless oil.LC-MS(ES,m/z):260[M+ H]+。
Step 4：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (trifluoromethyl) 4-thiazolecarboxylic acid ethyl ester
Similar to the operation described in universal method U, the chloro- 5- of 2- (trifluoromethyl) 4-thiazolecarboxylic acid ethyl esters and (R)- Trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title compound Thing (300mg, 72%), it is yellow solid.LC-MS(ES,m/z):439[M+H]+。
Step 5：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (trifluoromethyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) -5- (trifluoromethyl) 4-thiazolecarboxylic acid ethyl esters and ammonia reacts, obtain title compound (180mg, 67%), it is white solid.LC-MS(ES,m/z):410[M+H]+.1HNMR(300MHz,CD3OD):δ8.24(s,1H),8.11- 8.08(m,1H),7.68-7.65(m,1H),7.58-7.54(m,1H),3.55-3.47(m,2H),2.96-2.94(s,3H), 2.65-2.50(m,1H),2.38-2.32(m,1H)。
Embodiment 8
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (fluoroforms Base) -1H- pyrazole-3-formamides
Step 1：Synthesize the iodo- 1H- pyrazoles -3- carboxylates of 1- (3- bromophenyls) -4-
Similar to the operation described in universal method C, the iodo- 1H- pyrazoles -3- carboxylates of 4- and 3- bromophenylboronic acids are anti- Should, title compound (1.6g, 83%) is obtained, is white solid.LC-MS(ES,m/z):421[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (trifluoromethyl) -1H- pyrazoles -3- carboxylates
By the iodo- 1H- pyrazoles -3- carboxylates of 1- (3- bromophenyls) -4- (500mg, 1.188mmol, 1.00 equivalent), iodine Change cuprous (45mg, 0.236mmol, 0.20 equivalent), 2,2- bis- fluoro- 2- (fluorosulfonyl) acetoxymethyl ester (342mg, 1.782mmol, 1.50 equivalents) solution in N,N-dimethylformamide (12mL) stirs 14 hours in 80 DEG C.Reactant is molten Liquid is diluted with water, and is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silicagel column Chromatography ethyl acetate/petroleum ether (1:4) it is purified by flash, obtains title compound (300mg, 70%), is yellow solid. LC-MS(ES,m/z):363[M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (trifluoromethyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (trifluoromethyl) -1H- pyrazoles -3- formic acid Ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (180mg, 78%), For yellow solid.LC-MS(ES,m/z):422[M+H]+。
Step 4：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (trifluoromethyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (trifluoromethyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (53.7mg, 32%), it is yellow solid.LC-MS(ES,m/z):393[M+H]+.1H NMR(300MHz,CD3OD):δ8.88(s, 1H),8.07-8.06(m,1H),7.95-7.92(m,1H),7.57-7.50(m,2H),3.51-3.47(m,2H),2.94(s, 3H),2.64-2.56(m,1H),2.37-2.28(m,1H)。
Embodiment 9
Synthesize 4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases] acetenyl] phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method M, the bromo- 1H- pyrazoles -3- carboxylic acid methyl esters of 4- and 1,5- dimethyl -4- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) -1H- pyrazoles reacts, and obtains title compound (440mg, 50%), it is yellow oil.LC-MS(ES,m/z):221[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylic acid methyls Ester
Similar to the operation described in universal method C, 4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1H- pyrazoles -3- first Acid methyl ester reacts with 3- bromophenylboronic acids, obtains title compound (300mg, 40%), is light yellow oil.LC-MS(ES,m/ z):375[M+H]+。
Step 3：Synthesize 4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (1,5- dimethyl -1H- pyrazoles -4- bases) - 1H- pyrazoles -3- carboxylic acid methyl esters and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound Thing (240mg, 69%), it is yellow oil.LC-MS(ES,m/z):434[M+H]+。
Step 4：Synthesize 4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- (1,5- dimethyl -1H- pyrazoles -4- bases) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylic acid methyl esters and ammonia it is anti- Should, title compound (10.8mg, 5%) is obtained, is white solid.LC-MS(ES,m/z):419[M+H]+.1H NMR (300MHz,CD3OD):δ8.34(s,1H),8.06(m,1H),7.96-7.92(m,1H),7.58(s,1H),7.55-7.44(m, 2H),3.83(s,3H),3.52-3.45(m,2H),2.94(s,3H),2.64-2.57(m,1H),2.35-2.29(m,1H), 2.28(s,3H)。
Embodiment 10
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (1- first Base -1H- pyrazoles -4- bases amino) thiazole -4-carboxamide
Step 1：Synthesis 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1,3- 4-thiazolecarboxylic acid ethyl esters
Under nitrogen, by the chloro- 2- of 5- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] benzene Base) -1,3- 4-thiazolecarboxylic acids ethyl ester (207mg, 0.512mmol, 1.00 equivalent), 1- methyl isophthalic acid H- pyrazoles -4- amine (240mg, 2.471mmol, 4.829 equivalent), 2nd generation RuPhos Pd pre-catalysts (58mg, 0.075mmol, 0.146 equivalent), RuPhos (69mg, 0.148mmol, 0.289 equivalent), cesium carbonate (160mg, 0.491mmol, 0.960 equivalent) are in 1,4- bis- Evil Solution in alkane (10mL) stirs 1 hour in 80 DEG C.Solution is diluted with water, and is extracted with ethyl acetate.Merge organic layer, through anhydrous Sodium sulphate is dried, and is concentrated in vacuo.Residue is through silica gel column chromatography methylene chloride/methanol (30:1) it is purified by flash, is marked Compound (190mg, 82%) is inscribed, is brown solid.LC-MS(ES,m/z):466[M+H]+。
Step 2：Synthesis 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1,3- 4-thiazolecarboxylic acids
Similar to the operation described in universal method J, 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1,3- 4-thiazolecarboxylic acids ethyl esters and hydroxide Nak response, title compound (150mg, 86%) is obtained, be light brown oil.LC-MS(ES,m/z):438[M+H]+。
Step 3：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (1- methyl isophthalic acid H- pyrazoles -4- bases amino) thiazole -4-carboxamide
Similar to the operation described in universal method B, 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1,3-thiazoles -4- formic acid and ammonium chloride reacts, Title compound (8.3mg, 10%) is obtained, is light yellow solid.LC-MS(ES,m/z):437[M+H]+.1H NMR(400MHz, CD3OD,ppm):δ7.95(s,1H),7.83-7.81(m,2H),7.59(s,1H),7.48-7.40(m,2H),3.92(s,3H), 3.52-3.46(m,2H),2.95(s,3H),2.64-2.58(m,2H),2.37-2.30(m,1H)。
Embodiment 11
(R) -5- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1,2 is synthesized, 4- thiadiazoles -3- formamides
Step 1：Synthesize (3R) -3- [2- [3- (the bromo- 1,2,4- thiadiazoles -5- bases of 3-) -4- fluorophenyls] acetenyl] -3- hydroxyls Base -1- methylpyrrolidin- 2- ketone
Similar to the operation described in universal method X, the bromo- 5- of 3- chloro- 1,2,4- thiadiazoles and (R)-trifluoro (fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtain title compound (300mg, 15%), it is yellow solid.LC-MS(ES,m/z):396[M+H]+.Step 2：Synthesis 5- (the fluoro- 5- of 2- [2- [(3R)- 3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,2,4- thiadiazoles -3- formonitrile HCNs
Under nitrogen, (3R) -3- [2- [3- (thiadiazoles -5- bases of 3- bromo- 1,2,4-) -4- fluorophenyls] acetenyl] -3- hydroxyls - 1- methylpyrrolidin- 2- ketone (300mg, 0.757mmol, 1.00 equivalent) and CuCN (135mg, 1.507mmol, 1.99 equivalent) exist Solution in NMP (10mL) is heated 1 hour in 150 DEG C with microwave irradiation.After cooling, mixture dchloromethane is used Water and salt water washing.Organic layer is concentrated in vacuo through anhydrous sodium sulfate drying.Residue through silica gel column chromatography with dichloromethane/ Methanol (10:1) it is purified by flash, obtains title compound (160mg, 62%), is brown oil.LC-MS(ES,m/z):343[M+H ]+。
Step 3：Synthesize (R) -5- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) -1,2,4- thiadiazoles -3- formamides
Similar to the operation described in universal method D, 5- (the fluoro- 5- of 2- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases] acetenyl] phenyl) -1,2,4- thiadiazoles -3- formonitrile HCNs and hydrogenation (dimethyl phosphonous acid-kp) [double (dimethyl of hydrogen Phosphino--kp)] platinum (II) reaction, title compound (15.7mg, 9%) is obtained, is white solid.LC-MS(ES,m/z):361[M +H]+.1H NMR(400MHz,CD3OD):δ8.50-8.48(m,1H),7.65-7.62(m,1H),7.37-7.32(m,1H), 3.41-3.35(m,2H),2.84(s,3H),2.53-2.47(m,1H),2.25-2.20(m,1H)。
Embodiment 12
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (1- first Base -1H- pyrazoles -4- bases amino) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- bromo- 1- (3- methoxyphenyls) -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method C, the bromo- 1H- pyrazoles -3- carboxylic acid methyl esters of 4- and 3- bromophenylboronic acids are anti- Should, title compound (2.1g, 46%) is obtained, is white solid.LC-MS(ES,m/z):311[M+H]+。
Step 2：Synthesize 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1H- pyrazoles -3- first Acid
Under nitrogen, the iodo- 1- of 4- (3- methoxyphenyls) -1H- pyrazoles -3- carboxylates (200mg, 0.537mmol, 1.00 equivalents), 1- methyl isophthalic acid H- pyrazoles -4- amine (160mg, 1.647mmol, 1.00 equivalent), t-BuXPhos (20mg, 0.047mmol, 0.10 equivalent), the 3rd generation t-BuXPhos pre-catalyst (40mg, 0.050mmol, 0.10 equivalent), t-BuONa The solution microwave irradiation of (80mg, 0.832mmol, 1.50 equivalent) in 1,4- dioxanes (12mL) irradiates 60 points in 90 DEG C Clock.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography methylene chloride/methanol (10:1) it is purified by flash, is marked Compound (120mg, 71%) is inscribed, is reddish oil.LC-MS(ES,m/z):314[M+H]+。
Step 3：Synthesize 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1H- pyrazoles -3- first Acid amides
Similar to the operation described in universal method B, 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) Amino] -1H- pyrazoles -3- formic acid and ammonium chloride reacts, obtains title compound (400mg, 89%), be yellow solid.LC-MS (ES,m/z):313[M+H]+。
Step 4：Synthesize 1- (3- hydroxy phenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1H- pyrazoles -3- formyls Amine
Under agitation in 0 DEG C to 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1H- pyrroles Tribromo borine is added dropwise in solution of the azoles -3- formamides (400mg, 1.281mmol, 1.00 equivalent) in dichloromethane (30mL) (962mg, 3.840mmol, 3.00 equivalent).Resulting solution is stirred at room temperature 2 hours.Reactant is quenched by methanol, and vacuum is dense Contracting.Residue is through silica gel column chromatography methylene chloride/methanol (10:1) be purified by flash, obtain title compound (310mg, 81%), it is yellow solid.LC-MS(ES,m/z):299[M+H]+。
Step 5：Synthesize trifluoromethayl sulfonic acid 3- [3- carbamyls -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1H- Pyrazol-1-yl] phenylester
By 1- (3- hydroxy phenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -4- bases) amino] -1H- pyrazole-3-formamides Fluoro- N- phenyl-N- (fluoroform) the sulfonyl Methanesulfomide of (310mg, 1.039mmol, 1.00 equivalent), 1,1,1- tri- It is small that the solution of (740mg, 2.071mmol, 2.00 equivalent) and triethylamine (3mL) in dichloromethane (30mL) is stirred at room temperature 14 When.The pH of solution is adjusted to 8, mixture is extracted with dichloromethane.Merge organic layer, it is dense through anhydrous sodium sulfate drying, vacuum Contracting.Residue is through silica gel column chromatography ethyl acetate/petroleum ether (5:1) be purified by flash, obtain title compound (280mg, 63%), it is light yellow solid.LC-MS(ES,m/z):431[M+H]+。
Step 6：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (1- methyl isophthalic acid H- pyrazoles -4- bases amino) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, trifluoromethayl sulfonic acid 3- [3- carbamyls -4- [(1- methyl isophthalic acids H- Pyrazoles -4- bases) amino] -1H- pyrazol-1-yls] phenylester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- ketone it is anti- Should, title compound (44.5mg, 30%) is obtained, is light yellow solid.
LC-MS(ES,m/z):420[M+H]+。
1H NMR(400MHz,CD3OD):δ7.91-7.90(m,1H),7.87(s,1H),7.81-7.78(m,1H),7.56 (s,1H),7.39-7.29(m,3H),3.77(s,3H),3.40-3.35(m,2H),2.84(s,3H),2.53-2.47(m,1H), 2.26-2.19(m,1H)。
Embodiment 13
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridine - 2- yls) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- methoxyphenyls) -4- (pyridine -2- bases) -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method Q, the bromo- 1- of 4- (3- methoxyphenyls) -1H- pyrazoles -3- carboxylic acid methyls Ester reacts with 2- (tributylstamlyl) pyridine, obtains title compound (500mg, 72%), is light yellow solid.LC-MS (ES,m/z):310[M+H]+。
Step 2：Synthesize 1- (3- methoxyphenyls) -4- (pyridine -2- bases) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- methoxyphenyls) -4- (pyridine -2- bases) -1H- pyrazoles -3- Carboxylic acid methyl ester reacts with ammonia, obtains title compound (480mg, 95%), is light yellow solid.LC-MS(ES,m/z):295 [M+H]+。
Step 3：Synthesize 1- (3- hydroxy phenyls) -4- (pyridine -2- bases) -1H- pyrazole-3-formamides
Under agitation in 0 DEG C to 1- (3- methoxyphenyls) -4- (pyridine -2- bases) -1H- pyrazole-3-formamides (460mg, 1.563mmol, 1.00 equivalents) Boron tribromide (1.2g, 4.790mmol, 3.00 is added dropwise in solution in dichloromethane (50mL) Equivalent).Gained mixture is stirred 2 hours in 0 DEG C, and reactant is quenched by methanol.Resulting solution is concentrated in vacuo, residue warp Silica gel column chromatography methylene chloride/methanol (5:1) it is purified by flash, obtains title compound (430mg, 98%), is light yellow Solid.LC-MS(ES,m/z):281[M+H]+。
Step 4：Synthesize trifluoromethayl sulfonic acid 3- [3- carbamyls -4- (pyridine -2- bases) -1H- pyrazol-1-yls] phenylester
By 1- (3- hydroxy phenyls) -4- (pyridine -2- bases) -1H- pyrazole-3-formamides (420mg, 1.498mmol, 1.00 Equivalent), fluoro- N- phenyl-N- (fluoroform) the sulfonyls Methanesulfomides (1.067g, 2.987mmol, 2.00 equivalent) of 1,1,1- tri- It is stirred at room temperature 14 hours with solution of the triethylamine (5mL) in dichloromethane (50mL).The pH of reaction solution is adjusted to 8, Mixture is extracted with dichloromethane.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silica gel column chromatography Method methylene chloride/methanol (10:1) it is purified by flash, obtains title compound (580mg, 94%), is light yellow solid.LC-MS (ES,m/z):413[M+H]+。
Step 5：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridine -2- bases) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, trifluoromethayl sulfonic acid 3- [3- carbamyls -4- (pyridine -2- bases) - 1H- pyrazol-1-yls] phenylester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (44.2mg, 30%), it is white solid.LC-MS(ES,m/z):402[M+H]+.1H NMR(400MHz,CD3OD):δ8.86(s, 1H),8.61-8.59(m,1H),8.13-8.12(m,1H),8.01-7.99(m,2H),7.92-7.88(m,1H),7.58-7.50 (m,2H),7.40-7.37(m,1H),3.53-3.49(m,2H),2.96(s,3H),2.62-2.61(m,1H),2.38-2.33 (m,1H)。
Embodiment 14
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (oxa- rings Butane -3- bases amino) thiazole -4-carboxamide
Step 1：Synthesis 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- [(oxetanes -3- bases) amino] -1,3- 4-thiazolecarboxylic acid ethyl esters
Under nitrogen, the chloro- 2- of 5- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] benzene Base) -1,3- 4-thiazolecarboxylic acids ethyl ester (207mg, 0.512mmol, 1.00 equivalent), oxetanes -3- amine (187mg, 2.558mmol, 5.00 equivalents), RuPhos (24mg, 0.051mmol, 0.101 equivalent), RuPhos-PdCl-2nd G (40mg, 0.051mmol, 0.101 equivalent), cesium carbonate (166mg, 0.511mmol, 1.00 equivalent) it is molten in 1,4- dioxanes (10mL) Liquid stirs 1 hour in 80 DEG C.Solution is diluted with water, and is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, very Sky concentration.Residue purifies through silica gel column chromatography and with methylene chloride/methanol (20:1) elute, obtain title compound (150mg, 69%), it is pale solid.LC-MS(ES,m/z):442[M+H]+。
Step 2：Synthesis 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- [(oxetanes -3- bases) amino] -1,3- 4-thiazolecarboxylic acids
Similar to the operation described in universal method J, 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- [(oxetanes -3- bases) amino] -1,3- 4-thiazolecarboxylic acids ethyl esters and potassium hydroxide it is anti- Should, title compound (90mg, 78%) is obtained, is light brown oil.LC-MS(ES,m/z):414[M+H]+。
Step 3：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (oxetanes -3- bases amino) thiazole -4-carboxamide
Similar to the operation described in universal method B, 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- [(oxetanes -3- bases) amino] -1,3-thiazoles -4- formic acid and ammonium chloride reacts, obtains Title compound (16.0mg, 18%), it is pale solid.LC-MS(ES,m/z):413[M+H]+.1H NMR(400MHz, CD3OD):δ7.95(s,1H),7.84-7.82(m,1H),7.47-7.43(m,2H),5.08-4.98(m,2H),4.73-4.68 (m,3H),3.50-3.34(m,2H),2.96(s,3H),2.65-2.58(m,1H),2.38-2.29(m,1H)。
Embodiment 15
Synthesize (R) -5- ethyls -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiophene Azoles -4- formamides
Step 1：Synthesize (R) -5- ethyls -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) 4-thiazolecarboxylic acid ethyl ester
Be put into microwave vial the bromo- 5- Ethyl-thiazols -4- carboxylic acid methyl esters (200.0mg, 0.80mmol) of 2-, (3R) - 3- hydroxyl -1- methyl -3- [2- [3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl] acetylene Base] pyrrolidin-2-one (355.0mg, 1.04mmol), potassium acetate (141mg, 1.44mmol), sodium carbonate (144mg, 1.36mmol) and 1,1'- connection (diphenyl phosphine) ferrocene-palladium chloride (II) chloride dichloromethane complex (53mg, 0.064mmol).Add the ACN (8mL) and water (2mL) of degassing.Bottle is closed the lid, reactant mixture is under microwave condition Stirred 30 minutes in 110 DEG C.Reactant mixture is poured into ethyl acetate and water, is filtered through Celite pad.Organic layer water and salt Water washing, through Na2SO4Dry, filtering and vacuum concentration.Thick material is pure with heptane/ethyl acetate elution through silica gel column chromatography Change, obtain 183.3mg (59.6%), for expected product.LC-MS(ES,m/z):385[M+H]+。
Step 2：Synthesising title compound
Similar to the operation described in universal method S, (R) -5- ethyls -2- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) 4-thiazolecarboxylic acid ethyl ester handled with the saturated solution of ammonia in methyl alcohol, marked Compound (52.5mg, 52.4%) is inscribed, is solid.LC-MS(ES,m/z):370[M+H]+.1H NMR(400MHz,DMSO-d6)δ 8.07–8.05(m,1H),8.00–7.94(m,1H),7.92(s,1H),7.55–7.49(m,3H),6.49(s,1H),3.37– 3.34(m,3H),3.30–3.29(m,1H),2.80(s,3H),2.48–2.42(m,1H),2.24–2.15(m,1H),1.27(t, J=7.5Hz, 3H).
