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HK1211922B - Pyrazolyl quinoxaline kinase inhibitors - Google Patents

Pyrazolyl quinoxaline kinase inhibitors Download PDF

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Publication number
HK1211922B
HK1211922B HK15112661.6A HK15112661A HK1211922B HK 1211922 B HK1211922 B HK 1211922B HK 15112661 A HK15112661 A HK 15112661A HK 1211922 B HK1211922 B HK 1211922B
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HK
Hong Kong
Prior art keywords
substituted
alkyl
radical
group
hydroxy
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HK15112661.6A
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Chinese (zh)
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HK1211922A1 (en
Inventor
Saxty Gordon
William Murray Christopher
Berdini Valerio
Ebai Besong Gilbert
Charles Frederick Hamlett Christopher
Norbert Johnson Christopher
John Woodhead Steven
Reader Michael
Charles Rees David
Anne Mevellec Laurence
René Angibaud Patrick
Jean Edgard Freyne Eddy
Cornelis Hortense Govaerts Tom
Erwin Edmond Weerts Johan
Pietro Suren Perera Timothy
Arnodus Hendrika Joseph Gilissen Ronaldus
Wroblowski Berthold
Fernand Armand Lacrampe Jean
Papanikos Alexandra
Alexis Georges Querolle Olivier
Therésè Jeanne Pasquier Elisabeth
Noëlle Constance Pilatte Isabelle
Ghislain André Bonnet Pascal
Constant Johan Embrechts Werner
Akkari Rhalid
Meerpoel Lieven
Original Assignee
Astex Therapeutics Limited
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Priority claimed from GB201007286A external-priority patent/GB201007286D0/en
Application filed by Astex Therapeutics Limited filed Critical Astex Therapeutics Limited
Publication of HK1211922A1 publication Critical patent/HK1211922A1/en
Publication of HK1211922B publication Critical patent/HK1211922B/en

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Description

Pyrazolyl quinoxaline kinase inhibitors
The application is a divisional application of an invention patent application with the application number of 201180021785.5 and the application date of 2011, 4 and 28 and the name of the invention is 'pyrazolyl quinoxaline kinase inhibitor'.
Technical Field
The present invention relates to novel quinoxaline derived compounds, pharmaceutical compositions containing said compounds, processes for preparing said compounds and the use of said compounds in the treatment of diseases, for example cancer.
Background
WO 2006/092430, WO 2008/003702, WO 01/68047, WO 2005/007099, WO 2004/098494, WO 2009/141386, WO 2004/030635, WO 2008/141065, WO 2011/026579, WO 2011/028947 and WO 00/42026, each of which discloses a series of heterocyclyl derivatives.
Disclosure of Invention
According to a first aspect of the present invention there is provided a compound of formula (I):
(I)
including any tautomeric or stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, C1-6Alkyl radical, C2-4Alkenyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, cyano C1-4Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl by-P (= O) (OH)2Substituted C1-6Alkyl or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group;
each R1aIndependently selected from: hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino or-NH (C)3-8Cycloalkyl) substituted C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl and C substituted by one or more fluorine atoms1-4An alkyl group;
each R2Independently selected from hydroxy, halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy-halogeno-C1-4Alkyl, hydroxy-halogeno-C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl, halo C1-4Alkoxy radical C1-4Alkyl radical, each of which is C1-4C wherein alkyl may be optionally substituted by one or two hydroxy groups1-4Alkoxy radical C1-4Alkyl, hydroxy-halogeno-C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkyl radical, by-C (= O) -R13Substituted C1-4Alkyl radical, by R13Substituted C1-4Alkoxy radical, by-C (= O) -R13Substituted C1-4Alkoxy, -C (= O) -R13is-NR7R8Substituted C1-4Alkyl radical, by-C (= O) -NR7R8Substituted C1-4Alkyl radical, by-NR7R8Substituted C1-4Alkoxy radical, by-C (= O) -NR7R8Substituted C1-4Alkoxy, -NR7R8and-C (= O) -NR7R8(ii) a Or when two R are2When groups are attached to adjacent carbon atoms, they may be joined together to form radicals of the formula:
-O-(C(R17)2)p-O-；
-X-CH = CH-; or
-X-CH = N-; wherein R is17Represents hydrogen or fluorine, p represents 1 or 2, X represents O or S;
R3represents hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy radicals, by-NR10R11Substituted C1-6Alkoxy radical, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, optionally substituted by-O-C (= O) -C1-6Alkyl-substituted halogeno C1-6Alkyl, optionally substituted by-O-C (= O) -C1-6Alkyl-substituted hydroxy C1-6Alkyl, hydroxy C2-6Alkenyl, hydroxy C2-6Alkynyl, hydroxy-halogeno-C1-6Alkyl, cyano C1-6Alkyl, C substituted by carboxyl1-6Alkyl radical, substituted by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radical, quilt C1-6Alkoxy radical C1-6alkyl-O-C (= O) -substituted C1-6Alkyl radical, quilt C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl radical, substituted by-O-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6The alkyl group may be optionally substituted by oneOr two hydroxy groups or by-O-C (= O) -C1-6Alkyl substituted C1-6Alkoxy radical C1-6Alkyl radical, quilt C1-6Alkoxy-substituted C2-6Alkenyl radical, by C1-6Alkoxy-substituted C2-6Alkynyl radical, by R9Substituted and optionally substituted by-O-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkenyl radical, by R9Substituted C2-6Alkynyl radicals, by-NR10R11Substituted C1-6Alkyl radical, by-NR10R11Substituted C2-6Alkenyl radicals, by-NR10R11Substituted C2-6Alkynyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12is-C (= O) -NR10R11Substituted C1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, R13quilt-P (= O) (OH)2Substituted C1-6Alkyl or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group;
R4and R5Each independently represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxyhalogeno C1-6 alkyl, wherein each C1-6 alkyl group may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR4R5Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-6Alkyl radical, R13Or by R13Substituted C1-6An alkyl group;
R6represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C is3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4-to 7-membered monocyclic heterocyclyl, optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: cyano radicals, C1-6Alkyl, cyano C1-6Alkyl, hydroxy, carboxyl, hydroxy C1-6Alkyl, halogen, halogeno C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-O-C (= O) -, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is represented by-S (= S)O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R7and R8Each independently represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl or C1-6Alkoxy radical C1-6An alkyl group;
R9represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, naphthyl, or a 3-to 12-membered monocyclic or bicyclic heterocyclic group containing at least one heteroatom selected from N, O or S, said C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, naphthyl or 3-to 12-membered monocyclic or bicyclic heterocyclyl are each optionally and each independently substituted with 1,2,3, 4 or 5 substituents: each substituent is independently selected from: = O, C1-4Alkyl, hydroxy, carboxyl, hydroxy C1-4Alkyl, cyano C1-4Alkyl radical, C1-4alkyl-O-C (= O) -, by C1-4alkyl-O-C (= O) -substituted C1-4Alkyl radical, C1-4alkyl-C (= O) -, in which each C is1-4C wherein alkyl may be optionally substituted by one or two hydroxy groups1-4Alkoxy radical C1-4Alkyl, halogen, halogeno C1-4Alkyl, hydroxy-halogeno-C1-4Alkyl, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-4Alkyl radical, by-C (= O) -NR14R15Substituted C1-4Alkyl radical, C1-4Alkoxy, -S (= O)2-C1-4Alkyl, -S (= O)2-halo C1-4Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-NR14R15Substituted C1-4Alkyl radicalquilt-NH-S (= O)2-C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-4Alkyl radical, R13，-C(=O)-R13Is by R13Substituted C1-4Alkyl, optionally substituted by R16Substituted phenyl, wherein phenyl is optionally substituted with R16Substituted phenyl radicals C1-6Alkyl, a 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl is optionally substituted by R16Substitution;