Embodiment 16
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -6,8- dihydros - 5H- imidazos [5,1-c] [1,4] oxazine -3- formamides
Step 1：Synthesize 3- [methoxyl group (methyl) carbamyl] morpholine -4- carboxylates
Similar to the operation described in universal method B, 4- [(tert-butoxy) carbonyl] morpholine -3- formic acid and methoxyl group (first Base) amine hydrochlorate reaction, title compound (3.5g, 59%) is obtained, is white solid.LC-MS(ES,m/z):275[M+H]+。
Step 2：Synthesize 3- [(3- bromophenyls) carbonyl] morpholine -4- carboxylates
Under nitrogen by n-BuLi (8mL, the 2M solution in THF, 1.10 equivalents) be added dropwise to 1,3- dibromobenzenes (3.44g, 14.58mmol, 1.00 equivalents) in solution in tetrahydrofuran (200mL).Resulting solution stirs 2 hours in -78 DEG C, in -78 DEG C be added dropwise in tetrahydrofuran (100mL) 3- [methoxyl group (methyl) carbamyl] morpholine -4- carboxylates (4.00g, 14.58mmol, 1.00 equivalents).Resulting solution stirs other 3 hours in -78 DEG C.Reactant is by adding ammonium chloride saturated solution It is quenched, is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silicagel column color Spectrometry ethyl acetate/petroleum ether (1:3) it is purified by flash, obtains title compound (2.0g, 37%), is white solid.LC-MS (ES,m/z):370[M+H]+。
Step 3：Synthesize 3- (3- bromophenyls) -4H, 6H, 7H- imidazos [4,3-c] [1,4] oxazines
Under nitrogen, by 3- [(3- bromophenyls) carbonyl] morpholine -4- carboxylates (2g, 5.40mmol, 1.00 equivalent) Solution in formamide (20mL) and acetic acid (2mL) is irradiated 25 minutes in 170 DEG C with microwave irradiation.Solution water is dilute Release, be extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is used through silica gel column chromatography Ethyl acetate/petroleum ether (1:10) it is purified by flash, obtains title compound (720mg, 48%), is yellow solid.LC-MS(ES, m/z):279[M+H]+。
Step 4：Synthesize the iodo- 4H of 3- (3- bromophenyls) -1-, 6H, 7H- imidazos [4,3-c] [1,4] oxazines
Under nitrogen, to 3- (3- bromophenyls) -4H, 6H, 7H- imidazos [4,3-c] [Isosorbide-5-Nitrae] oxazines (500mg, 1.79mmol, 1.00 equivalents) add in solution in tetrahydrofuran (20mL) lithium diisopropylamine (0.9mL, 2M THF solution, 1.00 Equivalent).Resulting solution stirs 2 hours in -78 DEG C, iodine (454mg, 1.79mmol, 1.00 added in tetrahydrofuran (5mL) Equivalent).Resulting solution stirs other 1 hour in -78 DEG C.Reactant is quenched by adding saturated aqueous ammonium chloride, uses acetic acid Ethyl ester extracts.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue through silica gel column chromatography with ethyl acetate/ Petroleum ether (1:10) it is purified by flash, obtains title compound (500mg, 69%), is light yellow solid.LC-MS(ES,m/z): 405[M+H]+。
Step 5：Synthesize 3- (3- bromophenyls) -4H, 6H, 7H- imidazos [4,3-c] [1,4] oxazine -1- carboxylic acid methyl esters
Similar to the operation described in universal method O, 3- (3- bromophenyls) -1- iodo- 4H, 6H, 7H- imidazos [4,3-c] [Isosorbide-5-Nitrae] oxazines and reaction of carbon monoxide, title compound (210mg, 56%) is obtained, be yellow solid.LC-MS(ES,m/z): 337[M+H]+。
Step 6：Synthesis 3- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4H, 6H, 7H- imidazo [4,3-c] [1,4] oxazine -1- carboxylic acid methyl esters
Similar to the operation described in universal method G, 3- (3- bromophenyls) -4H, 6H, 7H- imidazos [4,3-c] [Isosorbide-5-Nitrae] Oxazine -1- carboxylic acid methyl esters and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (90mg, 38%), it is yellow solid.LC-MS(ES,m/z):396[M+H]+。
Step 7：(R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -6 is synthesized, 8- dihydro -5H- imidazos [5,1-c] [1,4] oxazine -3- formamides
Similar to the operation described in universal method S, 3- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4H, 6H, [Isosorbide-5-Nitrae] oxazine -1- carboxylic acid methyl esters react 7H- imidazos [4,3-c] with ammonia, are marked Compound (38.4mg, 50%) is inscribed, is pale solid.LC-MS(ES,m/z):381[M+H]+.1H NMR(300MHz, CD3OD):δ 7.69 (s, 1H), 7.54 (d, J=7.5Hz, 1H), 7.41-7.33 (m, 2H), 5.06 (s, 2H), 4.49 (t, J= 5.4Hz, 2H), 4.04 (t, J=5.1Hz, 2H), 3.48-3.44 (m, 2H), 2.92 (s, 3H), 2.61-2.53 (m, 1H), 2.34-2.25(m,1H)。
Embodiment 17
Synthesize (R) -4- (cyclopropanecarbonyl amino) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- cyclopropane acylamino- -1H- pyrazoles -3- carboxylates
In room temperature to 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (500mg, 1.612mmol, 1.00 Equivalent), triethylamine (323mg, 3.192mmol, 1.98 equivalent) is at dichloromethane (20mL, 314.601mmol, 195.15 equivalent) In agitating solution in be added dropwise cyclopropane carbonyl chlorine (254mg, 2.430mmol, 1.507 equivalent).It is small that mixture is stirred at room temperature 2 When.After the completion of, resulting solution is concentrated in vacuo, and residue is loaded on silicagel column, with ethyl acetate/petroleum ether (1:2) elute. Title compound (470mg, 77%) is produced, is pale solid.LC-MS(ES,m/z):378[M+H]+。
Step 2：Synthesize 4- cyclopropane acylamino-s -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- cyclopropane acylamino- -1H- pyrazoles -3- first Sour ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (185mg, 80%), it is pale solid.LC-MS(ES,m/z):437[M+H]+.Step 3：Synthesis (R) -4- (cyclopropanecarbonyl amino) - 1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- cyclopropane acylamino-s -1- (3- [2- [(3R) -3- hydroxyl -1- first Base -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (77.2mg, 49%), it is white solid.LC-MS(ES,m/z):408[M+H]+.1H NMR(300MHz,CD3OD):δ8.70(s, 1H), 7.96 (s, 1H), 7.83 (d, J=8.1Hz, 1H), 7.51-7.41 (m, 2H), 3.49-3.44 (m, 2H), 2.92 (s, 3H),2.59-2.49(m,1H),2.39-2.22(m,1H),1.85-1.75(m,1H),0.99-0.91(m,4H)。
Embodiment 18
Synthesize (R) -4- acetylaminohydroxyphenylarsonic acids 1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- acetylaminohydroxyphenylarsonic acids 1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates
By 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (500mg, 1.612mmol, 1.00 equivalent) It is stirred at room temperature 12 hours with solution of the triethylamine (329mg, 3.251mmol, 2.017 equivalent) in dichloromethane (20mL). Gained reactant mixture is concentrated in vacuo, and residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1:3) elute. Title compound (450mg, 79%) is generated, is pale solid.LC-MS(ES,m/z):352[M+H]+。
Step 2：Synthesize (R) -4- acetylaminohydroxyphenylarsonic acids 1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetylene Base) phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 4- acetylaminohydroxyphenylarsonic acids 1- (3- bromophenyls) -1H- pyrazoles -3- formic acid second Base ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (170mg, 73%), are Pale solid.LC-MS(ES,m/z):411[M+H]+。
Step 3：Synthesize (R) -4- acetylaminohydroxyphenylarsonic acids 1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetylene Base) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, (R) -4- acetylaminohydroxyphenylarsonic acids 1- (3- ((3- hydroxyl -1- methyl -2- oxygen For pyrrolidin-3-yl) acetenyl) phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (93.7mg, 59%), it is white solid.LC-MS(ES,m/z):382[M+H]+.1H NMR(400MHz,CD3OD):δ8.77(s, 1H),7.99(s,1H),7.88-7.86(m,1H),7.54-7.45(m,2H),3.55-3.46(m,2H),2.95(s,3H), 2.65-2.59(m,1H),2.37-2.30(m,1H),2.27(s,3H)。
Embodiment 19
Synthesis (R) -4- amino -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) - 1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- nitro -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, 4- nitro -1H- pyrazoles -3- carboxylates and 3- bromophenylboronic acids Reaction, obtains title compound (11g, 60%), is pale solid.LC-MS(ES,m/z):340[M+H]+。
Step 2：Synthesize 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates
In room temperature under agitation to 1- (3- bromophenyls) -4- nitro -1H- pyrazoles -3- carboxylates (6.800g, 19.992mmol, 1.00 equivalents) and reactant mixture of the Raney nickel (3.0g) in ethanol (50mL) in hydrazine hydrate is added dropwise (2.16g, 43.148mmol, 2.00 equivalent) 1 hour.Gained reactant mixture is dilute with 200mL ethanol and 200mL dichloromethane Release.Solid is filtered out, gained mixture is concentrated in vacuo.Residue is loaded on silicagel column, with ethyl acetate/petroleum ether (1:1) Elution, obtains 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (5.5g, 89%), is pale solid.LC- MS(ES,m/z):310[M+H]+。
Step 3：Synthesize 4- amino -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetylene Base] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates With (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, title compound (185mg, 78%) is obtained, is greyish white Color solid.LC-MS(ES,m/z):369[M+H]+。
Step 4：Synthesize 4- amino -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetylene Base] phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- amino -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxos Pyrrolidin-3-yl] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (52.8mg, 31%), it is pale solid.LC-MS(ES,m/z):340[M+H]+.1H NMR(300MHz,CD3OD):δ7.91(s,1H), 7.80-7.77(m,2H),7.48-7.37(m,2H),3.51-3.46(m,2H),2.94(s,3H),2.64-2.56(m,1H), 2.37-2.27(m,1H)。
Embodiment 20 and 21
Synthesize 4- ((1S, 2R) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides and 4- ((1R, 2S) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
(be separated into individually unknown stereoisomer and be arbitrarily attributed to (S, R) or (R, S))
Step 1：Synthesize 1- (3- bromophenyls) -4- [(2- fluorine cyclopropane) acylamino-] -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method B, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates Reacted with (trans) -2- fluorine cyclopropane -1- formic acid, obtain title compound (678mg, 88%), be yellow oil.LC-MS(ES, m/z):396[M+H]+。
Step 2：Synthesize 4- [(trans 2- fluorine cyclopropane) acylamino-] -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxygen For pyrrolidin-3-yl] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [(2- fluorine cyclopropane) acylamino-] -1H- pyrroles Azoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (530mg, 68%), it is pale solid.LC-MS(ES,m/z):455[M+H]+。
Step 3：Synthesize 4- ((1S, 2R) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides and 4- ((1R, 2S) -2- fluorine cyclopropanecarbonyl ammonia Base) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- [(2- fluorine cyclopropane) acylamino-] -1- (3- [2- [(3R) -3- hydroxyls Base -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtains 91.0mg (18%) is the first elution (referred to herein as 1S, 2R- isomers) isomers and 91.4mg (18%) of white solid For second of elution (referred to herein as 1R, 2S- isomers) isomers of white solid.The arbitrarily three-dimensional of two kinds of isomers of ownership Learn.The first eluting isomer:tR=9.57min (Chiralcel OJ-H, 0.46*25cm, Hex:IPA=50:50,1ml/ min)；Second of eluting isomer:tR=13.89min (Chiralcel OJ-H, 0.46*25cm, Hex:IPA=50:50, 1ml/min)；Two kinds of isomers show identical LC-MS and1HNMR, it is as follows.
LC-MS(ES,m/z):426[M+H]+.1H NMR(300MHz,CD3OD):δ8.85(s,1H),7.96(s,1H), 7.85-7.81(m,1H),7.52-7.42(m,2H),4.97-4.75(m,1H),3.51-3.47(m,2H),2.94(s,3H), 2.64-2.56(m,1H),2.40-2.30(m,2H),1.62-1.47(m,1H),1.42-1.31(m,1H)。
Embodiment 22
Synthesize 4- ((1R, 2R) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -1H- pyrazoles -3- formic acid Ethyl ester
Similar to the operation described in universal method B, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates Reacted with (1R, 2R) -2- fluorine cyclopropane -1- formic acid, obtain title compound (350mg, 91%), be yellow oil.LC-MS(ES, m/z):396[M+H]+。
Step 2：Synthesis 4- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -1- (3- [2- [(3R) -3- hydroxyl -1- methyl - 2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [[(1R, 2R) -2- fluorine cyclopropane] acyl ammonia Base] -1H- pyrazoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title Compound (273mg, 68%), it is yellow oil.LC-MS(ES,m/z):455[M+H]+。
Step 3：Synthesize 4- ((1R, 2R) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia it is anti- Should, title compound (107.6mg, 42%) is obtained, is white solid.LC-MS(ES,m/z):426[M+H]+.1H NMR (300MHz,CD3OD):δ 8.79 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=7.5Hz, 1H), 7.54-7.43 (m, 2H), 5.01-4.78(m,1H),3.52-3.47(m,2H),2.94(s,3H),2.64-2.57(m,1H),2.37-2.28(m,1H), 2.10-2.04(m,1H),1.79-1.70(m,1H),1.30-1.23(m,1H)。
Embodiment 23
Synthesize 4- ((1S, 2S) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -1H- pyrazoles -3- formic acid Ethyl ester
Similar to the operation described in universal method B, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates Reacted with (1S, 2S) -2- fluorine cyclopropane -1- formic acid, obtain title compound (334mg, 87%), be yellow oil.LC-MS(ES, m/z):396[M+H]+。
Step 2：Synthesis 4- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -1- (3- [2- [(3R) -3- hydroxyl -1- methyl - 2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [[(1S, 2S) -2- fluorine cyclopropane] acyl ammonia Base] -1H- pyrazoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title Compound (239mg, 62%), it is yellow oil.LC-MS(ES,m/z):455[M+H]+。
Step 3：Synthesize 4- ((1S, 2S) -2- fluorine cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia it is anti- Should, title compound (39.3mg, 18%) is obtained, is white solid.LC-MS(ES,m/z):426[M+H]+.1H NMR (300MHz,CD3OD):δ 8.79 (s, 1H), 8.00 (s, 1H), 7.88 (d, J=7.5Hz, 1H), 7.54-7.44 (m, 2H), 5.03-4.78(m,1H),3.52-3.47(m,2H),2.84(s,3H),2.64-2.57(m,1H),2.37-2.28(m,1H), 2.10-2.05(m,1H),1.85-1.71(m,1H),1.30-1.23(m,1H)。
Embodiment 24
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- propionyl ammonia Base -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- propionamido -1H- pyrazoles -3- carboxylates
4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (200mg, 0.645mmol, 1.00 equivalent), third Acyl chlorides (0.06mL, 0.648mmol, 3.35 equivalent) and triethylamine (0.06mL, 0.432mmol, 2.23 equivalent) are in dichloromethane Solution in (5mL) is stirred at room temperature 30 minutes.Gained mixture is concentrated in vacuo, and residue is purified and used through silica gel column chromatography Methylene chloride/methanol (10:1) elute, obtain title compound (200mg, 85%), be white solid.LC-MS(ES,m/z): 366[M+H]+。
Step 2：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- propionamido -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- propionamido -1H- pyrazoles -3- formic acid second Base ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (160mg, 69%), are Brown solid.LC-MS(ES,m/z):425[M+H]+。
Step 3：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- Propionamido -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- propionamido -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (51.6mg, 37%), it is pale solid.LC-MS(ES,m/z):396[M+H]+.1H NMR(400MHz,CD3OD):δ8.78- 7.79(m,1H),8.00(s,1H),7.86-7.88(m,1H),7.45-7.54(m,2H),3.47-3.53(m,2H),2.95(s, 3H),2.64-2.59(m,1H),2.51-2.47(m,2H),2.37-2.30(m,1H),2.31(m,3H)。
Embodiment 25 and 26
Synthesize 4- ((R) -2,2- difluoro cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides and 4- ((S) -2,2- difluoro cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
(be separated into individually unknown stereoisomer and be arbitrarily attributed to (R) or (R))
Step 1：Synthesize 1- (3- bromophenyls) -4- [(2,2- difluoros cyclopropane) acylamino-] -1H- pyrazoles -3- formic acid ethyls Ester
Similar to the operation described in universal method B, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates Reacted with 2,2- difluoro cyclopropane -1- formic acid, obtain title compound (650mg, 79%), be pale solid.LC-MS(ES, m/z):414[M+H]+。
Step 2：Synthesize racemic 4- [(2,2- difluoros cyclopropane) acylamino-] -1- (3- [2- [(3R) -3- hydroxyl -1- first Base -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [(2,2- difluoro cyclopropane) acylamino-] - 1H- pyrazoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound Thing (400mg, 85%), it is pale solid.LC-MS(ES,m/z):473[M+H]+。
Step 3：Synthesize 4- ((R) -2,2- difluoro cyclopropanecarbonyls amino) -1- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides and 4- ((S) -2,2- difluoro cyclopropanecarbonyl ammonia Base) -1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- [(2,2- difluoro cyclopropane) acylamino-] -1- (3- [2- [(3R) - 3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtains It is white to the first eluate (referred to herein as (1R)-isomers) and 39.3mg (21%) that 54.1mg (29%) is white solid Second of eluate (referred to herein as (1S)-isomers) of color solid.The arbitrarily spatial chemistry of two kinds of isomers of ownership.
The first eluting isomer:tR=16.40min ((R, R) WHELK-O1,0.45*25cm, Hex (0.2%IPA): EtOH=65:35,1ml/min)；Second of eluting isomer:tR=18.55min ((R, R) WHELK-O1,0.45*25cm, Hex (0.2%IPA):EtOH=65:35,1ml/min)；Two kinds of isomers show equivalent LC-MS and1H NMR, following institute Show.
LC-MS(ES,m/z):444[M+H]+.1H NMR(300MHz,CD3OD):δ8.76(s,1H),7.97(s,1H), 7.85-7.82 (d, J=8.7Hz, 1H), 7.51-7.41 (m, 2H), 3.53-3.41 (m, 2H), 2.94 (s, 3H), 2.90-2.87 (m,1H),2.62-2.54(m,1H),2.35-2.26(m,1H),2.16-2.04(m,1H),1.94-1.84(m,1H)。
Embodiment 27
Synthesize (R) -4- (1- fluorine cyclopropanecarbonyls amino) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- [(1- fluorine cyclopropane) acylamino-] -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method B, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates Reacted with 1- fluorine cyclopropane -1- formic acid, obtain title compound (390mg, 82%), be white solid.LC-MS(ES,m/z): 396[M+H]+。
Step 2：Synthesize (R) -4- (1- fluorine cyclopropanecarbonyls amino) -1- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Alkane -3- bases) acetenyl) phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [(1- fluorine cyclopropane) acylamino-] -1H- pyrroles Azoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (408mg, 91%), it is brown solid.LC-MS(ES,m/z):455[M+H]+。
Step 3：Synthesize (R) -4- (1- fluorine cyclopropanecarbonyls amino) -1- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Alkane -3- bases) acetenyl) phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method S, 4- [(1- fluorine cyclopropane) acylamino-] -1- (3- [2- [(3R) -3- hydroxyls Base -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, marked Compound (56mg, 16%) is inscribed, is white solid.LC-MS(ES,m/z):426[M+H]+.1H NMR(400MHz,CD3OD):δ 8.83 (s, 1H), 8.02 (s, 1H), 7.90 (d, J=1.2Hz, 1H), 7.89-7.51 (m, 1H), 7.47 (m, 1H), 3.53- 3.47(m,2H),2.95(s,3H),2.65-2.59(m,1H),2.37-2.30(m,1H),1.53-1.51(m,1H),1.49- 1.42(m,3H)。
Embodiment 28
Synthesize (R) -4- (3,3- dimethyl urea groups) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- [(dimethylcarbamoyl) amino] -1H- pyrazoles -3- carboxylates
4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (200mg, 0.645mmol, 1.00 equivalent), N, N- dimethyl carbamyl chlorides (84mg, 0.781mmol, 1.20 equivalent) and triethylamine (131mg, 1.295mmol, 2.00 equivalent) exist Solution in dichloromethane (10mL) is stirred at room temperature 2 hours.Resulting solution is concentrated in vacuo, and residue is pure through silica gel column chromatography Change and with methylene chloride/methanol (10:1) elute, obtain title compound (180mg, 62%), be yellow solid.LC-MS(ES, m/z):381[M+H]+。
Step 2：Synthesize 4- [(dimethylcarbamoyl) amino] -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxos Pyrrolidin-3-yl] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [(dimethylcarbamoyl) amino] -1H- Pyrazoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (90mg, 62%), it is yellow solid.LC-MS(ES,m/z):440[M+H]+。
Step 3：Synthesize (R) -4- (3,3- dimethyl urea groups) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- [(dimethylcarbamoyl) amino] -1- (3- [2- [(3R) -3- Hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtains Title compound (42.8mg, 50%), it is yellow solid.LC-MS(ES,m/z):411[M+H]+.1H NMR(300MHz,DMSO- d6):δ9.27(s,1H),8.62(s,1H),8.06(s,1H),8.00(s,1H),7.94-7.91(m,1H),7.67(s,1H), 7.54-7.49 (m, 1H), 7.39-7.36 (d, J=7.8Hz, 1H), 6.513 (s, 1H), 3.38-3.32 (m, 2H), 2.94 (s, 6H),2.80(s,3H),2.45-2.41(m,1H),2.23-2.14(m,1H)。
Embodiment 29
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (2- methoxies Base acetylamino) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- (2- methoxyacetamidos) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method B, 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates Reacted with 2- methoxyacetic acids, obtain title compound (200mg, 46%), be yellow solid.LC-MS(ES,m/z):382[M+ H]+。
Step 2：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (2- methoxyacetamidos) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (2- methoxyacetamidos) -1H- pyrroles Azoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (200mg, 52%), it is yellow solid.LC-MS(ES,m/z):441[M+H]+。
Step 3：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (2- methoxyacetamidos) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (2- methoxyacetamidos) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title Compound (54.1mg, 28%), it is light yellow solid.LC-MS(ES,m/z):412[M+H]+.1H NMR(300MHz,DMSO- d6):δ10.37(s,1H),8.90(s,1H),8.10(s,1H),8.04(s,1H),8.00-7.96(m,1H),7.69(s,1H), 7.56-7.50 (m, 1H), 7.41-7.39 (d, J=7.5Hz, 1H), 6.51 (s, 1H), 4.06 (s, 2H), 3.43 (s, 3H), 3.38-3.30(m,2H),2.80(s,3H),2.45-2.41(m,1H),2.24-2.15(m,1H)。
Embodiment 30
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- isobutyryls Amino -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- (2- methylpropionylaminos) -1H- pyrazoles -3- carboxylates
By 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (200mg, 0.645mmol, 1.00 equivalent), Isobutyryl chloride (83mg, 0.779mmol, 1.21 equivalent) and triethylamine (130mg, 1.285mmol, 1.99 equivalent) are in dichloromethane Solution in (15mL) is stirred at room temperature 30 minutes.Resulting solution is concentrated in vacuo, and residue is purified and used through silica gel column chromatography Ethyl acetate/petroleum ether (1:10) elute.Title compound (120mg, 49%) is generated, is yellow solid.LC-MS(ES,m/ z):380[M+H]+。
Step 2：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (2- methylpropionylaminos) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (2- methylpropionylaminos) -1H- pyrazoles - 3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (120mg, 87%), it is yellow oil.LC-MS(ES,m/z):439[M+H]+。
Step 3：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- Isobutyryl amino -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (2- methylpropionylaminos) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtains titled Compound (57.5mg, 62%), it is white solid.LC-MS(ES,m/z):410[M+H]+.1H NMR(300MHz,CD3OD):δ 8.77(s,1H),7.99(s,1H),7.88-7.85(m,1H),7.54-7.43(m,2H),3.55-3.47(m,2H),2.73(s, 3H),2.73-2.56(m,2H),2.37-2.28(m,1H),1.25(s,6H)。
Embodiment 31
Synthesis (R) -4- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1- methyl - 1H- imidazoles -2- formamides
Step 1：Synthesize (R) -4- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1- Methyl isophthalic acid H- imidazoles -2- carboxylic acid methyl esters
By (3R) -3- hydroxyl -1- methyl -3- [2- [3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolans alkane - 2- yls) phenyl] acetenyl] pyrrolidin-2-one (73mg., 0.21mmol), the bromo- 1- methyl isophthalic acids h- imidazoles -2- carboxylic acid methyl esters of 4- (40mg, 0.18mmol), cesium fluoride (54mg, 0.36mmol) and double (triphenyl phasphine) palladium chloride (II) (12.5mg, 0.018mmol) the solution degassing in ethanol (1.5mL) and water (1.0mL).Reactant mixture is added in microwave in 100 DEG C Heat 45 minutes.Reactant filters through diatomite.Crude product then carries out rHPLC, obtained through purified by flash chromatography (MeOH/DCM) To product (27mg, 42.7%).LC-MS(ES,m/z):354[M+H]+。
Step 2：Synthesize (R) -4- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1- Methyl isophthalic acid H- imidazoles -2- carboxylic acid methyl esters
Similar to the operation described in universal method S, (R) -4- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) -1- methyl isophthalic acid H- imidazoles -2- carboxylic acid methyl esters and ammonia reacts, obtain title compound (13.4mg, 42.5%).
LC-MS(ES,m/z):339[M+H]+。1H NMR(400MHz,DMSO)δ7.94–7.88(m,2H),7.85–7.76 (m,2H),7.58–7.46(m,1H),7.43–7.37(m,1H),7.32–7.26(m,1H),6.52–6.39(s,1H),3.98– 3.96(s,3H),3.38–3.33(m,2H),2.82–2.78(s,3H),2.47–2.39(m,1H),2.23–2.14(m,1H)。
Embodiment 32
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (methyl ammonia Base) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- (N- methylacetamidos) -1H- pyrazoles -3- carboxylates
By 1- (3- bromophenyls) -4- acetylaminohydroxyphenylarsonic acid 1H- pyrazoles -3- carboxylates, (300mg, 0.852mmol, 1.00 work as Amount), methyl iodide (142mg, 1.00mmol, 1.17 equivalent) and sodium hydride (61mg, 2.542mmol, 2.984 equivalent) be in N, N- bis- Solution in NMF (10mL) stirs 2 hours in 0 DEG C.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography Purifying and with ethyl acetate/petroleum ether (1:10) elute, obtain title compound (270mg, 87%), be yellow solid.LC-MS (ES,m/z):366[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (N- methylacetamidos) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- bromophenyls) -4- (N- methylacetamidos) -1H- pyrazoles - 3- carboxylates react with ammonia, obtain title compound (200mg, 87%), are yellow solid.LC-MS(ES,m/z):337 [M+H]+。
Step 3：Synthesize 1- (3- bromophenyls) -4- (methylamino) -1H- pyrazole-3-formamides
By 1- (3- bromophenyls) -4- (N- methylacetamidos) -1H- pyrazole-3-formamides (200mg, 0.593mmol, 1.00 equivalents) solution in methanol (10mL) and hydrochloric acid (5mL) be stirred at room temperature overnight.After the completion of, it is water-soluble with sodium hydroxide Liquid adjusts the pH to 7 of solution, is then extracted with dichloromethane.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.It is residual Excess purifies through silica gel column chromatography and with methylene chloride/methanol (10:1) elute, obtain title compound (100mg, 57%), For white solid.LC-MS(ES,m/z):295[M+H]+。
Step 4：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (methylamino) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (methylamino) -1H- pyrazoles -3- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (46.7mg, 44%), are White solid.LC-MS(ES,m/z):354[M+H]+.1H NMR(300MHz,CD3OD):δ7.96-7.95(s,1H),7.86- 7.82(m,1H),7.77(s,1H),7.49-7.43(m,1H),7.39-7.36(m,1H),3.51-3.46(m,2H),2.94(s, 3H),2.83(s,3H),2.63-2.36(m,1H),2.34-2.27(m,1H)。
Embodiment 33
Synthesize (R) -5- acetylaminohydroxyphenylarsonic acids 2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) thiazole -4-carboxamide
Step 1：Synthesize (R) -5- acetylaminohydroxyphenylarsonic acids 2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetylene Base) phenyl) thiazole -4-carboxamide
By 5- amino -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 1,3- thiazole -4-carboxamides (100mg, 0.281mmol, 1.00 equivalent), acetic acid acetyl base ester (0.04mL, 0.426mmol, 1.52 equivalents), solution of the triethylamine (0.04mL, 0.288mmol, 1.03 equivalent) in acetonitrile (10mL) it is 12 small in 25 DEG C of stirrings When.Resulting solution is concentrated in vacuo, and residue purifies through silica gel column chromatography and with methylene chloride/methanol (20:1) elute.Produce Title compound (14.6mg, 13%), is white solid.LC-MS(ES,m/z):399[M+H]+.1H NMR(400MHz, CD3OD):δ 8.10 (s, 1H), 7.98-7.96 (d, J=8.0Hz, 1H), 7.55-7.46 (m, 2H), 3.55-3.46 (m, 2H), 2.96(s,3H),2.65-2.59(m,1H),2.37-2.28(m,1H),2.30(s,3H)。
Embodiment 34
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -2'- methyl - 4,4'- joins (1H- pyrazoles) -3- formamides
Step 1：Synthesize 4- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method M, the iodo- 1H- pyrazoles -3- carboxylates of 4- and 1- methyl -4- (4,4, 5,5- tetramethyls -1,3,2- dioxaborolan alkane -2- bases) -1H- pyrazoles reaction, obtain title compound (352mg, 18%), it is yellow solid.LCMS (ES, m/z) is determined by LC-MS:221[M+H]+。
Step 2：Synthesize 1- (2- bromophenyls) -4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, 4- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- pyrroles's -3- formic acid second Base ester is reacted with 3- bromophenylboronic acids, is obtained title compound (239mg, 40%), is yellow oil.LC-MS(ES,m/z):375 [M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (1- methyl isophthalic acid H- pyrazole-3-yls) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (1- methyl isophthalic acid H- pyrazole-3-yls) -1H- Pyrazoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (130mg, 80%), it is yellow oil.LC-MS(ES,m/z):434[M+H]+。
Step 4：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -2'- Methyl -4,4'- joins (1H- pyrazoles) -3- formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (1- methyl isophthalic acid H- pyrazoles -4- bases) -1H- pyrazoles -3- carboxylates and ammonia reacts, marked Compound (10.3mg, 7%) is inscribed, is white solid.LC-MS(ES,m/z):405[M+H]+.1H NMR(400MHz,CD3OD):δ 8.64(s,1H),8.20(s,1H),8.07(s,1H),7.96-7.93(m,2H),7.54-7.52(m 1H),7.48-7.47(m, 1H),3.94(s,3H),3.51(m,2H),2.96(s,3H),2.65-2.61(m,1H),2.39-2.31(m,1H)。
Embodiment 35
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridine - 2- bases amino) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- [(pyridine -2- bases) amino] -1H- pyrazoles -3- carboxylates
Under nitrogen, by 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (300mg, 0.967mmol, 1.00 equivalents), 2- iodine pyridines (238mg, 1.161mmol, 1.20 equivalent), RuPhos (90mg, 0.193mmol, 0.20 equivalent), RuPhos-PdCl-2nd G (150mg, 0.193mmol, 0.20 equivalent) and cesium carbonate (473mg, 1.452mmol, 1.50 equivalent) Solution in dimethyl sulfoxide (30mL) is stirred overnight in 100 DEG C.Solution is diluted with water, and is extracted with ethyl acetate.Merge organic Layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1: 50) elute, obtain title compound (50mg, 13%), be white solid.LC-MS(ES,m/z):387[M+H]+。
Step 2：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- [(pyridine -2- bases) amino] -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- [(pyridine -2- bases) amino] -1H- pyrazoles - 3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (40mg, 70%), it is yellow solid.LC-MS(ES,m/z):466[M+H]+。
Step 3：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridine -2- bases amino) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- [(pyridine -2- bases) amino] -1H- pyrazoles -3- carboxylates and ammonia reacts, obtains titled Compound (15.6mg, 42%), it is white solid.LC-MS(ES,m/z):417[M+H]+.1H NMR(400MHz,CD3OD):δ 8.96(s,1H),8.30-8.29(m,1H),8.014(s,1H),7.92-7.90(m,1H),7.62-7.58(m,1H),7.54- 7.50 (m, 1H), 7.44-7.43 (d, J=7.6Hz, 1H), 6.88-6.86 (d, J=8.4Hz, 1H), 6.81-6.78 (m, 1H), 3.56-3.47(m,2H),2.96(s,3H),2.66-2.56(m,1H),2.38-2.31(m,1H)。