or when R is9When the two substituents of (a) are attached to the same atom, they may be taken together to form a 4-to 7-membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S;
R10and R11Each independently represents hydrogen, carboxyl, C1-6Alkyl, cyano C1-6Alkyl radical, by-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl, -C (= O) -R6，-C(=O)-C1-6Alkyl, -C (= O) -hydroxy C1-6Alkyl, -C (= O) -halo C1-6Alkyl, -C (= O) -hydroxyhaloC1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted byC1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R12represents hydrogen or optionally substituted by C1-4Alkoxy-substituted C1-4An alkyl group;
R13represents C3-8Cycloalkyl or a saturated 4-to 6-membered monocyclic heterocyclyl group containing at least one heteroatom selected from N, O or S, wherein said C is3-8The cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1,2 or 3 substituents each independently selected from halogen, hydroxy, C1-6Alkyl, -C (= O) -C1-6Alkyl radical, C1-6Alkoxy or-NR14R15；
R14And R15Each independently represents hydrogen, or halogeno C1-4Alkyl, or C optionally substituted by a substituent selected from the group consisting of1-4Alkyl groups: hydroxy radical, C1-4Alkoxy, amino or mono-or di (C)1-4Alkyl) amino;
R16represents hydroxy, halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, -NR14R15or-C (= O) NR14R15；
An N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
In one embodiment, there is provided formula (I)0) The compound of (1):
including any stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, C1-6Alkyl radical, C2-4Alkenyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxyhalogeno C1-6 alkyl, wherein each C1-6 alkyl group may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl by-P (= O) (OH)2Substituted C1-6Alkyl, or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group;
each R2Independently selected from halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy-halogeno-C1-4Alkyl, hydroxy-halogeno-C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl, halo C1-4Alkoxy radical C1-4Alkyl radical, each of which is C1-4The alkyl group may be optionally substitutedOne or two hydroxy-substituted C1-4Alkoxy radical C1-4Alkyl, hydroxy-halogeno-C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkyl radical, by-C (= O) -R13Substituted C1-4Alkyl radical, by R13Substituted C1-4Alkoxy radical, by-C (= O) -R13Substituted C1-4Alkoxy, -C (= O) -R13is-NR7R8Substituted C1-4Alkyl radical, by-C (= O) -NR7R8Substituted C1-4Alkyl radical, by-NR7R8Substituted C1-4Alkoxy radical, by-C (= O) -NR7R8Substituted C1-4Alkoxy, -NR7R8or-C (= O) -NR7R8；
R3Represents hydroxy, C1-6Alkoxy, hydroxy C1-6Alkoxy radicals, by-NR10R11Substituted C1-6Alkoxy radical, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy C2-6Alkenyl, hydroxy C2-6Alkynyl, hydroxy-halogeno-C1-6Alkyl, cyano C1-6Alkyl, C substituted by carboxyl1-6Alkyl radical, substituted by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radical, quilt C1-6Alkoxy radical C1-6alkyl-O-C (= O) -substituted C1-6Alkyl radical, quilt C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl radical, substituted by-O-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, quilt C1-6Alkoxy-substituted C2-6Alkenyl radical, by C1-6Alkoxy-substituted C2-6Alkynyl radical, by R9Substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkenyl radical, by R9Substituted C2-6Alkynyl radicals, by-NR10R11Substituted C1-6Alkyl radical, by-NR10R11Substituted C2-6Alkenyl radicals, by-NR10R11Substituted C2-6Alkynyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12is-C (= O) -NR10R11Substituted C1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, R13quilt-P (= O) (OH)2Substituted C1-6Alkyl, or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group;
R4and R5Independently represent hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-6Alkyl radical, R13Or by R13Substituted C1-6An alkyl group;
R6represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C3-8 cycloalkyl, C3-8 cycloalkenyl, phenyl, 4-to 7-membered monocyclic heterocyclyl is optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: cyano radicals, C1-6Alkyl, cyano C1-6Alkyl, hydroxy, carboxyl, hydroxy C1-6Alkyl, halogen, halogeno C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-O-C (= O) -, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR4R5Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R7and R8Independently represent hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl or C1-6Alkoxy radical C1-6An alkyl group;
R9represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, naphthyl, or a 3-to 12-membered monocyclic or bicyclic heterocyclic group containing at least one heteroatom selected from N, O or S, said C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, naphthyl, or 3-to 12-membered monocyclic or bicyclic heterocyclyl are each optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: = O, C1-4Alkyl, hydroxy, carboxyl, hydroxy C1-4Alkyl, cyano C1-4Alkyl radical, C1-4alkyl-O-C (= O) -, by C1-4alkyl-O-C (= O) -substituted C1-4Alkyl radical, C1-4alkyl-C (= O) -, in which each C is1-4C wherein alkyl may be optionally substituted by one or two hydroxy groups1-4Alkoxy radical C1-4Alkyl, halogen, halogeno C1-4Alkyl, hydroxy-halogeno-C1-4Alkyl, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-4Alkyl radical, by-C (= O) -NR14R15Substituted C1-4Alkyl radical, C1-4Alkoxy, -S (= O)2-C1-4Alkyl, -S (= O)2-halo C1-4Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-NR14R15Substituted C1-4Alkyl radical, by-NH-S (= O)2-C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-halo C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-4Alkyl radical, R13，-C(=O)-R13Is by R13Substituted C1-4Alkyl, optionally substituted by R16Substituted phenyl, wherein phenyl is optionally substituted with R16Substituted phenyl radicals C1-6Alkyl radical ofA 5 or 6 membered aromatic monocyclic heterocyclic group having at least one heteroatom selected from N, O or S, wherein said heterocyclic group is optionally substituted by R16Substitution;
or when R is9When the two substituents of (a) are attached to the same atom, they may be taken together to form a 4-to 7-membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S;
R10and R11Each independently represents hydrogen, C1-6Alkyl, cyano C1-6Alkyl radical, by-NR14R15Substituted C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxyhalogeno C1-6 alkyl, wherein each C1-6 alkyl group may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl, -C (= O) -R6，-C(=O)-C1-6Alkyl, -C (= O) -hydroxy C1-6Alkyl, -C (= O) -halo C1-6Alkyl, -C (= O) -hydroxyhaloC1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R12represents hydrogen or optionally substituted by C1-4Alkoxy-substituted C1-4An alkyl group;
R13represents C3-8Cycloalkyl or a saturated 4-to 6-membered monocyclic heterocycle containing at least one heteroatomA heteroatom selected from N, O or S, wherein said C is3-8The cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1,2 or 3 substituents each independently selected from halogen, hydroxy, C1-6Alkyl, -C (= O) -C1-6Alkyl radical, C1-6Alkoxy or-NR14R15；
R14And R15Each independently represents hydrogen, or halogeno C1-4Alkyl, or C optionally substituted by a substituent selected from the group consisting of1-4Alkyl groups: hydroxy radical, C1-4Alkoxy, amino or mono-or di (C)1-4Alkyl) amino;
R16represents hydroxy, halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, -NR14R15or-C (= O) NR14R15；
An N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
WO 2006/092430, WO 2008/003702, WO 01/68047, WO 2005/007099, WO 2004/098494, WO 2009/141386, WO 2004/030635, WO 2008/141065, WO 2011/026579, WO 2011/028947 and WO 00/42026, each of which discloses a series of heterocyclyl derivatives.