Embodiment 36
Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (1- first Base -1H- pyrazole-3-yls amino) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- iodo- 1- (3- methoxyphenyls) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, the iodo- 1H- pyrazoles -3- carboxylates of 4- and 3- methoxyphenyl boron Acid reaction, title compound (1.6g, crude product) is obtained, be reddish oil.LC-MS(ES,m/z):373[M+H]+。
Step 2：Synthesize 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) amino] -1H- pyrazoles -3- first Sour ethyl ester
Under nitrogen, by the iodo- 1- of 4- (3- methoxyphenyls) -1H- pyrazoles -3- carboxylates (1.2g, 3.224mmol, 1.00 equivalents), 1-N, 2-N- dimethyl cyclohexane -1,2- diamines (464mg, 3.262mmol, 1.00 equivalent), 1- methyl isophthalic acids H- Pyrazoles -3- amine (1.6g, 16.475mmol, 1.00 equivalent), potassium phosphate (876mg, 4.127mmol, 2.00 equivalent), cuprous iodide (I) solution of (265mg, 1.391mmol, 0.500 equivalent) in dimethyl sulfoxide (14mL) stirs 12 hours in 80 DEG C.Solution is used Water dilutes, and is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silica gel column chromatography Method purifies and with ethyl acetate/petroleum ether (1:4) elute, obtain title compound (580mg, 53%), be light yellow solid. LC-MS(ES,m/z):342[M+H]+。
Step 3：Synthesize 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) amino] -1H- pyrazoles -3- first Acid amides
Similar to the operation described in universal method S, 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) Amino] -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazoles -3- Base) amino] -1H- pyrazole-3-formamides title compound (500mg, 94%), be light yellow oil.LC-MS(ES,m/z): 313[M+H]+。
Step 4：Synthesize 1- (3- hydroxy phenyls) -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) amino] -1H- pyrazoles -3- formyls Amine
In 0 DEG C under agitation to 1- (3- methoxyphenyls) -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) amino] -1H- pyrroles Tribromo borine is added dropwise in solution of the azoles -3- formamides (500mg, 1.60mmol, 1.00 equivalent) in dichloromethane (20mL) (1.98g, 7.90mmol, 1.00 equivalent).Resulting solution is stirred at room temperature 2 hours.Reactant is quenched with methanol.Gained mixture It is concentrated in vacuo, residue purifies through silica gel column chromatography and with methylene chloride/methanol (10:1) elute, obtain title compound (400mg, 84%), it is yellow solid.LC-MS(ES,m/z):299[M+H]+。
Step 5：Synthesize trifluoromethayl sulfonic acid 3- [3- carbamyls -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) amino] -1H- Pyrazol-1-yl] phenylester
In 0 DEG C under agitation to 1- (3- hydroxy phenyls) -4- [(1- methyl isophthalic acid H- pyrazole-3-yls) amino] -1H- pyrazoles - Diisopropyl ethyl is added dropwise in solution of the 3- formamides (180mg, 0.603mmol, 1.00 equivalent) in dichloromethane (30mL) Amine (234mg, 1.811mmol, 3.00 equivalent), then in 0 DEG C under agitation be added dropwise Trifluoromethanesulfonic anhydride (169mg, 0.599mmol, 1.50 equivalents).Resulting solution stirs 2 hours in 0 DEG C.Solution is adjusted to pH 8, is extracted with ethyl acetate.Merge Organic layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies and used ethyl acetate/petroleum ether through silica gel column chromatography (1:1) elute, obtain title compound 130mg (50%), be light yellow solid.LC-MS(ES,m/z):431[M+H]+。
Step 6：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (1- methyl isophthalic acid H- pyrazole-3-yls amino) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, trifluoromethayl sulfonic acid 3- [3- carbamyls -4- [(1- methyl isophthalic acids H- Pyrazole-3-yl) amino] -1H- pyrazol-1-yls] phenylester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- ketone it is anti- Should, title compound (20.8mg, 12%) is obtained, is pale solid.LC-MS(ES,m/z):420[M+H]+.1H NMR (300MHz,CD3OD):δ 8.45 (s, 1H), 8.00 (s, 1H), 7.99-7.88 (m, 1H), 7.53-7.49 (t, J=8Hz, 1H), 7.44-7.41(m,2H),5.90(s,1H)3.83(s,3H),3.55-3.46(m,2H),3.15(s,3H),2.65-2.60(m, 1H),2.38-2.31(m,1H)。
Embodiment 37
Synthesize (R) -5- (3,3- dimethyl urea groups) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) thiazole -4-carboxamide
Step 1：Synthesize 5- [(dimethylcarbamoyl) amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl esters
By 5- amino -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acids ethyl ester, (400mg, 1.069mmol, 1.00 work as Amount), triethylamine (6mL, 43.166mmol, 40.38 equivalent), N, N- dimethyl carbamyl chlorides (137mg, 1.274mmol, 1.19 Equivalent) solution in dichloromethane (70mL) stirs 2 days in 40 DEG C.Resulting solution is concentrated in vacuo, and residue is through silicagel column color Spectrometry purifies and with ethyl acetate/petroleum ether (1:5) elute.Title compound (300mg, 63%) is generated, is yellow solid. LC-MS(ES,m/z):446[M+H]+。
Step 2：Synthesize 5- [(dimethylcarbamoyl) amino] -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxos Pyrrolidin-3-yl] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 5- [(dimethylcarbamoyl) amino] -2- (3- iodophenyls) -1, 3- 4-thiazolecarboxylic acids ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (100mg, 65%), it is yellow oil.LC-MS(ES,m/z):457[M+H]+。
Step 3：Synthesize (R) -5- (3,3- dimethyl urea groups) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 5- [(dimethylcarbamoyl) amino] -2- (3- [2- [(3R) -3- Hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3-thiazoles -4- carboxylates and ammonia reacts, obtains Title compound (55.8mg, 60%), it is light yellow solid.LC-MS(ES,m/z):428[M+H]+.1H NMR(300MHz, DMSO-d6):δ11.45(s,1H),8.03-8.00(m,2H),7.93-7.89(m,1H),7.75(s,1H),7.53-7.45(m, 2H),6.49(s,1H),3.38-3.31(m,2H),3.00(s,6H),2.81(s,3H),2.46-2.42(m,1H),2.27- 2.17(m,1H)。
Embodiment 38
Synthesize 5- ((1R, 2R) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Step 1：Synthesize 5- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acids Ethyl ester
Similar to the operation described in universal method B, 5- amino -2- (3- iodophenyls) -1,3-thiazoles -4- carboxylates Reacted with (1R, 2R) -2- fluorine cyclopropane -1- formic acid, obtain title compound (390mg, 63%), be white solid.LC-MS (ES,m/z):461[M+H]+。
Step 2：Synthesis 5- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -2- (3- [2- [(3R) -3- hydroxyl -1- methyl - 2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 5- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -2- (3- iodobenzenes Base) -1,3-thiazoles -4- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title Compound (180mg, 88%), it is red solid.LC-MS(ES,m/z):472[M+H]+。
Step 3：Synthesize 5- ((1R, 2R) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 5- [[(1R, 2R) -2- fluorine cyclopropane] acylamino-] -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acids ethyl ester and ammonia Reaction, obtains title compound (59.7mg, 35%), is white solid.LC-MS(ES,m/z):443[M+H]+.1H NMR (300MHz,CD3OD):δ8.11(s,1H),7.99-7.96(m,1H),7.56-7.46(m,2H),5.10-5.06(m,1H), 3.54-3.47(m,2H),2.96(s,3H),2.67-2.59(m,1H),2.39-2.30(m,1H),2.22-2.17(m,1H), 1.90-1.80(m,1H),1.41-1.32(m,1H)。
Embodiment 39
Synthesize 5- ((1S, 2S) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Step 1：Synthesize 5- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acids Ethyl ester
Similar to the operation described in universal method B, 5- amino -2- (3- iodophenyls) -1,3-thiazoles -4- carboxylates Reacted with (1S, 2S) -2- fluorine cyclopropane -1- formic acid, obtain title compound (450mg, 73%), be white solid.LC-MS (ES,m/z):461[M+H]+。
Step 2：Synthesis 5- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -2- (3- [2- [(3R) -3- hydroxyl -1- methyl - 2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 5- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -2- (3- iodobenzenes Base) -1,3-thiazoles -4- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title Compound (180mg, 88%), it is white solid.LC-MS(ES,m/z):472[M+H]+。
Step 3：Synthesize 5- ((1S, 2S) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 5- [[(1S, 2S) -2- fluorine cyclopropane] acylamino-] -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acids ethyl ester and ammonia Reaction, obtains title compound (41.5mg, 22%), is white solid.LC-MS(ES,m/z):443[M+H]+.1H NMR (300MHz,CD3OD):δ7.92(s,1H),7.81-7.78(m,1H),7.38-7.28(m,2H),4.92-4.89(s,1H), 3.55-3.31(m,2H),2.78(s,3H),2.48-2.41(m,1H),2.21-2.14(m,1H),2.11-1.99(m,1H), 1.70-1.61(m,1H),1.24-1.14(m,1H)。
Embodiment 40
Synthesize (R) -5- amino -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) Evil Azoles -4- formamides
Step 1：Synthesize 2- (3- Bromophenacyls amino) -2- cyanoacetic acid ethyl esters
In 0 DEG C to 2- amino -2- cyanoacetic acid ethyl ester 4- toluenesulfonates (730mg, 2.31mmol) in dichloromethane Pyridine (0.47mL, 5.77mmol) is added in solution in alkane (9.0mL), then add 3- bromo-benzoyl chlorides (0.45mL, 3.46mmol).Reactant mixture stirs 2 hours in 0 DEG C.Reactant is quenched with water, and is extracted with EtOAc.Organic layer sodium sulphate Dry, filtering and vacuum concentration.Crude product (EtOAc/ heptane, elutes) through purified by flash chromatography at 40%EtOAc, obtains Product (653mg, 90%).LC-MS(ES,m/z):311[M+H]+。
Step 2：Synthesize 5- amino -2- (3- bromophenyl) oxazole -4- carboxylates
By 2- [(3- benzoyl bromides) amino] -2- cyano group-ethyl acetate (100mg, 0.32mmol) in hydrogen chloride Stirred 4 hours in 100 DEG C in 1,4- dioxanes (1.60mL, the 6.4mmol) solution of (4mol/L).Reactant is concentrated, obtained Crude product (100mg, 100%).
LC-MS(ES,m/z):311。[M+H]+.
Step 3：Synthesize 2- (3- bromophenyls) -5- ((tert-butoxycarbonyl) amino) oxazole -4- carboxylates
To 5- amino -2-, (3- bromophenyl) oxazole -4- carboxylates (110mg, 0.35mmol) are in acetonitrile (3.5mL) Solution in add N, N- diisopropyl ethyl amines (0.30mL, 1.8mmol), 4-dimethylaminopyridine (4.3mg, 0.035mmol) and coke acid di-t-butyl ester (233mg, 1.06mmol).Reactant mixture stirs 18 hours in RT.Will reaction Thing is quenched with water, and is extracted with EtOAc.Organic layer is dried with sodium sulphate, filtering, is concentrated through rotovap.Crude product is through flash chromatography Method purifies (EtOAc/ heptane), obtains product (105mg, 72%).
LC-MS(ES,m/z):411[M+H]+。
Step 4：Synthesize (R) -5- ((tert-butoxycarbonyl) amino) -2- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Alkane -3- bases) acetenyl) phenyl) oxazole -4- carboxylates
By 2- (3- bromophenyls) -5- (tertbutyloxycarbonylamino) oxazole -4- carboxylates (90.0mg, 0.22mmol), (3R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- ketone (36.5mg, 0.26mmol), Pd (PPh3)2Cl2 The solution of (15mg, 0.022mmol) and TEA (0.75mL) in dimethyl sulfoxide (4.4mL) heats 40 points in microwave in 100 DEG C Clock.Reactant is quenched with water, and is quenched with EtOAc.Organic layer is dried over sodium sulfate, filters, and is concentrated in vacuo.Crude product is through quick color Spectrometry purifies (MeOH/DCM), obtains (90mg, 87.6%).
LC-MS(ES,m/z):470[M+H]+。
Step 5：Synthesize (R) -5- amino -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) oxazole -4- formamides
Ammonia is passed through 5- (tertbutyloxycarbonylamino) -2- [3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxos-pyrrole Cough up alkane -3- bases] acetenyl] solution of the phenyl] oxazole -4- carboxylates (90mg, 0.19mmol) in methanol (4.0mL) reaches 5 minutes.Reactant mixture stirs 24 hours in 50 DEG C.Crude product concentrates, and is purified through flash chromatography (MeOH/DCM), obtain- N- [4- carbamyls -2- [3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrroli -3- bases] acetenyl] phenyl] Evil Azoles -5- bases] ammonia carboxylate.
Will be in N- [4- carbamyls -2- [3- [2- [(3R) -3- hydroxyl -1- methyl -2- in 1,4- dioxanes (1.0mL) Oxo-pyrroli -3- bases] acetenyl] phenyl] oxazole -5- bases] ammonia carboxylate (84mg, 0.19mmol) and in 1,4- The solution of hydrochloric acid (4mol/L) in dioxane (0.95mL, 3.8mmol) stirs 18 hours in RT.Reactant concentrates, residue RHPLC is carried out, obtains product (12.8mg, 18%).LC-MS(ES,m/z):341[M+H]+。
1H NMR(400MHz,DMSO)δ7.85–7.81(m,1H),7.79–7.73(m,1H),7.54–7.48(m,1H), 7.48–7.43(m,1H),7.12–6.88(m,4H),6.53–6.48(s,1H),3.38–3.34(m,2H),2.83–2.78(s, 3H),2.47–2.40(m,1H),2.23–2.15(m,1H)。
Embodiment 41 and 42
Synthesize 5- ((1R, 2S) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- oxo pyrroles Cough up alkane -3- bases) acetenyl) phenyl) thiazole -4-carboxamide and 5- ((1S, 2R) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
(be separated into individually unknown stereoisomer and be arbitrarily attributed to (S, R) or (R, S))
Step 1：Synthesize 5- [(2- fluorine cyclopropane) acylamino-] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method B, 5- amino -2- (3- iodophenyls) -1,3-thiazoles -4- carboxylates Reacted with (trans) -2- fluorine cyclopropane -1- formic acid, obtain title compound (850mg, 69%), be white solid.LC-MS (ES,m/z):461[M+H]+。
Step 2：Synthesize 5- [trans-(2- fluorine cyclopropane) acylamino-] -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 5- [(2- fluorine cyclopropane) acylamino-] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (450mg, 88%), it is light yellow solid.LC-MS(ES,m/z):472[M+H]+。
Step 3：Synthesize 5- ((1R, 2S) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole -4-carboxamide and 5- ((1S, 2R) -2- fluorine cyclopropanecarbonyls amino) -2- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 5- [(2- fluorine cyclopropane) acylamino-] -2- (3- [2- [(3R) -3- hydroxyls Base -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3-thiazoles -4- carboxylates and ammonia reacts, obtains 25.6mg (6%) is the first elution (referred to herein as 1R, 2S- isomers) isomers of white solid and 21.8mg (5%) is Second of elution (referred to herein as 1S, 2R- isomers) isomers of white solid.
The arbitrarily spatial chemistry (the unknown single isomers of absolute stereochemical) of two kinds of isomers of ownership.The first elution Isomers:tR=12.26min (Chiralcel OJ-3,0.46*15cm, Hex (0,1%DEA):IPA=50:50,1ml/ min)；Second of eluting isomer:tR=19.00min (Chiralcel OJ-3,0.46*15cm, Hex (0,1%DEA):IPA =50:50,1ml/min)；Two kinds of isomers show equivalent LC-MS and1H NMR, it is as follows.