Detailed Description
Unless the context indicates otherwise, formula (I) in all sections of this document (including uses, methods and other aspects of the invention) includes all other sub-formulae (e.g., I '″, I') defined herein0, I0’,I0'',I0' ' '), subgroupings, preferences, embodiments and examples.
The prefix "C" as used hereinx-y"(wherein x and y are integers) refers to the number of carbon atoms in a given group. Thus, C1-6Alkyl having 1 to 6 carbon atoms, C3-6Cycloalkyl having 3 to 6 carbon atoms, C1-4Alkoxy having 1 to 4 carbonsAtoms, and the like.
As used herein, 'halo' or 'halogen' refers to a fluorine, chlorine, bromine or iodine atom.
The term 'C' as used herein as a group or part of a group1-4Alkyl 'or' C1-6Alkyl' refers to a straight or branched chain saturated hydrocarbon group containing 1 to 4 or 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
The term 'C' as used herein as a group or part of a group2-4Alkenyl 'or' C2-6Alkenyl' refers to a straight or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon double bond.
The term 'C' as used herein as a group or part of a group2-4Alkynyl 'or' C2-6Alkynyl' refers to a straight or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and containing a carbon-carbon triple bond.
The term 'C' as defined herein as a group or part of a group1-4Alkoxy 'or' C1-6Alkoxy' means-O-C1-4Alkyl or-O-C1-6Alkyl radical, wherein C1-4Alkyl and C1-6Alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, and the like.
The term 'C' as defined herein as a group or part of a group1-4Alkoxy radical C1-4Alkyl 'or' C1-6Alkoxy radical C1-6Alkyl' means C1-4alkyl-O-C1-4Alkyl or C1-6alkyl-O-C1-6Alkyl radical, wherein C1-4Alkyl and C1-6Alkyl is as defined herein. Examples of such groups include methoxyethyl, ethoxyethyl, propoxymethyl, butoxypropyl, and the like.
Herein makeBy the term ` C `3-8Cycloalkyl' refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
The term ` C ` as used herein3-8Cycloalkenyl' refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms having a carbon-carbon double bond.
The term 'hydroxy C' as used herein as a group or part of a group1-4Alkyl 'or' hydroxy C1-6Alkyl' means C as defined herein1-4Alkyl or C1-6Alkyl, wherein one or more hydrogen atoms are substituted by hydroxyl. Thus, the term ` hydroxy C `1-4Alkyl 'or' hydroxy C1-6Alkyl' including monohydroxy C1-4Alkyl, monohydroxy C1-6Alkyl and polyhydroxy C1-4Alkyl and polyhydroxy C1-6An alkyl group. One, two, three or more hydrogen atoms may be substituted by hydroxyl groups, so that the hydroxyl group C1-4Alkyl or hydroxy C1-6The alkyl group may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.
The term 'halo C' as used herein as a group or part of a group1-4Alkyl 'or' halo C1-6Alkyl' means C as defined herein1-4Alkyl or C1-6Alkyl, wherein one or more hydrogen atoms are substituted by halogen. Thus, the term' halo C1-4Alkyl 'or' halo C1-6Alkyl' including monohalogenated C1-4Alkyl, monohalo C1-6Alkyl and polyhaloC1-4Alkyl and polyhaloC1-6An alkyl group. There may be one, two, three or more hydrogen atoms substituted by halogen, so that there is halo C1-4Alkyl or halo C1-6The alkyl group may have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl groups and the like.
Herein as a group or radicalsThe term 'hydroxyhaloC' as used in part of1-4Alkyl 'or' hydroxy-halogeno-C1-6Alkyl' means C as defined herein1-4Alkyl or C1-6Alkyl, wherein one or more hydrogen atoms are substituted with hydroxyl and one or more hydrogen atoms are substituted with halogen. Thus, the term' hydroxyhaloC1-4Alkyl 'or' hydroxy-halogeno-C1-6Alkyl' means C1-4Alkyl or C1-6An alkyl group in which one, two, three or more hydrogen atoms are substituted with a hydroxyl group and one, two, three or more hydrogen atoms are substituted with a halogen.
The term 'hydroxy C' as used herein as a group or part of a group1-4Alkoxy 'or' hydroxy C1-6Alkoxy' means-O-C1-4Alkyl or-O-C1-6Alkyl radical, wherein C1-4Alkyl and C1-6Alkyl is as described above, and C1-4Alkyl or C1-6One or more hydrogen atoms of the alkyl group are substituted with a hydroxyl group. Thus, the term ` hydroxy C `1-4Alkoxy 'or' hydroxy C1-6Alkoxy' includes monohydroxy C1-4Alkoxy, monohydroxy C1-6Alkoxy and polyhydroxy C1-4Alkoxy and polyhydroxy C1-6An alkoxy group. One, two, three or more hydrogen atoms may be substituted by hydroxyl groups, so that the hydroxyl group C1-4Alkoxy or hydroxy C1-6The alkoxy group may have one, two, three or more hydroxyl groups. Examples of such groups include hydroxymethoxy, hydroxyethoxy, hydroxypropoxy and the like.
The term 'halo C' as used herein as a group or part of a group1-4Alkoxy 'or' halo C1-6Alkoxy' means-O-C as defined herein1-4Alkyl or-O-C1-6Alkyl, wherein one or more hydrogen atoms are substituted by halogen. Thus, the term' halo C1-4Alkoxy 'or' halo C1-6Alkoxy' including monohalo C1-4Alkoxy, monohalo C1-6Alkoxy and polyhaloC1-4Alkoxy and polyhaloC1-6An alkoxy group. Can be provided withOne, two, three or more hydrogen atoms are substituted by halogen, so, halo C1-4Alkoxy or halo C1-6The alkoxy group may have one, two, three or more halogens. Examples of such groups include fluoroethoxy, difluoromethoxy or trifluoromethoxy groups and the like.
The term 'hydroxyhaloC' as used herein as a group or part of a group1-4Alkoxy' means-O-C1-4Alkyl radical, wherein C1-4Alkyl is as defined herein, and wherein one or more hydrogen atoms are substituted with hydroxyl and one or more hydrogen atoms are substituted with halogen. Thus, the term' hydroxyhaloC1-4Alkoxy' means-O-C1-4Alkoxy, wherein one, two, three or more hydrogen atoms are substituted with hydroxy and one, two, three or more hydrogen atoms are substituted with halogen.