LC-MS(ES,m/z):443[M+H]+.1H NMR(300MHz,DMSO-d6):δ11.86(s,1H),8.10(s, 1H),8.06(s,1H),7.96-7.92(m,1H),7.84(s,1H),7.51-7.50(m,2H),6.49(s,1H),4.95(d,J =60Hz, 1H), 3.38-3.32 (m, 2H), 2.90-2.81 (m, 1H), 2.81 (s, 3H), 2.45-2.43 (m, 1H), 2.21- 2.17(m,1H),1.68-1.55(m,1H),1.37-1.30(m,1H)。
Embodiment 43
Synthesize (R) -3- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1,2,4- thiophenes Diazole -5- formamides
Step 1：Synthesize 3- bromo- 5- (1- ethoxyethenyls) -1,2,4- thiadiazoles
Similar to the operation described in universal method Q, the bromo- 5- of 3- chloro- 1,2,4- thiadiazoles and tributyl (1- ethyoxyl second Alkynyl) stannane reaction, title compound (1.5g, 64%) is obtained, is yellow solid.LC-MS(ES,m/z):235[M+H]+。
Step 2：Synthesize the bromo- 1,2,4- thiadiazoles -5- carboxylates of 3-
Similar to the operation described in universal method R, the bromo- 5- of 3- (1- ethoxyethenyls) -1,2,4- thiadiazoles with it is high Sodium iodate and potassium permanganate reaction, obtain title compound (650mg, 43%), are colorless oil.LC-MS(ES,m/z):237[M+ H]+。
Step 3：Synthesis 3- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 1,2,4- thiadiazoles -5- formic acid
Similar to the operation described in universal method U, the thiadiazoles -5- carboxylates of 3- bromo- 1,2,4- and (R)-trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title compound (90mg, 27%), it is brown solid.LC-MS(ES,m/z):344[M+H]+。
Step 4：Synthesis 3- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 1,2,4- thiadiazoles -5- formamides
Similar to the operation described in universal method B, 3- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -1,2,4- thiadiazoles -5- formic acid and ammonium chloride reacts, obtain title compound (12.1mg, 15%), it is white solid.LC-MS(ES,m/z):343[M+H]+.1HNMR(300MHz,CD3OD):δ8.43(s,1H),8.34- 8.31(m,1H),8.60-8.53(m,1H),8.50-8.48(m,1H),3.49-3.45(m,2H),2.92(s,3H),2.63- 2.55(m,1H),2.36-2.26(m,1H)。
Embodiment 44
Synthesize (R) -5- (difluoromethyl) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) thiazole -4-carboxamide
Step 1：Synthesize (R) -5- (difluoromethyl) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method U, the bromo- 5- of 2- (difluoromethyl) -1,3-thiazoles -4- formamides and (R) - Trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title compound Thing (43.2mg, 14%), it is white solid.LC-MS(ES,m/z):392[M+H]+.1H NMR(300MHz,CD3OD):δ8.22 (s,1H),8.10-8.04(m,1H),7.86(s,1H),7.68-7.63(m,1H),7.56-7.51(m,1H),3.55-3.48 (m,2H),2.95(s,3H),2.66-2.58(m,1H),2.38-2.29(m,1H)。
Embodiment 45
Synthesize (R) -5- amino -2- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) thiazole -4-carboxamide
Step 1：Synthesize 2- [(the bromo- 2- fluorophenyls of 5-) formamido group] -2- cyanoacetic acid ethyl esters
To 1- cyano group -2- ethyoxyl -2- oxoethanaminium -1- ammonium 4- methylbenzene -1- sulfonate (5.00g, 16.648mmol, 1.00 equivalents) pyridine (2.68mL, 33.295mmol, 2.00 equivalent) is added in solution in dichloromethane (150mL).Then The bromo- 2- fluorobenzoyl chlorides of 5- (4.00g, 16.845mmol, 1.01 equivalent) are added dropwise under agitation in 0 DEG C.Stirred 30 minutes in 0 DEG C Afterwards, by reactant mixture dchloromethane, with salt water washing, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue loading On to silicagel column and with ethyl acetate/petroleum ether (1:2) elute, obtain title compound (4.0g, 73%), be white solid. LC-MS(ES,m/z):329[M+H]+。
Step 2：Synthesize 5- amino -2- (the bromo- 2- fluorophenyls of 5-) -1,3- 4-thiazolecarboxylic acid ethyl esters
Under nitrogen, by 2- [(the bromo- 2- fluorophenyls of 5-) formamido group] -2- cyanoacetic acids ethyl ester (3.80g, 11.546mmol, 1.00 equivalents), Lawesson's reagents (5.14g, 12.708mmol, 1.10 equivalent) are in toluene (100mL) Suspension in 90 DEG C stir 12 hours.Resulting solution is diluted with ethyl acetate.With the pH value of 1N hydrochloric acid conditioning solutions to 3, so Adjusted afterwards with sodium bicarbonate aqueous solution to pH 8.Gained mixture salt water washing.Organic layer is through anhydrous sodium sulfate drying, vacuum Concentration.Residue is loaded on silicagel column and with dichloromethane/petroleum ether (1:3) elute, obtain title compound (2g, thick), For yellow solid.LC-MS(ES,m/z):345[M+H]+。
Step 3：Synthesize 5- [double [(tert-butoxy) carbonyl] amino] -2- (the bromo- 2- fluorophenyls of 5-) -1,3- thiazole -4- first Sour ethyl ester
By 5- amino -2- (the bromo- 2- fluorophenyls of 5-) -1,3- 4-thiazolecarboxylic acid ethyl esters (2.0g, 5.794mmol, 1.00 Equivalent), 4-dimethylaminopyridine (530mg, 4.338mmol, 0.75 equivalent) and coke acid di-t-butyl ester (2.58g, 11.821mmol, 2.04 equivalents) solution in acetonitrile (50mL) stirs 3 hours in 60 DEG C.Resulting solution is concentrated in vacuo, remaining Thing purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1:5) elute.Generate title compound (500mg, 16%), it is yellow solid.LC-MS(ES,m/z):545[M+H]+。
Step 4：Synthesize N- [2- (the bromo- 2- fluorophenyls of 5-) -4- carbamyl -1,3- thiazole -5- bases]-N- [(tertiary fourth oxygen Base) carbonyl] ammonia carboxylate
Similar to the operation described in universal method S, 5- [double [(tert-butoxy) carbonyl] amino] -2- (bromo- 2- fluorobenzene of 5- Base) -1,3-thiazoles -4- carboxylates and ammonia reacts, obtains title compound (450mg, thick), be yellow solid.LC-MS (ES,m/z):546[M+H]+。
Step 5：Synthesize 5- amino -2- (the bromo- 2- fluorophenyls of 5-) -1,3- thiazole -4-carboxamides
By N- [2- (the bromo- 2- fluorophenyls of 5-) -4- carbamyl -1,3- thiazole -5- bases]-N- [(tert-butoxy) carbonyl] ammonia Solution of the carboxylate (450mg, 0.871mmol, 1.00 equivalent) in 1,4- dioxanes (10mL, with hydrogen chloride saturation) It is stirred at room temperature overnight.After the completion of, solution adjusts pH to 7 with sodium hydrate aqueous solution, is then extracted with dichloromethane.It is associated with Machine layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with methylene chloride/methanol (10: 1) elute, obtain title compound (200mg, 73%), be yellow oil.LC-MS(ES,m/z):316[M+H]+。
Step 6：Synthesize 5- amino -2- (the fluoro- 5- of 2- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] Acetenyl] phenyl) -13- thiazole -4-carboxamides
Similar to the operation described in universal method G, 5- amino -2- (the bromo- 2- fluorophenyls of 5-) -1,3-thiazoles -4- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (14mg, 6%), are greyish white Color solid.LC-MS(ES,m/z):375[M+H]+.1H NMR(400MHz,DMSO-d6):δ 8.30 (dd, J=7.2,5.1Hz, 1H),7.57(s,1H),7.45-7.32(m,4H),7.09(s,1H),6.45(s,1H),3.37-3.33(m,2H),2.80(s, 3H),2.44-2.40(m,1H),2.23-2.14(m,1H)。
Embodiment 46
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (methyl ammonia Base) thiazole -4-carboxamide
Step 1：Synthesize 5- [[(tert-butoxy) carbonyl] (methyl) amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acids Ethyl ester
By 5- [[(tert-butoxy) carbonyl] amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl esters (500.00mg, 1.054mmol, 1.00 equivalent), cesium carbonate (685.56mg, 2.104mmol, 2.00 equivalent), methyl iodide The solution of (298.05mg, 2.100mmol, 1.99 equivalent) in dimethyl sulfoxide (30mL) stirs 1 hour in 45 DEG C.Resulting solution It is diluted with water, is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silicagel column color Spectrometry purifies and with ethyl acetate/petroleum ether (1:10) elute, obtain title compound (500mg, 97%), be light yellow oil. LC-MS(ES,m/z):489[M+H]+。
Step 2：Synthesize N- [4- carbamyls -2- (3- iodophenyls) -1,3- thiazole -5- bases] tertiary fourth of-N- methyl ammonia formic acid Base ester
Similar to the operation described in universal method S, 5- [[(tert-butoxy) carbonyl] amino] -2- (3- iodophenyls) -1, 3- 4-thiazolecarboxylic acids ethyl ester reacts with ammonia, obtains title compound (200mg, 40%), is yellow solid.LC-MS(ES,m/ z):460[M+H]+。
Step 3：Synthesis
By N- [4- carbamyls -2- (3- iodophenyls) -1,3- thiazole -5- bases]-N- methyl ammonia carboxylates The solution of (190.00mg, 0.414mmol, 1.00 equivalent) in 1,4- dioxanes (10mL, with hydrogen chloride saturation) stirs in room temperature Mix overnight.After the completion of, pH value of solution is adjusted to 7 with sodium hydrate aqueous solution, is then extracted with dichloromethane.Merge organic layer, warp Anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with methylene chloride/methanol (10:1) elute, Title compound (130mg, 87%) is obtained, is light yellow solid.LC-MS(ES,m/z):360[M+H]+。
Step 4：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (methylamino) thiazole -4-carboxamide
Similar to the operation described in universal method G, 2- (3- iodophenyls) -5- (methylamino) -1,3-thiazoles -4- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (42.3mg, 41%), are White solid.LC-MS(ES,m/z):371[M+H]+.1H NMR(400MHz,CD3OD):δ7.94(s,1H),7.83-7.08(m, 1H),7.46-7.40(m,2H),3.54-3.47(m,2H),3.09(s,3H),2.95(s,3H),2.64-2.58(m,1H), 2.37-2.30(m,1H)。
Embodiment 47
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridine - 3- yls) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- (pyridin-3-yl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method M, the iodo- 1H- pyrazoles -3- carboxylates of 4- and pyridin-3-yl boric acid Reaction, obtains title compound (390mg, 18%), is yellow oil.LC-MS(ES,m/z):218[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (pyridin-3-yl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, 4- (pyridin-3-yl) -1H- pyrazoles -3- carboxylates and 3- bromines Phenylboric acid reacts, and obtains title compound (210mg, 36%), is yellow oil.LC-MS(ES,m/z):372[M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (pyridin-3-yl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (pyridin-3-yl) -1H- pyrazoles -3- formic acid Ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (150mg, 65%), For yellow solid.LC-MS(ES,m/z):431[M+H]+。
Step 4：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridin-3-yl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (pyridin-3-yl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (28.8mg, 28%), it is white solid.LC-MS(ES,m/z):402[M+H]+.1H NMR(300MHz,CD3OD):δ8.82(s, 1H),8.66(s,1H),8.48-8.47(m,1H),8.17-8.10(m,2H),7.99-7.95(m,1H),7.57-7.45(m, 3H),3.55-3.45(m,2H),2.94(s,3H),2.65-2.57(m,1H),2.38-2.31(m,1H)。
Embodiment 48
Synthesize 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -4- (1- Methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method M, the iodo- 1H- pyrazoles -3- carboxylates of 4- and 1- methyl isophthalic acid H- pyrroles Azoles -5- ylboronic acids react, and obtain title compound (500mg, 45%), are yellow oil.LC-MS(ES,m/z):221[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, 4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazoles -3- formic acid second Base ester is reacted with 3- bromophenylboronic acids, is obtained title compound (410mg, 48%), is brown solid.LC-MS(ES,m/z): 375[M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- Pyrazoles -3- carboxylates are anti-with answering (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- ketone, obtain title compound (350mg, 76%), it is yellow solid.LC-MS(ES,m/z):434[M+H]+。
Step 4：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (1- methyl isophthalic acid H- pyrazoles -5- bases) -1H- pyrazoles -3- carboxylates and ammonia reacts, marked Compound (27.6mg, 7.6%) is inscribed, is white solid.LC-MS(ES,m/z):405[M+H]+.1H NMR(300MHz, CD3OD):δ 8.55 (s, 1H), 8.09 (d, J=1.5Hz, 1H), 7.99-7.95 (m, 1H), 7.58-7.49 (m, 3H), 6.39 (d, J=2.1Hz, 1H), 3.79 (s, 3H), 3.56-3.34 (m, 2H), 2.94 (s, 3H), 2.65-2.57 (m, 1H), 2.38- 2.29(m,1H)。
Embodiment 49
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridine - 4- yls) -1H- pyrazole-3-formamides
Step 1：Synthesize 4- (pyridin-4-yl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method M, the iodo- 1H- pyrazoles -3- carboxylates of 4- and pyridin-4-yl boric acid Reaction, obtains title compound (596mg, 36%), is yellow solid.LC-MS(ES,m/z):218[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (pyridin-4-yl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, 4- (pyridin-4-yl) -1H- pyrazoles -3- carboxylates and 3- bromines Phenylboric acid reacts, and obtains title compound (572mg, 56%), is white solid.LC-MS(ES,m/z):372[M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 4- (pyridin-4-yl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (pyridin-4-yl) -1H- pyrazoles -3- formic acid Ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (290mg, 46%), For yellow solid.Confirm LCMS.LC-MS(ES,m/z):431[M+H]+。
Step 4：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -4- (pyridin-4-yl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -4- (pyridin-4-yl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (39.6mg, 15%), it is white solid.LC-MS(ES,m/z):402[M+H]+.1H NMR(300MHz,CD3OD):δ8.80(s, 1H), 8.55 (d, J=6.3Hz, 2H), 8.10 (d, J=1.8Hz, 1H), 8.00-7.96 (m, 1H), 7.84-7.81 (m, 2H), 7.59-7.49(m,2H),3.56-3.48(m,2H),2.95(s,3H),2.65-2.58(m,1H),2.39-2.29(m,1H)。
Embodiment 50
(R) -3- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -1,2 is synthesized, 4- thiadiazoles -5- formamides
Step 1：Synthesize 3- (the fluoro- 5- of 2- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] Phenyl) -1,2,4- thiadiazoles -5- formic acid
Similar to the operation described in universal method U, the thiadiazoles -5- carboxylates of 3- bromo- 1,2,4- and (R)-trifluoro (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title compound Thing (120mg, 33%), it is red solid.LC-MS(ES,m/z):362[M+H]+。
Step 2：Synthesize (R) -3- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) -1,2,4- thiadiazoles -5- formamides
Similar to similar to the operation described in universal method B, 3- (the fluoro- 5- of 2- [2- [(3R) -3- hydroxyl -1- methyl -2- Oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,2,4- thiadiazoles -5- formic acid and ammonium chloride reacts, obtain title compound (15.6mg, 13%), it is white solid.LC-MS(ES,m/z):361[M+H]+.1H NMR(300MHz,CD3OD):δ8.39- 8.36(m,1H),7.65-7.60(m,1H),7.32-7.26(m,1H),3.49-3.30(m,2H),2.92(s,3H),2.62- 2.53(m,1H),2.35-2.25(m,1H)。
Embodiment 51
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (methyl sulphurs Acylamino-) thiazole -4-carboxamide
Step 1：Synthesize 2- (3- iodophenyls) -5- methanesulfonamido -1,3- thiazole -4-carboxamides
By 5- amino -2- (3- iodophenyls) -1,3- thiazole -4-carboxamides (300mg, 0.869mmol, 1.00 equivalent), three Ethamine (101mg, 0.998mmol, 1.15 equivalent) and Loprazolam methylsulfonyl base ester (227mg, 1.303mmol, 1.50 equivalent) Solution in dichloromethane (20mL) is stirred at room temperature 5 hours.Resulting solution is concentrated in vacuo.The inverted chromatography of crude product is pure Change, obtain title compound (195mg, 53%), be pale solid.LC-MS(ES,m/z):424[M+H]+。
Step 2：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (sulfonyloxy methyl amino) thiazole -4-carboxamide
Similar to the operation described in universal method G, 2- (3- iodophenyls) -5- methanesulfonamidos -1,3-thiazoles -4- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (65.7mg, 43%), are Pale solid.LC-MS(ES,m/z):435[M+H]+.1HNMR(400MHz,CD3OD):δ8.01(s,1H),7.92-7.90 (d, J=7.2Hz, 1H), 7.45-7.39 (m, 2H), 3.55-3.42 (m, 2H), 2.99 (s, 3H), 2.95 (s, 3H), 2.64- 2.59(m,1H),2.36-2.29(m,1H)。
Embodiment 52
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (2,2,2- Trifluoroethyl amino) thiazole -4-carboxamide
Step 1：Synthesize 5- [[(tert-butoxy) carbonyl] (2,2,2- trifluoroethyls) amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl ester
By 5- [[(tert-butoxy) carbonyl] amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl esters (500.00mg, 1.054mmol, 1.00 equivalent), trifluoromethayl sulfonic acid 2,2,2- trifluoroethyls ester (489.34mg, 2.108mmol, 2.00 equivalents), cesium carbonate (686.93mg, 2.108mmol, 2.00 equivalent) it is molten in dimethyl sulfoxide (20mL) Liquid stirs 12 hours in 55 DEG C.Resulting solution is diluted with water, and is extracted with ethyl acetate.Merge organic layer, done through anhydrous sodium sulfate It is dry, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1:10) elute, obtain titled Compound (400mg, 68%), it is yellow oil.LC-MS(ES,m/z):557[M+H]+。
Step 2：Synthesize N- [4- carbamyls -2- (3- iodophenyls) -1,3- thiazole -5- bases]-N- (2,2,2- trifluoro second Base) ammonia carboxylate
Similar to the operation described in universal method S, 5- [[(tert-butoxy) carbonyl] (2,2,2- trifluoroethyl) amino]- 2- (3- iodophenyls) -1,3-thiazoles -4- carboxylates react with ammonia, obtain title compound (180mg, 47%), are yellow Oil.LC-MS(ES,m/z):528[M+H]+。
Step 3：Synthesize 2- (3- iodophenyls) -5- [(2,2,2- trifluoroethyls) amino] -1,3- thiazole -4-carboxamides
By N- [4- carbamyls -2- (3- iodophenyls) -1,3- thiazole -5- bases]-N- (2,2,2- trifluoroethyls) ammonia formic acid Solution of the tertiary butyl ester (180mg, 0.341mmol, 1.00 equivalent) in 1,4- dioxanes (10mL, with hydrogen chloride saturation) is in room Temperature is stirred overnight.After the completion of, pH value of solution is adjusted to 7 with sodium hydrate aqueous solution, is then extracted with dichloromethane.Merge organic Layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with methylene chloride/methanol (10:1) Elution, obtains title compound (140mg, 96%), is yellow solid.LC-MS(ES,m/z):428[M+H]+。
Step 4：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (2,2,2- trifluoroethyls amino) thiazole -4-carboxamide
Similar to the operation described in universal method G, 2- (3- iodophenyls) -5- [(2,2,2- trifluoroethyl) amino] -1, 3- thiazole -4-carboxamides and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (63.4mg, 44%), it is white solid.LC-MS(ES,m/z):439[M+H]+.1H NMR(400MHz,CD3OD):δ7.98(s, 1H), 7.86-7.84 (d, J=7.6Hz, 1H), 7.50-7.42 (m, 2H), 4.13-4.06 (m, 2H), 3.54-3.47 (m, 2H), 2.95(s,3H),2.64-2.58(m,1H),2.37-2.30(m,1H)。
Embodiment 53
Synthesize (R) -5- (ethylamino) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) thiazole -4-carboxamide
Step 1：Synthesize 5- [[(tert-butoxy) carbonyl] (ethyl) amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acids Ethyl ester
By 5- [[(tert-butoxy) carbonyl] amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl esters (500.00mg, 1.054mmol, 1.00 equivalent), iodoethane (197.29mg, 1.265mmol, 1.20 equivalent), cesium carbonate The solution of (686.93mg, 2.108mmol, 2.00 equivalent) in dimethyl sulfoxide (30mL) stirs 4 hours in 40 DEG C.Solution water Dilution, is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silica gel column chromatography Purifying and with ethyl acetate/petroleum ether (1:10) elute, obtain title compound 490mg (93%), be light yellow oil.LC-MS (ES,m/z):503[M+H]+。
Step 2：Synthesize N- [4- carbamyls -2- (3- iodophenyls) -1,3- thiazole -5- bases]-N- (2,2,2- trifluoro second Base) ammonia carboxylate
Similar to the operation described in universal method S, 5- [[(tert-butoxy) carbonyl] (2,2,2- trifluoroethyl) amino]- 2- (3- iodophenyls) -1,3-thiazoles -4- carboxylates react with ammonia, obtain title compound (180mg, 93%), are yellow Oil.LC-MS(ES,m/z):474[M+H]+。
Step 3：Synthesize 5- (ethylamino) -2- (3- iodophenyls) -1,3- thiazole -4-carboxamides
By 5- [[(tert-butoxy) carbonyl] (ethyl) amino] -2- (3- iodophenyls) -1,3- 4-thiazolecarboxylic acid ethyl esters The solution of (180mg, 0.358mmol, 1.00 equivalent) in 1,4- dioxanes (10mL, with hydrogen chloride saturation) was stirred at room temperature Night.After the completion of, pH value of solution is adjusted to 7 with sodium hydrate aqueous solution, is then extracted with dichloromethane.Merge organic layer, through anhydrous Sodium sulphate is dried, and is concentrated in vacuo.Residue purifies through silica gel column chromatography and with methylene chloride/methanol (10:1) elute, obtain Title compound (130mg, 97%), it is light yellow solid.LC-MS(ES,m/z):374[M+H]+。
Step 4：Synthesize (R) -5- (ethylamino) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method G, 5- (ethylamino) -2- (3- iodophenyls) -1,3-thiazoles -4- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (31.2mg, 23%), are White solid.LC-MS(ES,m/z):385[M+H]+.1H NMR(400MHz,CD3OD):δ 7.94 (s, 1H), 7.81 (d, J= 7.2Hz,1H),7.46-7.40(m,2H),3.54-3.49(m,2H),3.39-3.36(m,2H),2.95(s,3H),2.64- 2.58 (m, 1H), 2.37-2.30 (m, 1H), 1.35 (t, J=7.2Hz, 3H).
Embodiment 54
Synthesize (R) -2- (5- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) -2- aminomethyl phenyls) thiophene Azoles -4- formamides
Step 1：Synthesize 2- (5- hydroxy-2-methyls phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method M, the bromo- 1,3-thiazoles -4- carboxylates of 2- and 4- methyl -3- (four Methyl isophthalic acid, 3,2- dioxaborolan alkane -2- bases) phenol reactant, title compound (4.48g, 96%) is obtained, is yellow Oil.LC-MS(ES,m/z):264[M+H]+。
Step 2：Synthesize 2- [2- methyl -5- [(fluoroform) sulfonyl epoxide] phenyl] -1,3- 4-thiazolecarboxylic acid ethyls Ester
By 2- (5- hydroxy-2-methyls phenyl) -1,3- 4-thiazolecarboxylic acids ethyl ester, (4.48g, 17.014mmol, 1.00 work as Amount), fluoro- N- phenyl-N- (fluoroform) the sulfonyls Methanesulfomides (9.1g, 25.472mmol, 1.50 equivalent) of 1,1,1- tri- and Solution of the triethylamine (8mL) in dichloromethane (50mL) is stirred at room temperature 12 hours.The pH to 8 of solution is adjusted, mixture is used Ethyl acetate extracts.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Residue is through silica gel column chromatography acetic acid Ethyl ester/petroleum ether (1:1) it is purified by flash, obtains title compound (3.85g, 57%), is white solid.LC-MS(ES,m/z): 396[M+H]+。
Step 3：Synthesize 2- (5- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] -2- first Base phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 2- [2- methyl -5- [(fluoroform) sulfonyl epoxide] phenyl] - 1,3-thiazoles -4- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound Thing (111mg, 57%), it is white solid.LC-MS(ES,m/z):385[M+H]+。
Step 4：Synthesize (R) -2- (5- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) -2- methylbenzenes Base) thiazole -4-carboxamide
Similar to the operation described in universal method S, 2- (5- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] -2- aminomethyl phenyls) -1,3-thiazoles -4- carboxylates and ammonia reacts, obtain title compound (18mg, 18%), it is white solid.LC-MS(ES,m/z):356[M+H]+.1HNMR(300MHz,CD3OD):δ8.33(s,1H),7.90 (d, J=1.5Hz, 1H), 7.48 (dd, J=7.8Hz, 1.5Hz, 1H), 7.38 (d, J=8.1Hz, 1H), 3.51-3.45 (m, 2H),2.94(m,3H),2.63(s,3H),2.60-2.55(m,1H),2.36-2.27(m,1H)。
Embodiment 55
Synthesize 1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -3a, 4,6, 6a- tetrahydrochysene -1H- furans simultaneously [3,4-c] pyrazole-3-formamide
Step 1：Synthesize 1- (3- iodophenyls) -1H, 3aH, 4H, 6H, 6aH- furans simultaneously [3,4-c] pyrazoles -3- formic acid ethyls Ester
Under agitation in -15 DEG C to the chloro- 2- of 2- [(E) -2- (3- iodophenyls) diazene -1- bases] ethyl acetate (3.6g, 10.21mmol, 1.00 equivalents) be added dropwise in solution in 2,5- dihydrofuran (10mL) triethylamine (1.03g, 10.18mmol, 1.00 equivalent).Resulting solution is stirred at room temperature overnight, is diluted with water, is extracted with ethyl acetate.Merge organic layer, through anhydrous sulphur Sour sodium is dried, and is concentrated in vacuo.Residue is through silica gel column chromatography ethyl acetate/petroleum ether (1:10) it is purified by flash.Generate Title compound (300mg, 7%), it is yellow solid.LC-MS(ES,m/z):387[M+H]+。
Step 2：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 1H, 3aH, 4H, 6H, 6aH- furans simultaneously [3,4-c] pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- iodophenyls) -1H, 3aH, 4H, 6H, 6aH- furans simultaneously [3,4- C] pyrazoles -3- carboxylates and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (170mg, 64%), it is yellow oil.LC-MS(ES,m/z):398[M+H]+。
Step 3：1- (3- (((R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -3a is synthesized, 4,6,6a- tetrahydrochysene -1H- furans simultaneously [3,4-c] pyrazole-3-formamide
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -1H, 3aH, 4H, 6H, simultaneously [3,4-c] pyrazoles -3- carboxylates react 6aH- furans with ammonia, obtain To title compound (72.6mg, 37%), for the mixture of stereoisomer.LC-MS(ES,m/z):369[M+H]+.1H NMR (300MHz,DMSO-d6):δ7.72(s,1H),7.31-7.13(m,3H),7.10-7.10(m,1H),6.93-6.91(m,1H), 6.42(s,1H),5.06-5.01(m,1H),4.15-3.97(m,3H),3.80-3.75(m,2H),3.38-3.31(m,2H), 2.79(s,3H),2.50-2.37(m,1H),2.22-2.15(m,1H)。
Embodiment 56
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -6,7- dihydros - 5H- pyrrolo-es [1,2-e] imidazoles -3- formamides
Step 1：The amyl- 4- alkynyls ester of synthesizing methane sulfonic acid
Under agitation in 0 DEG C to amyl- 4- alkynyls -ol (3g, 35.66mmol, 1.00 equivalent), triethylamine (5.77g, 57.02mmol, 1.60 equivalents) mesyl chloride (4.9g, 42.78mmol, 1.20 is added dropwise in solution in dichloromethane (20mL) Equivalent).After the completion of, by resulting solution dchloromethane, then with salt water washing.Organic layer through anhydrous sodium sulfate drying, It is concentrated in vacuo, obtains title compound (3.1g, 54%), be pale solid.LC-MS(ES,m/z):163[M+H]+。
Step 2：Synthesize the amyl- 1- alkynes of 5- azidos
To the amyl- 4- alkynyls ester of Loprazolam (3g, 18.495mmol, 1.00 equivalent) at N,N-dimethylformamide (20mL) In solution in add sodium azide (2.4g, 36.917mmol, 2.00 equivalent).Resulting solution is stirred at room temperature 2 hours, uses carbon Sour hydrogen sodium water solution dilution, is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, be concentrated in vacuo.Generate mark Compound (2.5g, thick) is inscribed, is brown solid.LC-MS(ES,m/z):110[M+H]+。
Step 3：Synthesize 5H, 6H, 7H- pyrrolo-es [1,2-c] imidazoles -3- carboxylates
By the amyl- 1- alkynes of 5- azidos (1.0g, 9.16mmol, 1.00 equivalent), 2- ethyoxyl -2- oxoacetonitriles (5mL, 50.46mmol, 5.50 equivalents), gold trichloride (iii) (139mg, 0.46mmol, 0.05 equivalent) and Loprazolam (969mg, 10.08mmol, 1.10 equivalents) solution in cyan carbonic acid methyl ester (5mL) is stirred at room temperature 12 hours.Resulting solution vacuum Concentration.Residue is dissolved with ethyl acetate, then with sodium bicarbonate aqueous solution and salt water washing.Organic layer is done through anhydrous sodium sulfate It is dry, it is concentrated in vacuo.Residue is through silica gel column chromatography methylene chloride/methanol (10:1) it is purified by flash, obtains title compound (350mg, thick), is light yellow solid.LC-MS(ES,m/z):167[M+H]+。
Step 4：Synthesize 1- iodo- 5H, 6H, 7H- pyrrolo-es [1,2-c] imidazoles -3- carboxylates
By 5H, 6H, (350.00mg, 1.94mmol, 1.00 work as 7H- pyrrolo-es [1,2-c] imidazoles -3- carboxylates Amount), solution of the N- iodine succinimide (436.98mg, 1.94mmol, 1.00 equivalent) in acetonitrile (5mL) in 70 DEG C stir 6 Hour.Reactant is quenched with sodium thiosulfate solution, is extracted with ethyl acetate.Merge organic layer, through anhydrous sodium sulfate drying, It is concentrated in vacuo.Residue is through silica gel column chromatography ethyl acetate/petroleum ether (1:1) it is purified by flash.Generate title compound (70mg, 12%), it is light yellow solid.LC-MS(ES,m/z):293[M+H]+。
Step 5：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5H, 6H, 7H- pyrrolo- [1,2-c] imidazoles -3- carboxylates
Similar to the operation described in universal method U, 1- iodo- 5H, 6H, 7H- pyrrolo-es [1,2-c] imidazoles -3- formic acid second Base ester and (R)-trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, are obtained It is white solid to title compound (20mg, 52%).LC-MS(ES,m/z):380[M+H]+。
Step 6：(R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -6 is synthesized, 7- dihydro -5H- pyrrolo-es [1,2-e] imidazoles -3- formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5H, 6H, 7H- pyrrolo-es [1,2-c] imidazoles -3- carboxylates and ammonia react, obtained titled Compound (5.8mg, 25%), it is white solid.LC-MS(ES,m/z):365[M+H]+.1H NMR(300MHz,CD3OD):δ7.84 (s,1H),7.77-7.70(m,1H),7.41-7.31(m,2H),4.38-4.33(m,2H),3.54-3.46(m,2H),3.15- 3.10(m,2H),2.94(s,3H),2.80-2.73(m,2H),2.63-2.55(m,1H),2.36-2.26(m,1H)。
Embodiment 57
Synthesize (R) -5- ((1H- pyrazol-1-yls) methyl) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) thiazole -4-carboxamide
Step 1：Synthesize 2- bromo- 5- (bromomethyl) -1,3- 4-thiazolecarboxylic acid methyl esters
By the bromo- 5- methyl-1,3-thiazoles -4- carboxylic acid methyl esters of 2- (500.00mg, 2.118mmol, 1.00 equivalent), N- bromines Succinimide (570mg, 3.203mmol, 1.51 equivalent) and benzoyl peroxide (217.08mg, 0.847mmol, 0.40 equivalent) Solution in carbon tetrachloride (80mL) stirs 14 hours in 80 DEG C.Resulting solution is concentrated in vacuo, and residue is through silica gel column chromatography Method purifies and with ethyl acetate/petroleum ether (1:30) elute.Title compound 650mg (97%) is generated, is yellow oil.LC- MS(ES,m/z):314[M+H]+。
Step 2：Synthesize 2- bromo- 5- (1H- pyrazol-1-yls methyl) -1,3- 4-thiazolecarboxylic acid methyl esters
By 2- bromo- 5- (bromomethyl) -1,3- 4-thiazolecarboxylic acids methyl esters (600.00mg, 1.905mmol, 1.00 equivalent), Cesium carbonate (1861.93mg, 5.715mmol, 3.00 equivalent) and 1H- pyrazoles (389.04mg, 5.715mmol, 3.00 equivalent) exist Solution in acetonitrile (50mL) is stirred at room temperature 3 hours.Resulting solution be concentrated in vacuo, residue through silica gel column chromatography purifying and With ethyl acetate/petroleum ether (1:5) elute.Title compound (85mg, 15%) is generated, is yellow solid.LC-MS(ES,m/ z):302[M+H]+。
Step 3：Synthesis 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- (1H- pyrazol-1-yls methyl) -1,3- 4-thiazolecarboxylic acid methyl esters
Similar to the operation described in universal method U, the bromo- 5- of 2- (1H- pyrazol-1-yls methyl) -1,3-thiazoles -4- formic acid Methyl ester and (R)-trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, Title compound (70mg, 61%) is obtained, is red solid.LC-MS(ES,m/z):437[M+H]+。
Step 4：Synthesize (R) -5- ((1H- pyrazol-1-yls) methyl) -2- (3- ((3- hydroxyl -1- methyl -2- oxo pyrroles Alkane -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- (1H- pyrazol-1-yls methyl) -1,3-thiazoles -4- carboxylic acid methyl esters and ammonia reacts, obtain title Compound (8.9mg, 13%), it is white solid.LC-MS(ES,m/z):422[M+H]+.1H NMR(300MHz,CD3OD):δ 8.07 (t, J=1.2Hz, 1H), 7.96-7.90 (m, 1H), 7.85 (s, 1H), 7.58-7.54 (m, 2H), 7.46 (t, J= 7.5Hz, 1H), 6.36 (t, J=2.1Hz, 1H), 6.07 (s, 2H), 3.48-3.46 (m, 2H), 2.93 (s, 3H), 2.65-2.55 (m,1H),2.35-2.25(m,1H)。
Embodiment 58
Synthesis (R) -2- (bis- fluoro- 5- of 2,4- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) - 5- methylthiazol -4- formamides
Step 1：Synthesize 2- (the bromo- 2,4 difluorobenzene bases of 5-) -5- methylthiazol -4- carboxylates
Similar to the operation described in universal method M, the bromo- 5- methylthiazols -4- carboxylates of 2- and 2- (5- bromo- 2, 4- difluorophenyls) -4,4,5,5- tetramethyls -1,3,2- dioxaborolans alkane reaction, obtain title compound (510mg, 69%), it is white solid.LC-MS(ES,m/z):362[M+H]+。
Step 2：Synthesize (R) -2- (bis- fluoro- 5- of 2,4- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) Phenyl) -5- methylthiazol -4- carboxylates
Similar to the operation described in universal method G, 2- (bromo- 2, the 4- difluorophenyls of 5-) -5- methylthiazol -4- formic acid second Base ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (200mg, 86%), are White solid.LC-MS(ES,m/z):421[M+H]+。
Step 3：Synthesize (R) -2- (bis- fluoro- 5- of 2,4- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) Phenyl) -5- methylthiazol -4- formamides
Similar to the operation described in universal method S, (R) -2- (2,4- bis- fluoro- 5- ((3- hydroxyl -1- methyl -2- oxos Pyrrolidin-3-yl) acetenyl) phenyl) -5- methylthiazol -4- carboxylates and ammonia reacts, obtain title compound (55.5mg, 29%), it is white solid.LC-MS(ES,m/z):392[M+H]+.1H NMR(300MHz,DMSO-d6):δ8.61- 8.57(m,1H),8.15(s,1H),7.70-7.65(m,1H),7.53(s,1H),6.58(s,1H),3.38-3.32(m,2H), 2.80(s,3H),2.78(s,3H),2.49-2.44(m,1H),2.25-2.20(m,1H)。
Embodiment 59
Synthesize (R) -5- (difluoromethyl) -2- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetylene Base) phenyl) thiazole -4-carboxamide
Step 1：Synthesize 2- bromo- 5- (two bromomethyls) -1,3- 4-thiazolecarboxylic acid methyl esters
To the bromo- 5- methyl-1,3-thiazoles -4- carboxylic acid methyl esters of 2- (350.00mg, 1.483mmol, 1.00 equivalent) and N- Peroxide benzene first is added in solution of the bromine succinimide (790mg, 4.439mmol, 2.99 equivalent) in carbon tetrachloride (20mL) Acyl (73mg, 0.285mmol, 0.19 equivalent).Resulting solution stirs 3 hours in 80 DEG C.Resulting solution is concentrated in vacuo, residue warp Silica gel column chromatography purifies and with ethyl acetate/petroleum ether (1:10) elute.Title compound (760mg, thick) is generated, is nothing Color oil.LC-MS(ES,m/z):394[M+H]+。
Step 2：Synthesize the bromo- 5- formoxyls -1,3- 4-thiazolecarboxylic acid methyl esters of 2-
By the bromo- 5- of 2- (two bromomethyls) -1,3- 4-thiazolecarboxylic acids methyl ester, (700.00mg, 1.777mmol, 1.00 work as Amount) and solution of the silver nitrate (610mg, 3.591mmol, 2.02 equivalent) in ethanol (20mL)/water (2mL) in 80 DEG C of stirrings 3 Hour.Precipitation is filtered out, filter vacuum concentration, title compound (560mg, thick) is obtained, is yellow solid.LC-MS(ES,m/ z):250[M+H]+。
Step 3：Synthesize 2- bromo- 5- (difluoromethyl) -1,3- 4-thiazolecarboxylic acid methyl esters
Similar to the operation described in universal method L, the bromo- 5- formoxyls -1,3-thiazoles -4- carboxylic acid methyl esters of 2- with it is double (2- methoxy ethyls) amino sulfur trifluoride reacts, and obtains title compound (270mg, 44%), is yellow solid.LC-MS (ES,m/z):272[M+H]+。
Step 4：Synthesize 2- bromo- 5- (difluoromethyl) -1,3- thiazole -4-carboxamides
Similar to the operation described in universal method S, the bromo- 5- of 2- (difluoromethyl) -1,3-thiazoles -4- carboxylic acid methyl esters with Ammonia reacts, and obtains title compound (250mg, 95%), is yellow solid.LC-MS(ES,m/z):257[M+H]+。
Step 5：Synthesize (R) -5- (difluoromethyl) -2- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method U, the bromo- 5- of 2- (difluoromethyl) -1,3-thiazoles -4- formamides and (R) - Trifluoro (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title Compound (52.0mg, 14%), it is pink solid.LC-MS(ES,m/z):410[M+H]+.1H NMR(300MHz,DMSO- d6):δ 8.60-8.57 (m, 1H), 8.52 (s, 1H), 8.03 (s, 1H), 7.93 (t, J=47.2Hz, 1H), 7.70-7.65 (m, 1H),7.58-7.51(m,1H),3.38-3.30(m,2H),2.81(s,3H),2.50-2.42(m,1H),2.27-2.18(m, 1H)。
Embodiment 60
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- Jia Ji Evil Azoles -4- formamides
Step 1：Synthesis 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- methyl isophthalic acids, 3- oxazole -4- formic acid esters
Similar to the operation described in universal method U, the bromo- 5- methyl isophthalic acids of 2-, 3- oxazole -4- carboxylates and (R)-three Fluorine (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title compound (403mg, 55%), it is light yellow solid.LC-MS(ES,m/z):369[M+H]+。
Step 2：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- Jia Ji oxazole -4- formamides
Similar to the operation described in universal method S, 2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- methyl isophthalic acids, 3- oxazole -4- carboxylates and ammonia reacts, obtain title compound (51mg, 16%), it is white solid.LC-MS(ES,m/z):340[M+H]+.1HNMR(300MHz,DMSO-d6):δ8.02-7.95(m, 2H),7.63-7.57(m,3H),7.48(s,1H),6.53(s,1H),3.38-3.31(m,2H),2.81(s,3H),2.65(s, 3H),2.47-2.43(m,1H),2.28-2.12(m,1H)。
Embodiment 61
Synthesis (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- methoxyl groups - 1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -5- hydroxyl -1H- pyrazoles -3- carboxylic acid methyl esters
By (3- bromophenyls) hydrazine hydrochloride (11g, 49.217mmol, 1.00 equivalent), butyl- 2- alkynes diacid dimethyl esters (7.1g, 49.952mmol, 1.02 equivalent) and triethylamine (10g, 98.824mmol, 2.01 equivalent) are in ethanol (100mL) Solution is in being heated at reflux 5 hours.Gained mixture is concentrated in vacuo.Residue is through silica gel column chromatography ethyl acetate/petroleum ether (1:2) it is purified by flash, obtains title compound (8.5g, 58%), is pale solid.LC-MS(ES,m/z):297[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -5- methoxyl group -1H- pyrazoles -3- carboxylic acid methyl esters
By 1- (3- bromophenyls) -5- hydroxyl -1H- pyrazoles -3- carboxylic acid methyl esters (4.00g, 12.86mmol, 1.00 equivalent), Methyl iodide (2.74g, 19.30mmol, 1.50 equivalent), cesium carbonate (6.28g, 19.27mmol, 1.50 equivalent) are in N, N- dimethyl Solution in formamide (60mL) is stirred at room temperature 3 hours.Solution is diluted with water, and is extracted with ethyl acetate.Merge organic layer, warp Anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue is through silica gel column chromatography ethyl acetate/petroleum ether (1:20) it is purified by flash, Title compound (2.3g, 55%) is obtained, is light yellow oil.LC-MS(ES,m/z):311[M+H]+。
Step 3：Synthesis 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- methoxyl group -1H- pyrazoles -3- carboxylic acid methyl esters