The term 'halo C' as used herein as a group or part of a group1-4Alkoxy radical C1-4Alkyl' means C1-4alkyl-O-C1-4Alkyl radical, wherein C1-4Alkyl is as defined herein, wherein one or two C1-4One or more hydrogen atoms of the alkyl group are substituted with a halogen. Thus, the term' halo C1-4Alkoxy radical C1-4Alkyl' means C1-4alkyl-O-C1-4Alkyl radical, one or two of which being C1-4One, two, three or more hydrogen atoms in the alkyl group are substituted by halogen, wherein C1-4Alkyl is as defined herein. Preferably, one C1-4One or more hydrogen atoms in the alkyl group are substituted with a halogen. Preferably, a halogen atom1-4Alkoxy radical C1-4Alkyl means halogenated C1-4Alkoxy-substituted C1-4An alkyl group.
The term 'hydroxyhaloC' as used herein as a group or part of a group1-4Alkoxy radical C1-4Alkyl' means C1-4alkyl-O-C1-4Alkyl radical, wherein C1-4Alkyl is as defined herein, wherein one or two C1-4With one or more hydrogen atoms of the alkyl radical being replaced by hydroxy groupsAnd, one or more hydrogen atoms are substituted with halogen. Thus, the term' hydroxyhaloC1-4Alkoxy radical C1-4Alkyl' means C1-4alkyl-O-C1-4Alkyl radical, one or two of which being C1-4One, two, three or more hydrogen atoms in the alkyl group are substituted by hydroxyl groups and one, two, three or more hydrogen atoms are substituted by halogen, wherein C1-4Alkyl is as defined herein.
The term ` hydroxy C ` as used herein2-6Alkenyl' means C2-6Alkenyl in which one or more hydrogen atoms are replaced by hydroxy, wherein C2-6Alkenyl groups are as defined herein.
The term ` C ` as used herein2-6Alkynyl' means C2-6Alkynyl in which one or more hydrogen atoms are replaced by hydroxy, wherein C2-6Alkynyl groups are as defined herein.
The term phenyl C as used herein1-6Alkyl means C as defined herein substituted by a phenyl group1-6An alkyl group.
The term cyano C as used herein1-4Alkyl or cyano C1-6Alkyl means C as defined herein substituted by one cyano group1-4Alkyl or C1-6An alkyl group.
The term "heterocyclyl" as used herein includes aromatic and non-aromatic ring systems unless the context indicates otherwise. Thus, for example, the term "heterocyclyl" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated heterocyclyl ring systems. Typically, such groups may be monocyclic or bicyclic groups, and may contain, for example, 3 to 12 ring members, more typically 5 to 10 ring members, unless the context indicates otherwise. 4 to 7 ring members include 4,5,6 or 7 atoms in the ring, and 4 to 6 ring members include 4,5 or 6 atoms in the ring. Examples of monocyclic groups are groups containing 3,4, 5,6,7 and 8 ring members, more typically 3 to 7 ring members, preferably 5,6 or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic groups are those containing 8, 9, 10, 11 and 12 ring members, and more typically 9 or 10 ring members. If a heterocyclyl group is referred to herein, the heterocyclyl ring may be optionally (i.e., unsubstituted or substituted) substituted with one or more substituents discussed herein, unless the context indicates otherwise.
The heterocyclyl group can be a heteroaryl group having 5 to 12 ring members, more typically 5 to 10 ring members. The term "heteroaryl" as used herein denotes a heterocyclic group having aromatic character. The term "heteroaryl" includes polycyclic (e.g., bicyclic) ring systems in which one or more of the rings is non-aromatic, with the proviso that: at least one ring is aromatic. In such polycyclic systems, groups may be attached through aromatic rings, or through non-aromatic rings.
Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, and more typically 5 to 10 ring members. Heteroaryl groups may be, for example, a five or six membered monocyclic ring or a bicyclic ring structure formed by fused five and six membered rings or two fused five membered rings. Each ring may contain up to about five heteroatoms, which are typically selected from nitrogen, sulfur, and oxygen. Typically, the heteroaryl ring contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2 heteroatoms, for example one heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atom in the heteroaryl ring may be a basic nitrogen atom, for example, in the case of imidazole or pyridine, or a substantially non-basic nitrogen atom, for example, in the case of indole or pyrrole nitrogens. Typically, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) is less than five.
Examples of five-membered heteroaryl groups include, but are not limited to: pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole and tetrazole groups.
Examples of six membered heteroaryl groups include, but are not limited to: pyridine, pyrazine, pyridazine, pyrimidine and triazine.
The bicyclic heteroaryl may be a group selected from, for example:
a) a benzene ring fused with a 5-or 6-membered ring containing 1,2 or 3 ring heteroatoms;
b) a pyridine ring fused with a 5-or 6-membered ring containing 0, 1,2 or 3 ring heteroatoms;
c) a pyrimidine ring fused to a 5 or 6 membered ring containing 0, 1 or 2 ring heteroatoms;
d) a pyrrole ring fused to a 5 or 6 membered ring containing 0, 1,2 or 3 ring heteroatoms;
e) a pyrazole ring fused to a 5-or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
f) an imidazole ring fused with a 5-or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
g) an oxazole ring fused to a 5 or 6 membered ring containing 0, 1 or 2 ring heteroatoms;
h) an isoxazole ring fused to a 5 or 6 membered ring containing 0, 1 or 2 ring heteroatoms;
i) a thiazole ring fused with a 5-or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
j) an isothiazole ring fused with a 5-or 6-membered ring containing 0, 1 or 2 ring heteroatoms;
k) a thiophene ring fused to a 5 or 6 membered ring containing 0, 1,2 or 3 ring heteroatoms;
l) a furan ring fused to a 5-or 6-membered ring containing 0, 1,2 or 3 ring heteroatoms;
m) a cyclohexyl ring fused to a 5 or 6 membered ring containing 0, 1,2 or 3 ring heteroatoms; and
a cyclopentyl ring fused to a 5 or 6 membered ring containing 1,2 or 3 ring heteroatoms.
Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to: imidazothiazoles (e.g., imidazo [2,1-b ] thiazole) and imidazoimidazoles (e.g., imidazo [1,2-a ] imidazole).
Specific examples of bicyclic heteroaryls containing a six-membered ring (fused to a five-membered ring) include, but are not limited to: benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indezine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo [1,5-a ] pyrimidine), triazolopyrimidine (e.g., [1,2,4] triazolo [1,5-a ] pyrimidine), benzodioxole, imidazopyridine, and pyrazolopyridine (e.g., pyrazolo [1,5-a ] pyridine) groups.
Specific examples of bicyclic heteroaryls containing two fused six-membered rings include, but are not limited to: quinoline, isoquinoline, chroman, thiochroman, benzopyran, isochroman, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
Examples of the polycyclic heteroaryl group containing an aromatic ring and a non-aromatic ring include: tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzo [ di (hydrobenzthiene), dihydrobenzofuran, 2, 3-dihydro-benzo [1,4] dioxine, benzo [1,3] dioxole, 4,5,6, 7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g. 5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine), indoline and indane groups.
The nitrogen-containing heteroaryl ring must contain at least one ring nitrogen atom. Additionally, each ring may contain up to about four additional heteroatoms typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to 3 heteroatoms, such as 1,2 or 3, more usually up to 2 nitrogens, e.g., one nitrogen. The nitrogen atom in the heteroaryl ring may be a basic nitrogen atom, for example, in the case of imidazole or pyridine, or a substantially non-basic nitrogen atom, for example, in the case of indole or pyrrole nitrogens. Typically, the number of basic nitrogen atoms present in the heteroaryl group (including any amino substituents of the ring) is less than five.
Examples of nitrogen-containing heteroaryl groups include, but are not limited to: pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2, 3-triazolyl, 1,2, 4-triazolyl), tetrazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl, indenylyl, isoindolinyl, purinyl (e.g., adenine [ 6-aminopurine ], guanine [ 2-amino-6-hydroxypurine ]), indazolyl, quinolizinyl, benzoxazinyl, benzodiazine, pyridopyridyl, quinoxalinyl, quinazolinyl, cinnamyl, phthalazinyl, naphthyridinyl and pteridinyl.
Examples of the nitrogen-containing polycyclic heteroaryl group having an aromatic ring and a non-aromatic ring include a tetrahydroisoquinolinyl group, a tetrahydroquinolinyl group and an indolinyl group.
Unless the context indicates otherwise, the term "non-aromatic" includes unsaturated ring systems that are not aromatic, partially saturated, and fully saturated heterocyclyl ring systems. The terms "unsaturated" and "partially saturated" refer to rings in which the ring structures contain atoms that share more than one valence bond, i.e., the rings contain at least one multiple bond, such as a C = C, C ℃ or N = C bond. The term "fully saturated" refers to rings without multiple bonds between ring atoms. Saturated heterocyclic groups include piperidine, morpholine, thiomorpholine, piperazine. Partially saturated heterocyclic groups include dihydropyrazoles, such as 2-dihydropyrazole and 3-dihydropyrazole.
Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more typically 5 to 10 ring members. Such groups may be monocyclic or bicyclic, for example, ring members typically having 1 to 5 heteroatoms (more typically ring members having 1,2,3 or 4 heteroatoms), which are typically selected from nitrogen, oxygen and sulfur. The heterocyclyl group can contain, for example, cyclic ether moieties (e.g., in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g., in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g., in pyrrolidine), cyclic amide moieties (e.g., in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g., in imidazolidin-2-one), cyclic ester moieties (e.g., in butyrolactone), cyclic sulfones (e.g., in sulfolane and sulfolene), cyclic sulfoxides, cyclic sulfonamides, and combinations thereof (e.g., thiomorpholine).
Specific examples include morpholine, piperidine (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl and 4-piperidyl), piperidone, pyrrolidine (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g., 4-tetrahydropyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-dihydropyrazole, pyrazolidine, piperazinone, piperazine and N-alkylpiperazine, such as N-methylpiperazine. Generally, preferred non-aromatic heterocyclic groups include saturated groups such as piperidine, pyrrolidine, azetidine, morpholine, piperazine and N-alkylpiperazine.
In nitrogen-containing non-aromatic heterocyclyl rings, the ring must contain at least one ring nitrogen atom. The heterocyclic group can contain, for example, a cyclic amine moiety (e.g., in pyrrolidine), a cyclic amide (e.g., pyrrolidone, piperidone, or caprolactam), a cyclic sulfonamide (e.g., isothiazolidine 1, 1-dioxide, [1,2] thiazinane 1, 1-dioxide, or [1,2] thiazepine 1, 1-dioxide), and combinations thereof.
Specific examples of the nitrogen-containing non-aromatic heterocyclic group include aziridine, morpholine, thiomorpholine, piperidine (e.g., 1-piperidyl, 2-piperidyl, 3-piperidyl and 4-piperidyl), pyrrolidine (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole, imidazoline, imidazolidinone, oxazoline, thiazoline, 6H-1,2, 5-thiadiazine, 2-dihydropyrazole, 3-dihydropyrazole, pyrazolidine, piperazine and N-alkylpiperazine, e.g., N-methylpiperazine.
The heterocyclic group may be a polycyclic fused ring system or a bridged ring system, for example, oxa-and aza analogues of bicycloalkanes, tricycloalkanes (e.g., adamantanes and oxa-adamantanes). For an explanation of the differences between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience,pages 131-133, 1992。
The heterocyclic groups may each be a heterocyclic group unsubstituted or substituted with one or more substituent groups. If the heterocyclyl group is a monocyclic or bicyclic heterocyclyl group, it is typically an unsubstituted or 1,2 or 3 substituted heterocyclyl group.
The term 'aryl' as used herein refers to carbocyclic aromatic groups including phenyl, naphthyl, indenyl and tetrahydronaphthyl.
In one embodiment, R1Represents hydrogen, C1-6Alkyl radical, C2-4Alkenyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, cyano C1-4Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl by-P (= O) (OH)2Substituted C1-6Alkyl or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group.
In one embodiment, R1Represents hydrogen, C1-6Alkyl radical, C2-4Alkenyl, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, or by-Si (CH)3)3Substituted C1-6An alkyl group.
In one embodiment, R1Represents hydrogen.
In one embodiment, R1Represents C1-6An alkyl group. R1Can represent-CH3，-CD3，-CH2CH3，-CH2CH2CH3，-CH2CH(CH3)2，-CH(CH3)2，-CH2CH(CH3)2. In one embodiment, R1represents-CH3. In another embodiment, R1represents-CD3。
In one embodiment, R1Represents C2-4An alkenyl group. R1Can represent-CH2-CH=CH2。
In one embodiment, R1Represents a hydroxyl group C1-6An alkyl group. R1Can represent-CH2CH2OH，-CH2C(CH3)2OH or CH2CHOHCH2OH。
In one embodiment, R1Represents halogeno C1-6An alkyl group. R1Can represent-CH2CH2F，CH2CH2CH2Cl or CH2CH2Br。
In one embodiment, R1Represents each of C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6An alkyl group. R1Can represent-CH2CH2OCH3。
In one embodiment, R1Is represented by-NR4R5Substituted C1-6An alkyl group.
In one embodiment, when R1Is represented by-NR4R5Substituted C1-6When alkyl, R4And R5Each represents hydrogen. R1Can represent-CH2CH2NH2or-CH2CH2CH2NH2。
In another embodiment, when R1Is represented by-NR4R5Substituted C1-6When alkyl, R4And R5One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3。R1Can represent-CH2CH2NHCH3。
In another embodiment, when R1Is represented by-NR4R5Substituted C1-6When alkyl, R4And R5One represents hydrogen and the other represents-S (= O)2-NR14R15Wherein R is14And R15Each represents C optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH3。R1Can represent-CH2CH2NHS(=O)2N(CH3)2。
In another embodiment, when R1Is represented by-NR4R5Substituted C1-6When alkyl, R4And R5One represents hydrogen and the other represents-S (= O)2-C1-6An alkyl group. R1Can represent-CH2CH2NHS(=O)2CH3。
In one embodiment, R1Is represented by-C (= O) -NR4R5Substituted C1-6An alkyl group.