Similar to the operation described in universal method G, 1- (3- bromophenyls) -5- methoxyl group -1H- pyrazoles -3- carboxylic acid methyls Ester and (R) -3- acetenyl -3- hydroxyl -1- ethyl pyrrolidine -2- reactive ketones, obtain title compound (200mg, 84%), are red Color oil.LC-MS(ES,m/z):384[M+H]+。
Step 4：Synthesize (R) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- Methoxyl group -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- methoxyl group -1H- pyrazoles -3- carboxylic acid methyl esters and ammonia reacts, obtain title compound (40.6mg, 21%), it is white solid.LC-MS(ES,m/z):355[M+H]+.1H NMR(300MHz,CD3OD):δ7.78(s, 1H),7.72-7.68(m,1H),7.40-7.33(m,2H),6.18(s,1H),3.94(s,3H),3.94-3.33(m,2H), 2.84(s,3H),2.53-2.46(m,1H),2.27-2.17(m,1H)。
Embodiment 62
Synthesize (R) -4- (cyclobutane formamido group) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- cyclobutane acylamino- -1H- pyrazoles -3- carboxylates
By 4- amino -1- (3- bromophenyls) -1H- pyrazoles -3- carboxylates (300mg, 0.967mmol, 1.00 equivalent), Cyclobutanecarbonyl chlorine (138mg, 1.164mmol, 1.20 equivalent) and triethylamine (1.5mL, 10.792mmol, 11.16 equivalent) exist Solution in dichloromethane (8mL) is stirred at room temperature 30 minutes.Resulting solution is concentrated in vacuo, and residue is pure through silica gel column chromatography Change and with ethyl acetate/petroleum ether (1:10) elute.Title compound (320mg, 84%) is generated, is yellow solid.LC-MS (ES,m/z):392[M+H]+。
Step 2：Synthesize 4- cyclobutane acylamino-s -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- cyclobutane acylamino- -1H- pyrazoles -3- first Sour ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (200mg, 87%), it is yellow oil.LC-MS(ES,m/z):451[M+H]+。
Step 3：Synthesize (R) -4- (cyclobutane formamido group) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base) acetenyl) phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 4- cyclobutane acylamino-s -1- (3- [2- [(3R) -3- hydroxyl -1- first Base -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1H- pyrazoles -3- carboxylates and ammonia reacts, obtain title compound (80.7mg, 43%), it is white solid.LC-MS(ES,m/z):422[M+H]+.1H NMR(300MHz,CD3OD):δ8.79(s, 1H),7.99(s,1H),7.88-7.86(m,1H),7.55-7.44(m,2H),3.53-3.47(m,2H),3.42-3.31(m, 1H),2.66(s,3H),2.65-2.58(m,1H),2.43-2.32(m,5H),2.31-2.26(m,1H),2.17-2.15(m, 1H)。
Embodiment 63
Synthesize (R) -5- (cyclopropanecarbonyl amino) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) second Alkynyl) phenyl) thiazole -4-carboxamide
Step 1：Synthesize 2- (3- bromophenyls) -5- cyclopropane acylamino- -1,3- 4-thiazolecarboxylic acid ethyl esters
By 5- amino -2- (3- bromophenyls) -1,3- 4-thiazolecarboxylic acids ethyl ester, (100mg, 0.306mmol, 1.00 work as Amount), cyclopropane carbonyl chlorine (30mg, 0.287mmol, 0.94 equivalent), triethylamine (0.1mL, 0.719mmol, 2.35 equivalent) exist Solution in dichloromethane (5mL) is stirred at room temperature 30 minutes.Resulting solution is concentrated in vacuo, the purified silica gel column chromatography of residue Method and with ethyl acetate/petroleum ether (1:10) elute.Title compound (100mg, 83%) is generated, is yellow solid.LC-MS (ES,m/z):381[M+H]+。
Step 2：Synthesize 5- cyclopropane acylamino-s -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines -3- Base] acetenyl] phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 2- (3- bromophenyls) -5- cyclopropane acylamino- -1,3-thiazoles -4- first Sour ethyl ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (100mg, 87%), it is white solid.LC-MS(ES,m/z):440[M+H]+.Step 3：Synthesize (R) -5- (cyclopropanecarbonyl amino) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 5- cyclopropane acylamino-s -2- (3- [2- [(3R) -3- hydroxyl -1- first Base -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) -1,3-thiazoles -4- carboxylates and ammonia reacts, obtain title compound Thing (35.4mg, 25%), it is white solid.LC-MS(ES,m/z):425[M+H]+.1H NMR(300MHz,CD3OD):δ7.98 (s, 1H), 7.85 (d, J=7.5Hz, 1H), 7.43-7.33 (m, 2H), 3.44-3.38 (m, 2H), 2.98 (s, 3H), 2.60- 2.46(m,1H),2.26-2.17(m,1H),1.90-1.78(m,1H),0.98-0.89(m,4H)。
Embodiment 64
Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (methoxyl groups Methyl) thiazole -4-carboxamide
Step 1：Synthesize 2- bromo- 5- (hydroxymethyl) -1,3- 4-thiazolecarboxylic acid methyl esters
Similar to the operation described in universal method K, the bromo- 5- formoxyls -1,3-thiazoles -4- carboxylic acid methyl esters of 2- and boron hydrogen Change sodium reaction, obtain title compound (2.2g, 73%), be white solid.LC-MS(ES,m/z):252[M+H]+。
Step 2：Synthesize 2- bromo- 5- (methoxy) -1,3- 4-thiazolecarboxylic acid methyl esters
By 2- bromo- 5- (hydroxymethyl) -1,3- 4-thiazolecarboxylic acids methyl esters (1g, 3.967mmol, 1.00 equivalent), hydrogenation Sodium (320mg, 8.001mmol, 2.02 equivalent, 60%), methyl iodide (0.3mL, 4.82mmol, 1.215 equivalent) is in N, N- diformazans Solution in base formamide (40mL) stirs 2 minutes in 0 DEG C.Reactant is quenched with water, and is extracted with ethyl acetate.Merge organic Layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1: 10) elute, obtain title compound (0.2g, 19%), be yellow oil.LC-MS(ES,m/z):266[M+H]+。
Step 3：Synthesize 2- bromo- 5- (methoxy) -1,3- thiazole -4-carboxamides
Similar to the operation described in universal method S, the bromo- 5- of 2- (methoxy) -1,3-thiazoles -4- carboxylic acid methyl esters Reacted with ammonia, obtain title compound (0.19g, 95%), be white solid.LC-MS(ES,m/z):251[M+H]+。
Step 4：Synthesize (R) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- (methoxy) thiazole -4-carboxamide
Similar to the operation described in universal method U, the bromo- 5- of 2- (methoxy) -1,3-thiazoles -4- formamides with (R)-trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title Compound (73.9mg, 25%), it is white solid.LC-MS(ES,m/z):386[M+H]+.1H NMR(300MHz,CD3OD):δ 8.12(s,1H),8.00-7.97(m,1H),7.58-7.46(m,2H),5.08(s,2H),3.51-3.47(m,5H),2.94(s, 3H),2.63-2.57(m,1H),2.37-2.31(m,1H)。
Embodiment 65
Synthesis (R) -4- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) thiazole - 2- formamides
Step 1：Synthesize the bromo- 1,3- thiazoles -2- carboxylic acid methyl esters of 4-
Similar to the operation described in universal method O, 2,4- bis- bromo- 1,3-thiazoles and reaction of carbon monoxide, title is obtained Compound (1.2g, 13%), it is light yellow solid.LC-MS(ES,m/z):222[M+H]+。
Step 2：Synthesize the bromo- 1,3- thiazoles -2- formamides of 4-
Similar to the operation described in universal method S, the bromo- 1,3-thiazoles -2- carboxylic acid methyl esters of 4- react with ammonia, are marked Compound (410mg, 88%) is inscribed, is light yellow solid.LC-MS(ES,m/z):207[M+H]+。
Step 3：Synthesize (R) -4- (the fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) thiazole -2- formamides
Similar to the operation described in universal method U, the bromo- 1,3-thiazoles -2- formamides of 4- and (R)-trifluoro (fluoro- 5- of 2- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtain title compound (46.1mg, 19%), it is white solid.LC-MS(ES,m/z):361[M+H]+.1H NMR(300MHz,CDCl3):δ8.46- 8.43(m,1H),8.18(s,1H),7.52-7.48(m,1H),7.28-7.22(m,1H),3.48-3.45(m,2H),2.94(s, 3H),2.63-2.53(m,1H),2.36-2.29(m,1H)。
Embodiment 66
Synthesize (R) -4- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) -5- methoxyl groups Thiazole -2- formamides
Step 1：Synthesize [(2- methoxyl group -2- oxoethyls) carbamyl] carboxylate
By 2- chloro-2-oxos ethyl acetate (20.1g, 147.216mmol, 1.00 equivalent), 2- amion acetic acid methyl esters Hydrochloride (12.6g, 100.355mmol, 0.68 equivalent), triethylamine (30.3g, 299.437mmol, 2.03 equivalent) are in dichloromethane Solution in alkane (800mL) stirs 4 hours in 25 DEG C.Solution is diluted with water, and is extracted with ethyl acetate.Merge organic layer, through nothing Aqueous sodium persulfate is dried, and is concentrated in vacuo.Residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1:4) elute.Production Title compound (17.5g, 63%) has been given birth to, has been yellow oil.LC-MS(ES,m/z):190[M+H]+。
Step 2：Synthesize 5- methoxyl group -1,3- thiazole -2- carboxylates
By 2- (2- methoxyl group -2- oxos acetylamino) ethyl acetate (5g, 26.432mmol, 1.00 equivalent), five sulphur It is small in 110 DEG C of stirrings 12 to change solution of two phosphorus (6.45g, 29.018mmol, 1.10 equivalent) in 1,4- dioxanes (150mL) When.Remove solid, filter vacuum concentration.Residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1:4) wash It is de-, title compound (0.24g, 5%) is obtained, is brown oil.LC-MS(ES,m/z):188[M+H]+。
Step 3：Synthesize the bromo- 5- methoxyl groups -1,3- thiazoles -2- carboxylates of 4-
By 5- methoxyl group -1,3- thiazole -2- carboxylates (188mg, 1.004mmol, 1.00 equivalent), N- bromine succinyls Solution of the imines (356mg, 2.00mmol, 1.99 equivalent) in acetonitrile (20mL) stirs 4 hours in 20 DEG C.Resulting solution vacuum Concentration, residue purify through silica gel column chromatography and with ethyl acetate/petroleum ethers (1:3) elute.Generate title compound (200mg, 75%), it is yellow solid.LC-MS(ES,m/z):266[M+H]+。
Step 4：Synthesis 4- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- methoxyl group -1,3- thiazole -2- carboxylates
Similar to the operation described in universal method U, the bromo- 5- methoxyl groups -1,3-thiazoles -2- carboxylates of 4- and (R) - Trifluoro (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) phenyl) boric acid nak response, obtains title compound Thing (84mg, 28%), it is yellow solid.LC-MS(ES,m/z):401[M+H]+。
Step 5：Synthesis 4- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] phenyl) - 5- methoxyl group -1,3- thiazole -2- formamides
Similar to the operation described in universal method S, 4- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] phenyl) -5- methoxyl groups -1,3-thiazoles -2- carboxylates and ammonia reacts, obtain title compound (28.3mg, 36%), it is white solid.LC-MS(ES,m/z):372[M+H]+.1H NMR(400MHz,CD3OD):δ8.17(s, 1H), 8.09-8.08 (d, J=7.2Hz, 1H), 7.44-7.38 (m, 2H), 4.20 (s, 3H), 3.54-3.47 (m, 2H), 2.95 (s,3H),2.64-2.58(m,1H),2.37-2.30(m,1H)。
Embodiment 67
Synthesize (R) -4- (difluoromethyl) -1- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) benzene Base) -1H- pyrazole-3-formamides
Step 1：Synthesize 1- (3- bromophenyls) -4- methyl isophthalic acid H- pyrazoles -3- carboxylates
Similar to the operation described in universal method C, 4- methyl isophthalic acid H- pyrazoles -3- carboxylates and 3- bromophenylboronic acids Reaction, obtains title compound (6.24g, 67%), is white solid.LC-MS(ES,m/z):309[M+H]+。
Step 2：Synthesize 1- (3- bromophenyls) -4- (two bromomethyls) -1H- pyrazoles -3- carboxylates
By 1- (3- bromophenyls) -4- methyl isophthalic acid H- pyrazoles -3- carboxylates, (1.236g, 3.998mmol, 1.00 work as Amount), (2.136g, 12.00mmol, 3.00 ought for AIBN (262.7mg, 1.60mmol, 0.40 equivalent) and N- bromines succinimide Amount) solution in carbon tetrachloride (100mL) stirs 12 hours in 80 DEG C.Solution is diluted with water, and is extracted with ethyl acetate.Merge Organic layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies and used ethyl acetate/petroleum ether through silica gel column chromatography (1:10) elute, obtain title compound (1.99g, thick), be light yellow solid.LC-MS(ES,m/z):465[M+H]+。
Step 3：Synthesize 1- (3- bromophenyls) -4- formoxyl -1H- pyrazoles -3- carboxylates
To 1- (3- bromophenyls) -4- (two bromomethyls) -1H- pyrazoles -3- carboxylates (1.167g, 2.499mmol, 1.00 equivalents) silver nitrate (1.062g, 6.252mmol, 1.00 equivalent) is added in solution in 1,4- dioxanes (10mL) exists Solution in water (4mL).Resulting solution stirs 12 hours in 70 DEG C, is then diluted with water, is extracted with ethyl acetate.Merge organic Layer, through anhydrous sodium sulfate drying, it is concentrated in vacuo.Residue purifies through silica gel column chromatography and with ethyl acetate/petroleum ether (1: 10) elute.Title compound (613mg, 76%) is generated, is light yellow solid.LC-MS(ES,m/z):323[M+H]+。
Step 4：Synthesize 1- (3- bromophenyls) -4- (difluoromethyl) -1H- pyrazoles -3- carboxylates
Similar to the operation described in universal method L, 1- (3- bromophenyls) -4- formoxyl -1H- pyrazoles -3- formic acid ethyls Ester reacts with double (2- methoxy ethyls) amino sulfur trifluorides, obtains title compound (539mg, 82%), is white solid. LC-MS(ES,m/z):345[M+H]+。
Step 5：Synthesize 1- (3- bromophenyls) -4- (difluoromethyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method S, 1- (3- bromophenyls) -4- (difluoromethyl) -1H- pyrazoles -3- formic acid Ethyl ester reacts with ammonia, obtains title compound (493mg, 75%), is white solid.LC-MS(ES,m/z):316[M+H]+。
Step 6：Synthesize 4- (difluoromethyl) -1- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] Acetenyl] phenyl) -1H- pyrazole-3-formamides
Similar to the operation described in universal method G, 1- (3- bromophenyls) -4- (difluoromethyl) -1H- pyrazoles -3- formyls Amine and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (89.1mg, 18%), are White solid.LC-MS(ES,m/z):375[M+H]+.1H NMR(300MHz,CD3OD):δ8.73-8.72(m,1H),8.09- 8.08(m,1H),7.97-7.93(m,1H),7.58-7.14(m,3H),3.54-3.50(m,2H),2.96(s,3H),2.66- 2.58(m,1H),2.39-2.30(m,1H)。
Embodiment 68
Synthesize (R) -2- (5- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) -2- methoxyphenyls) Thiazole -4-carboxamide
Step 1：Synthesize 2- (the bromo- 2- methoxyphenyls of 5-) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method M, the bromo- 1,3-thiazoles -4- carboxylates of 2- and the bromo- 2- methoxyl groups of 5- Phenylboric acid reacts, and obtains title compound (381mg, 33%), is white solid.LC-MS(ES,m/z):342[M+H]+。
Step 2：Synthesize 2- (5- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases] acetenyl] -2- first Phenyl) -1,3- 4-thiazolecarboxylic acid ethyl esters
Similar to the operation described in universal method G, 2- (the bromo- 2- methoxyphenyls of 5-) -1,3-thiazoles -4- formic acid ethyls Ester and (R) -3- acetenyl -3- hydroxyl -1- methylpyrrolidin- 2- reactive ketones, obtain title compound (279mg, 66%), for Huang Color oil.LC-MS(ES,m/z):401[M+H]+。
Step 3：Synthesize (R) -2- (5- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidine -3- bases) acetenyl) -2- methoxyl groups Phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method S, 2- (5- [2- [(3R) -3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls] acetenyl] -2- methoxyphenyls) -1,3-thiazoles -4- carboxylates and ammonia reacts, obtain title compound (35.8mg, 13%), it is white solid.LC-MS(ES,m/z):372[M+H]+.1H NMR(300MHz,CD3OD):δ8.61(s, 1H), 8.27 (s, 1H), 7.60-7.56 (m, 1H), 7.23 (d, J=8.7Hz, 1H), 4.11 (s, 3H), 3.57-3.45 (m, 2H),2.95(s,3H),2.65-2.57(m,1H),2.37-2.28(m,1H)。
Embodiment 69
Synthesis (R) -5- (3,3- difluoro cyclobutane formamido group) -2- (3- ((3- hydroxyl -1- methyl -2- oxo-pyrrolidines - 3- yls) acetenyl) phenyl) thiazole -4-carboxamide
Step 1：Synthesize (R) -5- (3,3- difluoro cyclobutane formamido group) -2- (3- ((3- hydroxyl -1- methyl -2- oxos Pyrrolidin-3-yl) acetenyl) phenyl) thiazole -4-carboxamide
Similar to the operation described in universal method B, 5- amino -2- (3- [2- [(3R) -3- hydroxyl -1- methyl -2- oxos Pyrrolidin-3-yl] acetenyl] phenyl) -1,3-thiazoles -4- formamides and 3,3- difluoro cyclobutane -1- formic acid reacts, marked Compound (45mg, 17%) is inscribed, is pale solid.LC-MS(ES,m/z):475[M+H]+.1H NMR(300MHz,CD3OD): δ8.12(s,1H),7.99-7.96(m,1H),7.57-7.46(m,2H),3.55-3.47(m,2H),3.37-3.34(m,1H), 2.98(s,3H),2.94-2.87(m,4H),2.66-2.61(m,1H),2.60-2.34(m,1H)。
Biological examples
NIK enzyme levels are analyzed：(BellBrook is analyzed using Transcreener ADP (adenosine -5 '-diphosphonic acid) Labs the ability of nuclear Factor-Kappa B (NF-kB)-inducible kinase (NIK) catalysis adenosine -5 '-triphosphoric acid (ATP) hydrolysis) has been monitored.Will NIK (0.5nM) is purified as derived from baculovirus infection insect cell expression system with test-compound in 50mM 2- [4- (2- Hydroxyethyl) piperazine -1- bases] 1-3.5 hours are incubated together in ethanesulfonic acid buffer (pH 7.2), the buffer solution contains 10mM MgCl2, 2mM dithiothreitol (DTT)s, 10 μM of ATP, 0.01%Triton X-100,0.1% gamma globulin from ox blood, 1% Dimethyl sulfoxide (DMSO), 7 μ g/mL ADP antibody and 5nM ADP-MR121633 tracers.By adding 20mM 2,2', 2 ", 2 " ' reactant is quenched in-(nitrilo of ethane -1,2- diyls two) tetraacethyl and 0.01%Brij 35.Produced during being reacted used in NIK ADP replace with the tracer of antibody binding, which results in fluorescence polarization reduction, and it uses Fluorescence Correlation Spectroscopy Plus reader (Evotec AG) are measured by the laser excitation at 633nm.NIK inhibitor Equilibrium dissociation constant (Ki) value calculated by active vs. inhibitor concentrations curve using Morrison ' s quadratic equations, its The potential combined closely is illustrated, and also by applying relative to its Michaelis constant (Km) conversion factor, which illustrate Concentration of substrate used in Reverse transcriptase and analysis.For the NIK described in table 2 below, the compound that table 1 is listed has accordingly Inhibiting value (NIK ADP-FP, Ki, unit is micromole).