In one embodiment, when R1Is represented by-C (= O) -NR4R5Substituted C1-6When alkyl, R4And R5Each represents C1-6Alkyl radicals, e.g. -CH3。R1Can represent-CH2C(=O)N(CH3)2。
In another embodiment, when R1Is represented by-C (= O) -NR4R5Substituted C1-6When alkyl, R4And R5One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3。R1Can represent-CH2C(=O)NHCH3or-C (CH)3)2C(=O)NHCH3。
In another embodiment, when R1Is represented by-C (= O) -NR4R5Substituted C1-6When alkyl, R4And R5One of them represents hydrogen and the other represents a hydroxyl group C1-6Alkyl radicals, e.g. -CH2CH2OH。R1Can represent-C (CH)3)2C(=O)NHCH2CH2OH or-CH2C(=O)NHCH2CH2OH。
In another embodiment, when R1Is represented by-C (= O) -NR4R5Substituted C1-6When alkyl, R4And R5One of them represents hydrogen and the other represents C1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6Alkyl groups may be optionally substituted by one or two hydroxy groups, e.g. -CH2CH2OCH3。R1Can represent-CH2C(=O)NHCH2CH2OCH3or-C (CH)3)2C(=O)NHCH2CH2OCH3。
In another embodiment, when R1Is represented by-C (= O) -NR4R5Substituted C1-6When alkyl, R4And R5One of them represents hydrogen and the other represents R13Substituted C1-6An alkyl group. R13May represent a saturated 5-membered monocyclic heterocyclic group containing at least one nitrogen heteroatom, such as pyrrolidine. R1Can represent-CH2-C(=O)-NH-CH2-CH2- (pyrrolidin-1-yl).
In another embodiment, when R1Is represented by-C (= O) -NR4R5Substituted C1-6When alkyl, R4And R5One represents hydrogen and the other represents-S (= O)2-C1-6Alkyl substituted C1-6An alkyl group. R1Can represent-CH2CH2CH2NHCH2CH2-S(=O)2-CH3。
In one embodiment, R1represents-S (= O)2-C1-6An alkyl group. R1Can represent-S (= O)2-CH3。
In one embodimentIn, R1represents-S (= O)2-NR14R15。R14And R15May each represent C optionally substituted by hydroxy1-4Alkyl radicals, e.g. R14And R15May all represent-CH3。R1Can represent-S (= O)2-N(CH3)2。
In one embodiment, R1Is represented by-S (= O)2-C1-6Alkyl substituted C1-6An alkyl group. R1Can represent-CH2CH2S(=O)2-CH3。
In one embodiment, R1Is represented by-NH-S (= O)2-C1-6Alkyl substituted C1-6An alkyl group. R1Can represent-CH2CH2NHS(=O)2-CH3。
In one embodiment, R1Represents R6。R6May represent a saturated 4-, 5-or 6-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S, which may be optionally substituted.
In one embodiment, when R1Represents R6When R is6Represents piperidinyl, for example 4-piperidinyl.
In one embodiment, when R1Represents R6When R is6Represents tetrahydropyranyl, for example 2-tetrahydropyranyl or 4-tetrahydropyranyl.
In one embodiment, when R1Represents R6When R is6Represents tetrahydrofuranyl, for example 3-tetrahydrofuranyl.
In another embodiment, when R1Represents R6When R is6Represents a hydroxyl group C1-6Alkyl-substituted azetidinyl. Hydroxy radical C1-6The alkyl group may be-CH2CH2OH。R6Can represent。
In another embodiment, when R1Represents R6When R is6Represents a C1-6alkyl-O-C (= O) -group-substituted piperidinyl. The C is1-6The alkyl-O-C (= O) -group may be (CH)3)3C-O-C(=O)-。R6May represent a nitrogen atom surrounded by (CH)3)3C-O-C (= O) -substituted 4-piperidinyl groups.
In another embodiment, when R1Represents R6When R is6Represents one-S (= O)2-C1-6Alkyl-substituted piperidinyl. the-S (= O)2-C1-6Alkyl may be-S (= O)2CH3。R6May represent a nitrogen atom surrounded by-S (= O)2CH3Substituted 4-piperidinyl. In another embodiment, when R1Represents R6When R is6Represents a C1-6Alkyl-substituted piperidinyl. The C is1-6The alkyl group may be-CH3。R6May represent a nitrogen atom surrounded by-CH3Substituted 4-piperidinyl.
In one embodiment, R1Is represented by R6Substituted C1-6An alkyl group. R6May represent a saturated 4-, 5-or 6-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S, which may be optionally substituted. R6Can represent pyrrolidinyl, thienyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl.
R1May represent methyl or ethyl, each of which is substituted by 4-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl or 4-tetrahydropyranyl. R1May represent propyl substituted by a morpholinyl group, wherein the morpholinyl group is linked to the propyl via an N heteroatom. In another embodiment, heterocyclyl may be substituted with one substituent selected from the group consisting of: halogen, C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy radical，C1-6alkyl-O-C (= O) -. The substituent may be-Cl, -CH3，-OH，-CH2CH2OH，-CH2CH2CH2OH，-OCH3，(CH3)3C-O-C(=O)-。
R1May represent methyl, ethyl or propyl, each substituted by: at the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperidinyl substituted on the nitrogen by-CH3Substituted 4-piperidinyl radicals substituted at the nitrogen atom (N1) by (CH)3)3C-O-C (= O) -substituted 4-piperazinyl substituted at the nitrogen atom (N1) by-CH2CH24-piperazinyl substituted by OH, with-CH at the nitrogen atom (N1)2CH2CH24-piperazinyl substituted by OH, 4-piperidinyl substituted by-OH in the 4-position, or-O-CH in the 4-position3Substituted 4-piperidinyl. R1May represent methyl substituted by 2-thienyl, wherein 2-thienyl is substituted by chloro in the 5-position. In another embodiment, the heterocyclyl may be substituted with two substituents selected from the group consisting of: hydroxy radical, C1-6Alkoxy radical, C1-6alkyl-O-C (= O) -. The substituent may be-OH, -OCH3，(CH3)3C-O-C(=O)-。R1May represent methyl substituted by 4-piperidinyl, wherein 4-piperidinyl is substituted on the nitrogen atom by (CH)3)3C-O-C (= O) and substitution at the 4-position with-OH.
In one embodiment, R1Is represented by-C (= O) R6Substituted C1-6An alkyl group. R6May represent a saturated 4-, 5-or 6-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S, which may be optionally substituted. R6May represent piperazinyl or pyrrolidinyl.
In one embodiment, when R1Is represented by-C (= O) R6Substituted C1-6When alkyl, R6Represents a piperazinyl group. R1Can represent-C (CH)3)2-C (= O) - (piperazin-4-yl).
In a further embodiment of the process of the present invention,when R is1represents-C (= O) -R6Substituted C1-6When alkyl, R6Represents a C1-6alkyl-O-C (= O) -groups (e.g. C (CH)3)3-O-C (= O) -) substituted piperazinyl. R1May represent a nitrogen atom, substituted in position 1 by C (CH)3)3-O-C (= O) -substituted-C (CH)3)2-C (= O) - (piperazin-4-yl).
In another embodiment, when R1represents-C (= O) -R6Substituted C1-6When alkyl, R6Represents pyrrolidinyl substituted by one hydroxy group. R1May represent-CH substituted in position 3 by-OH2-C (= O) - (pyrrolidin-1-yl).