Cell experiment：Several experiments be have developed to describe the cytoactive of NIK inhibitor.
(1) can be used for describing whether test-compound can be deposited via NIK suppression to suppress NF-kB signals without influenceing cell First analysis living.In this analysis, human embryo kidney 293 cells are induced with the tetracycline containing cytomegalovirus promoter NIK DNA constructs add two kinds of reporter molecule DNA constructs to carry out stable transfection.A kind of reporter molecule is from ELAM-1 genes NF-kB response elements three repeat units control under encode firefly luciferase, reflect NIK active waters in cell It is flat, and other reporters constructive expression Renilla fluoresceins under the control of herpes simplex virus thymidine kinase promoter Enzyme, the general measurement as cell survival.Cell is being contained into 1 μ together with the compound (final 0.2%DMSO) of various concentrations Cultivate 24 hours in the culture medium of g/mL Doxycyclines and the hyclone (Clontech) of 10%tet- approvals, then use Dual Glo Luciferase Assay Systems (Promega), according to seller scheme detect reporter molecule signal.
(2) second jacket cells analyze the suppression for being used to define NIK inhibitor NF-kB signal transductions non-classical to classical vs. The selectivity of system, it is depended on is determined using core transposition of the high intension cell imaging to p52 (NF-kB2) and REL-A (p65) Amount.Analyzed for p52 (non-classical NF-kB signal transductions) core transposition, the compound of HeLa cell various concentrations is (final 0.2%DMSO) handled in the culture medium containing 10% hyclone, then with 100ng/mL anti-lymphotoyin beta receptors Antibody (R＆D Systems) stimulates 5 hours.In REL-A cores transposition analysis, by HeLa cells and compound (final 0.2% DMSO) cultivated together in the culture medium containing 10% hyclone 4.5 hours, they are then used into 10ng/mL neoplasm necrosises The factor (TNF)-α (R＆D Systems) is stimulated 30 minutes.Cell is fixed with 4% paraformaldehyde, by adding in phosphoric acid buffer 0.1%Triton X-100 in salt solution carry out permeableization processing, then p52 antibody (Millipore) anti-with 2ug/mL or 400ng/Ml anti-REL-A (p65) antibody (Santa Cruz Biotechnology) incubates together.Finally, by cell with The secondary antibody (Invitrogen) and DRAQ5DNA traces (Biostatus) of Alexa488- marks are cultivated together.Using Opera reader (Perkin Elmer) are imaged, and data are carried out by means of Acapella softwares (Perkin Elmer) Analysis.P52 the or REL-A transpositions for entering core are quantified by the ratio of core and cytoplasm signal intensity.In these cells 50% suppresses required inhibitor concentration (IC in analysis50Value) derived by the curve of signal vs. inhibitor concentrations.For NIK p52 transpositions are analyzed, and the compound listed in table 1A and 1B has corresponding inhibiting value (IC50, micromole), as given in table 2 Go out like that.
Table 2

Claims (33)

1. formula (I) compound or its stereoisomer, dynamic isomer, solvate, prodrug or salt:
Wherein：
Ring A is monocyclic or condensed-bicyclic；
Q is N or C, wherein when Q is N, then A1Key between Q is not double bond and Q and A4Between key be not double bond；
A1It is NR1、N、S、CR1Or CHR1；
A2It is NR2、N、O、S、CR2Or CHR2；
A3It is N or C；
A4It is N；And
A1-A4In one, two or three be N, wherein:
R1It is each independently selected from H, halogen, NRaRb、NHC(O)NRaRb、NHS(O)2CH3、C1-C3Alkyl, C3-C7Cycloalkyl, C1- C3Alkoxy and 3-11 circle heterocycles bases, wherein R1Alkyl optionally by F, OH, CN, SH, C1-C3Alkoxy or 3-11 circle heterocycles bases Substitution；R1Cycloalkyl optionally by F, OH, CN, SH, CH3Or CF3Substitution；R1Alkoxy optionally substituted by F, OH, CN or SH； And R1Heterocyclic radical optionally by F, OH, CN, SH, CF3Or C1-C3Alkyl substitutes,
R2It is each independently selected from H, NRaRb、C1-C6Alkyl, C3-C7Cycloalkyl, C1-C6Alkoxy, phenyl and 3-11 circle heterocycles Base, wherein R2Optionally by RcSubstitution；Or
R1And R2The atom connected together with them is formed selected from C3-C7The ring-type of cycloalkyl, phenyl and 3-11 circle heterocycles bases Group, wherein the cyclic group is optionally by RdSubstitution；
R4Selected from H, C1-C6Alkyl, CH2F and CH2OH；
R5It is 3-11 circle heterocycles bases, optionally by ReOr-C (=O) N (C1-C6Alkyl)2Substitution；Or
R4And R5Formed together optionally by ReSubstituted C3-C11Cycloalkyl or optionally by ReSubstituted 3-11 circle heterocycles bases；
A5-A8One of be N and remaining be CR6Or all CR6；
R6At each occurrence independently selected from H, F, Cl, NH2、NHCH3、N(CH3)2、OH、OCH3、OCHF2、OCH2F、OCF3、 SH、SCH3、SCHF2、SCH2F、CN、CH3、CHF2、CH2F、CH2OH、CF3、NO2And N3；
RaSelected from H and optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substituted C1-C6Alkyl；
RbSelected from H, C1-C6Alkyl, C1-C6Alkoxy, C3-C6Cycloalkyl, C (O) Rg, phenyl and 3-11 circle heterocycles bases, wherein RbCan With optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3Substitution；
RcAnd RdIt is each independently selected from halogen ,-(X1)0-1-CN、-(X1)0-1-NO2、-(X1)0-1-SF5、-(X1)0-1-OH、- (X1)0-1-NH2、-(X1)0-1-N(H)(R1a)、-(X1)0-1-N(R1b)(R1a)、-(X1)0-1-CF3、C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, oxo base ,-(X1)0-1-C1-C6Alkyl ,-(X1)0-1-C3-C10Ring Alkyl ,-O-C3-C10Cycloalkyl ,-(X1)0-1- 3-11 circle heterocycles base ,-(X1)0-1-C6-C10Aryl ,-C (=O) (X1)1-C3-C10Ring Alkyl ,-C (=O) (X1)1- 3-11 circle heterocycles base ,-(X1)0-1- C (=Y1)N(H)(R1a)、-(X1)0-1- C (=Y1)NH2、- (X1)0-1- C (=Y1)N(R1a)(R1b)、-(X1)0-1- C (=Y1)OR1a、-(X1)0-1- C (=Y1)OH、-(X1)0-1- N (H) C (= Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(R1a)、-(X1)0-1-N(R1b) C (=Y1)(H)、-(X1)0-1- N (H) C (=Y1) OR1a、-(X1)0-1-N(R1b) C (=Y1)OR1a、-(X1)0-1-S(O)1-2R1a、-(X1)0-1-N(H)S(O)1-2R1a、-(X1)0-1-N (R1b)S(O)1-2R1a、-(X1)0-1-S(O)0-1N(H)(R1a)、-(X1)0-1-S(O)0-1N(R1b)(R1a)、-(X1)0-1-S(O)0- 1NH2、-(X1)0-1- S (=O) (=NR1b)R1a、-(X1)0-1- C (=Y1)R1a、-(X1)0-1- C (=Y1)H、-(X1)0-1- C (= NOH)R1a、-(X1)0-1- C (=NOR1b)R1a、-(X1)0-1- NHC (=Y1)N(H)(R1a)、-(X1)0-1- NHC (=Y1)NH2、- (X1)0-1- NHC (=Y1)N(R1b)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N(H)(R1a)、-(X1)0-1-N(R1a) C (=Y1)N (R1a)(R1b)、-(X1)0-1-N(R1a) C (=Y1)NH2、-(X1)0-1- OC (=Y1)R1a、-(X1)0-1- OC (=Y1)H、-(X1)0-1- OC (=Y1)OR1a、-(X1)0-1- OP (=Y1)(OR1a)(OR1b)、-(X1)-SC (=Y1)OR1aWith-(X1)-SC (=Y1)N(R1a) (R1b), wherein X1Selected from C1-C6Alkylidene, C1-C6Sub- miscellaneous alkyl, C2-C6Alkenylene, C2-C6Alkynylene, C1-C6Alkylidene epoxide, C3-C7Cycloalkylidene, the sub- heterocyclic radical of 3-11 members and phenylene；R1aAnd R1bIt is each independently selected from C1-C6Alkyl, C1-C6Alkyl halide Base, C1-C6Miscellaneous alkyl, C3-C7Cycloalkyl, (C3-C7Cycloalkylidene) C1-C6Alkyl, 3-11 circle heterocycles base, (the sub- heterocyclic radical of 3-11 members) C1-C6Alkyl, C6Aryl and (C6-C10Arlydene) C1-C6Alkyl, or R1aAnd R1bOptionally combined when being connected with identical nitrogen-atoms Formed comprising the 0-3 other heteroatomic 3-11 circle heterocycles bases selected from N, O and S；Y1It is O, NR1cOr S, wherein R1cBe H or C1-C6Alkyl；Wherein RcOr RdThe arbitrary portion including R of substituent1a、R1bAnd R1cIt is further independently of one another at each occurrence By 0 to 4 RfSubstituent substitutes, described RfSubstituent is selected from halogen, CN, NO2、SF5、OH、NH2、-N(C1-C6Alkyl)2、-NH (C1-C6Alkyl), oxo base, C1-C6Alkyl ,-(C2-C6Alkynylene)-(3-11 circle heterocycles bases, wherein the heterocyclic radical is optionally by Re Substitution), C1-C6Hydroxy alkyl, C1-C6Miscellaneous alkyl, C1-C6Alkoxy, C1-C6Alkyl sulfenyl, C3-C7Cycloalkyl, 3-11 circle heterocycles Base ,-C (=O) N (H) (C1-C6Alkyl) ,-C (=O) N (C1-C6Alkyl)2,-C (=O) NH2,-C (=O) OC1-C6Alkyl ,-C (= O) OH ,-N (H) C (=O) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) (C1-C6Alkyl) ,-N (H) C (=O) OC1-C6Alkane Base ,-N (C1-C6Alkyl) C (=O) OC1-C6(halo) alkyl ,-S (O)1-2C1-C6Alkyl ,-N (H) S (O)1-2C1-C6Alkyl ,-N (C1-C6Alkyl) S (O)1-2C1-C6Alkyl ,-S (O)0-1N(H)(C1-C6Alkyl) ,-S (O)0-1N(C1-C6Alkyl)2、-S(O)0- 1NH2,-C (=O) C1-C6Alkyl ,-C (=O) C3-C7Cycloalkyl ,-C (=NOH) C1-C6Alkyl ,-C (=NOC1-C6Alkyl) C1-C6 Alkyl ,-NHC (=O) N (H) (C1-C6Alkyl) ,-NHC (=O) N (C1-C6Alkyl)2,-NHC (=O) NH2、-N(C1-C6Alkyl) C (=O) N (H) (C1-C6Alkyl) ,-N (C1-C6Alkyl) C (=O) NH2,-OC (=O) C1-C6Alkyl ,-OC (=O) OC1-C6Alkane Base ,-OP (=O) (OC1-C6Alkyl)2,-SC (=O) OC1-C6Alkyl and-SC (=O) N (C1-C6Alkyl)2, wherein RfAny alkane Base section is optionally optionally substituted by halogen；
ReSelected from halogen, OH, C1-C6Alkyl and oxo base；And
RgSelected from C1-C6Alkyl and C3-C6Cycloalkyl, wherein RgCan be optionally by C1-C3Alkoxy, F, OH, CN, SH, CH3Or CF3 Substitution；
Condition is that the compound is not the compound selected from compound 1x -199x.
2. the compound of claim 1 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein Q are C, And the compound has formula (II):
Its middle ring A, A1、A2、A3、A4、A5、A6、A7、A8、R4And R5As defined in claim 1.
3. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, its middle ring A is monocyclic.
4. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A1It is N or CHR1。
5. the compound of claim 4 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A1Be N, A2It is S and A3It is C.
6. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A2It is N, O or CHR2。
7. the compound or stereoisomer of claim 6, dynamic isomer, solvate, prodrug or salt, wherein A1It is S, A2 It is N and A3It is C.
8. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A2It is O.
9. the compound of claim 8 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A1It is CR1、A2It is O and A3It is C.
10. the compound of claim 1 or claim 2 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A1It is NR1, S or CR1；And A2It is NR2, S or CR2。
11. the compound of claim 10 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, its middle ring A It is monocyclic.
12. the compound of claim 11 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A1It is NR1。
13. the compound of claim 12 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A2It is CR2And A3It is C.
14. the compound of claim 11 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A1It is CR1。
15. the compound of claim 14 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A2It is CR2And A3It is N.
16. the compound of claim 10 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A1It is S。
17. the compound of claim 11 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein A2It is CR2And A3It is C.
18. the compound of any one of claim 1 to 17 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein A5、A6、A7And A8It is CR independently of one another6, wherein R6At each occurrence independently selected from H, F, OCH3And CH3, and n It is 0.
19. the compound of any one of claim 1 to 17 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, its middle ring B is substituted phenyl and Q is C；And the compound has formula (III):
Wherein n is 0,1 or 2, R6It is each independently selected from F, Cl, OCH3、CH3And CF3。
20. the compound of any one of claim 1 to 19 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein R4And R5Formed optionally by R together with the carbon connected with themeSubstituted C8-C10Cycloalkyl.
21. the compound of any one of claim 1 to 19 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein R4And R5Formed optionally by R together with the carbon connected with themeSubstituted 4-9 circle heterocycles bases.
22. the compound of any one of claim 1 to 19 or its stereoisomer, dynamic isomer, solvate, prodrug or Salt, wherein following part:
It is defined as
Wherein:
A9It is O, NR11Or CR11R12, wherein R11And R12It is each independently selected from H, halogen, OH and C1-C3Alkyl；
R7And R8It is each independently selected from halogen, OH, C1-C6Alkyl, or R7And R8Formation=O together, and
R9And R10It is each independently selected from H and Re, or R9And R10The atom connected together with them is formed optionally by ReSubstitution C5-C6Cycloalkyl or optionally by ReSubstituted 5-6 circle heterocycles bases.
23. the compound of claim 22 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein R7With R8Formation=O together；R9And R10Individually H；And A9It is NR11, wherein R11It is C1-C3Alkyl.
24. the compound of claim 22 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein described PartIt is
25. the compound of claim 1 or its stereoisomer, dynamic isomer, solvate, prodrug or salt, wherein described Compound is selected from：
It is compound or its stereoisomer, dynamic isomer comprising any one of claim 1 to 25, molten 26. pharmaceutical composition Agent compound or prodrug or its officinal salt and pharmaceutical acceptable carrier, diluent or excipient.
27. used in therapy such as the compound or pharmaceutical composition of any one of claim 1 to 26.
28. such as purposes of the compound or pharmaceutical composition of any one of claim 1 to 26 in inflammatory conditions are treated.
29. the compound or pharmaceutical composition such as any one of claim 1 to 26 are preparing the medicament for being used for treating inflammatory conditions In purposes.
30. the purposes of claim 28 or 29, wherein the inflammatory conditions are selected from lupus, systemic loupus erythematosus, COPD, nose Inflammation, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and graft rejection.
31. treating the method for inflammatory conditions in patients, this method is included to patient using effective dose such as claim 1 to 26 The compound or pharmaceutical composition of any one.
32. the method for claim 31, wherein the inflammatory conditions are selected from lupus, systemic loupus erythematosus, COPD, rhinitis, more Hair property hardening, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and graft rejection.
33. the preparation method of formula (I) compound of claim 1,
Wherein Q, A1-A8、R4And R5As defined in any one of claim 1 to 25, this method includes：
Make in the presence of (a) (i) palladium (0) catalyst or (a) (ii) copper catalyst and (b) alkali, under Suzuki reaction conditions Formula (A) compound：
Wherein X is Cl, Br or I,
Contacted with formula (B) compound,
Wherein [M] is boric acid, borate or trifluoroborate,
Obtain formula (I) compound.
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CN112209916A (en) * 2020-10-23 2021-01-12 河北师范大学 Ruthenium complex, preparation method and catalytic application
CN112209916B (en) * 2020-10-23 2021-06-01 河北师范大学 Ruthenium complex, preparation method and catalytic application

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