In one embodiment, R1Is represented by R6Substituted hydroxy radical C1-6Alkyl radical, R6May represent a saturated 4-, 5-or 6-membered monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S, which may be optionally substituted. R6May represent piperidinyl, for example 1-piperidinyl. R1Can represent-CH2CHOHCH2-piperidin-1-yl.
In one embodiment, R1Is represented by-Si (CH)3)3Substituted C1-6An alkyl group. R1Can represent-CH2Si(CH3)3。
In one embodiment, R1Represents cyano group C1-4An alkyl group. R1Can represent-CH2CH2CN。
In one embodiment, each R is1aIndependently selected from: hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino or-NH (C)3-8Cycloalkyl) substituted C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl and C substituted by one or more fluorine atoms1-4An alkyl group.
In a fruitIn embodiments, each R1aIndependently selected from: hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl radical, di (C)1-4Alkyl) amino-substituted C1-4Alkyl, and C substituted by one or more fluorine atoms1-4An alkyl group.
In one embodiment, one or two R groups1aRepresents hydrogen. In one embodiment, each R is1aRepresents hydrogen.
In one embodiment, one or two R groups1aRepresents C1-4Alkyl radicals, e.g. -CH3，-CH2CH3. In one embodiment, each R is1aRepresents C1-4Alkyl radicals, e.g. -CH3。
In one embodiment, one or two R groups1aRepresents a hydroxyl group C1-4Alkyl radicals, e.g. -CH2OH，-CH2CH2OH，-CH2CH2CH2OH。
In one embodiment, one or two R groups1aRepresents two (C)1-4Alkyl) amino-substituted C1-4Alkyl radicals, e.g. -CH2N(CH3)2. In one embodiment, one or two R are1aRepresents C substituted by one or more fluorine atoms1-4Alkyl radicals, e.g. CF3。
In one embodiment:
(i) a R1aRepresents hydrogen, another R1aRepresents C1-4Alkyl radicals, e.g. -CH3，-CH2CH3；
(ii) A R1aRepresents hydrogen, another R1aRepresents a hydroxyl group C1-4Alkyl radicals, e.g. -CH2OH，-CH2CH2OH，-CH2CH2CH2OH；
(iii) A R1aRepresents hydrogen, another R1aRepresenting one or more fluorineAtom-substituted C1-4Alkyl radicals, e.g. CF3(ii) a Or
(iv) Each R1aIndependently represent C1-4Alkyl radicals, e.g. each R1arepresents-CH3。
In one embodiment, R1Is methyl, R1aIs hydrogen or methyl.
In one embodiment, each R is2Independently selected from: hydroxy, halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13Is being NR7R8Substituted C1-4Alkyl radical, by NR7R8Substituted C1-4Alkoxy, -NR7R8and-C (= O) -NR7R8(ii) a Or when two R are2When groups are attached to adjacent carbon atoms, they may be joined together to form a compound of the formula-O- (C (R)17)2)p-O-wherein R is17Represents hydrogen or fluorine, and p represents 1 or 2.
In one embodiment, each R is2Independently selected from: halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13Is being NR7R8Substituted C1-4Alkyl radical, by NR7R8Substituted C1-4Alkoxy, -NR7R8or-C (= O) -NR7R8。
In one embodiment, one or more R2RepresentsA hydroxyl group.
In one embodiment, one or more R2Represents halogen, for example fluorine, chlorine or bromine.
In one embodiment, one or more R2Represents cyano.
In one embodiment, one or more R2Represents C1-4Alkyl radicals, e.g. -CH3。
In one embodiment, one or more R2Represents C2-4Alkenyl, e.g. -CH = CH2。
In one embodiment, one or more R2Represents C1-4Alkoxy radicals, e.g. CH3O-，(CH3)2CHO-，CH3CH2O-, or CD3O-。
In one embodiment, one or more R2Represents a hydroxyl group C1-4Alkyl radicals, e.g. -CH2OH。
In one embodiment, one or more R2Represents a hydroxyl group C1-4Alkoxy radicals, e.g. -OCH2CH2OH。
In one embodiment, one or more R2Represents halogeno C1-4Alkyl radicals, e.g. CF3。
In one embodiment, one or more R2Represents halogeno C1-4Alkoxy radicals, e.g. -OCH2CH2F or-O-CHF2-. In one embodiment, one or more R2represents-OCH2CH2F or-O-CHF2or-OCF3。
In one embodiment, one or more R2Represents C1-4Alkoxy radical C1-4Alkyl radicals, e.g. -CH2CH2OCH3。
At one endIn one embodiment, one or more R2Represents R13。R13May represent a saturated 5-membered monocyclic heterocyclic group containing two oxygen heteroatoms, such as dioxolanyl, especially 2-dioxolanyl.
In one embodiment, one or more R2Is represented by R13Substituted C1-4An alkoxy group. R13Can represent C3-8Cycloalkyl groups, such as cyclopropyl. One or more R2Can represent-OCH2C3H5。
In one embodiment, one or more R2represents-C (= O) -R13。R13May represent a saturated 5-membered monocyclic heterocyclic group containing at least one nitrogen heteroatom, such as pyrrolidinyl. R2May represent-C (= O) - (1-pyrrolidinyl).
In one embodiment, one or more R2Is represented by-NR7R8Substituted C1-4An alkyl group. In one embodiment, R7And R8Each represents hydrogen. One or more R2Can represent-CH2NH2. In another embodiment, R7And R8Can each independently represent C1-6Alkyl radicals, e.g. -CH2CH3or-CH3. One or more R2Can represent-CH2N(CH2CH3)2，-CH2N(CH3)2or-CH2N(CH2CH3)(CH3)。
In one embodiment, one or more R2Is represented by-NR7R8Substituted C1-4An alkoxy group. In one embodiment, R7And R8One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3. One or more R2Can represent-OCH2CH2NHCH3. In one embodiment, R7And R8Each represents hydrogen. One or more R2Can represent-OCH2CH2NH2。
In one embodiment, one or more R2represents-NR7R8. In one embodiment, R7And R8One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3. In one embodiment, each R is7And R8Represents C1-6Alkyl radicals, e.g. -CH3。
In one embodiment, one or more R2represents-C (= O) -NR7R8. In one embodiment, R7And R8One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3。
In one embodiment, when two R are present2When groups are attached to adjacent carbon atoms, they may be joined together to form a compound of the formula-O- (C (R)17)2)p-O-wherein R is17Represents hydrogen and p represents 1.
In one embodiment, n is equal to 0. In one embodiment, n is equal to 1. In one embodiment, n is equal to 2. In one embodiment, n is equal to 3. In one embodiment, n is equal to 4.
In one embodiment, n is equal to 1. R2May be at 3 bits. R2Can represent
(i) Halogen substituted C1-4Alkoxy radicals, e.g. -O-CHF2；
(ii) C1-4Alkoxy radicals, e.g. CH3O-or (CH)3)2CHO-；
(iii) A cyano group; or
(iv) -NR7R8For example-NHCH3。
In one embodiment, n is equal to 1. R2May be at 3 bits.R2May represent a halogen atom C1-4Alkoxy radicals, e.g. OCF3。
In one embodiment, n is equal to 1. R2May be at 3 bits. R2Can represent C1-4Alkoxy radicals, e.g. CH3O-is formed. In one embodiment, n is equal to 1. R2May be at 3 bits. R2Can represent-NR7R8Wherein R is7And R8Each independently represents C1-6Alkyl radicals, e.g. -N (CH)3)2。
In one embodiment, n is equal to 2. A R2May be in 3 bits, another may be in 5 bits:
(i) each R2Can represent C1-4Alkoxy radicals, e.g. per R2May be CH3O-, or R at position 32May be (CH)3)2CHO-, R in position 52May be CH3O-, or R at position 32May be CH3O-R in position 52May be a CD3O-；
(ii) R in position 32May represent halogen, e.g. fluorine, chlorine or bromine, R in position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-、CD3O-or CH3CH2O-；
(iii) R in position 32Can represent C1-4Alkyl radicals, e.g., -CH3R in the 5-position2Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(iv) R in position 32May represent cyano, R in position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(v) R in position 32May represent NR7R8Substituted C1-4Alkyl radicals, e.g. -CH2NH2or-CH2N(CH3)2or-CH2N(CH2CH3)2or-CH2N(CH2CH3)(CH3) R in the 5-position2Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(vi) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52May represent-C (= O) -NR7R8For example-C (= O) NHCH3or-C (= O) NH2；
(vii) R in position 32May represent a hydroxyl group C1-4Alkoxy radicals, e.g. -OCH2CH2OH, R in the 5 position2Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(viii) R in position 32May represent-C (= O) -R13E.g. -C (= O) - (pyrrolidin-1-yl), R at the 5-position2Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(ix) R in position 32Can represent R13Substituted C1-4Alkoxy radicals, e.g. -OCH2C3H5R in position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(x) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52May represent NR7R8Substituted C1-4Alkoxy radicals, e.g. -OCH2CH2NHCH3or-OCH2CH2NH2；
(xi) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52Can represent C2-4Alkenyl, e.g. -CH = CH2；
(xii) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52Can represent C1-4Alkoxy radical C1-4Alkyl radicals, e.g. -CH2CH2OCH3(ii) a Or R in position 32May be CH3O-, R at position 52May be CH3OCH2-；
(xiii) R in position 32Can represent R13E.g. 2-dioxolanyl, R in position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(xiv) R in position 32May represent a hydroxyl group C1-4Alkoxy radicals, e.g. -OCH2CH2OH, R in position 52May represent halogen, for example fluorine;
(xv) R in position 32May represent a halogen atom C1-4Alkoxy radicals, e.g. -OCH2CH2F, R at position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(xvi) R in position 32May represent halogen, e.g. fluorine, R in position 52May represent-C (= O) -NR7R8For example-C (= O) NHCH3；
(xvii) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52May represent halogen, for example fluorine; or
(xviii) R in position 32May represent a hydroxyl group C1-6Alkyl radicals, e.g. -CH2OH, R in position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-。
In one embodiment, n is equal to 2. A R2May be in 3 bits, another may be in 5 bits:
(i) r in position 32May represent a hydroxyl group, R in the 5-position2Can represent C1-4Alkoxy radicals, e.g. CH3O-；
(ii) Each R2May represent halogen, for example chlorine;
(iii) r in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52Can represent-NR7R8Substituted C1-4Alkyl radical, wherein R7And R8Can each independently represent C1-6Alkyl radicals, e.g. -CH2N(CH2CH3)2；
(iv) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52May represent a halogen atom C1-4Alkoxy radicals, e.g. OCHF2；
(v) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R at position 52May represent a halogen atom C1-4Alkyl radicals, e.g. -CHF2(ii) a Or
(vi) Each R2May represent a hydroxyl group.
In one embodiment, n is equal to 2. A R2May be at 3 bits and the other may be at 5 bits. Each R2Can represent C1-4Alkoxy radicals, e.g. per R2May be CH3O-，(CH3)2CHO-，CH3CH2O-，CD3O-is formed. In one embodiment, two R are2Are all, for example, CH3O-or CD3O-is formed. In one embodiment, two R are2Are all CH3O-。
In one embodiment, n is equal to 2. A R2May be at 4 bits and the other may be at 5 bits. Each R2Can represent C1-4Alkoxy radicals, e.g. per R2May be CH3O-。
In one embodiment, n is equal to 2. A R2May be at 5 bits and the other may be at 6 bits. Each R2Can represent C1-4Alkoxy radicals, e.g. per R2May be CH3O-。
In one embodiment, n is equal to 2. A R2May be in 2 bits, another may be in 5 bits:
(i) each R2Can represent C1-4Alkoxy, e.g. each R2May be CH3O-; or
(ii) R in the 2 position2May be halogen, e.g. chlorine, R in position 52Can represent C1-4Alkoxy radicals, e.g. CH3O-。
In one embodiment, n is equal to 3. A R2May be in 2 bits, one may be in 3 bits, one may be in 5 bits:
(i) r in the 2 position2May represent halogen, e.g. chlorine, R in the 3-and 5-positions2Can each represent C1-4Alkoxy, e.g. each R2May be CH3O-; or
(ii) R in the 2 position2Can represent C1-4Alkyl radicals, e.g. -CH3R in the 3-and 5-positions2Can each represent C1-4Alkoxy, e.g. each R2May be CH3O-。
In one embodiment, n is equal to 3. A R2May be in 3 bits, one may be in 4 bits, one may be in 5 bits:
(i) r in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R in the 4-and 5-positions2May each represent halogen, for example fluorine; or
(ii) R in position 32Can represent C1-4Alkoxy radicals, e.g. CH3O-, R in the 4-and 5-positions2Can be combined together to form a compound of the formula-O- (C (R)17)2)p-O-wherein R is17Represents hydrogen and p represents 1.
In one embodiment, n is equal to 3. A R2May be in 2 bits, one may be in 3 bits, one may be in 5 bits: (i) r in the 2 position2May represent halogen, e.g. fluorine, in position 3 and 5R of (A) to (B)2Can each represent C1-4Alkoxy radicals, e.g. CH3O-。
In one embodiment, n is equal to 4. A R2R may be in 2 bits, one may be in 3 bits, one may be in 5 bits, one may be in 6 bits, 2 bits and 6 bits2May each represent halogen, e.g. chlorine or fluorine, R in the 3-and 5-positions2Can each represent C1-4Alkoxy radicals, e.g. CH3O-。
R3Can represent C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, hydroxy C2-6Alkynyl, halo C1-6Alkyl, optionally substituted by-O-C (= O) -C1-6Alkyl-substituted halogeno C1-6Alkyl (e.g. substituted), by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted by one or two hydroxy groups or by-O-C (= O) -C1-6Alkyl substituted C1-6Alkoxy radical C1-6Alkyl radical, by R9Substituted C1-6Alkyl radical, by-NR10R11Substituted C1-6Alkyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -NR10R11Substituted C1-6Alkyl, C substituted by carboxyl1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, by R9Substituted and optionally substituted by-O-C (= O) -C1-6Alkyl substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12，-S(=O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkenyl radical, by R9Substituted C2-6Alkynyl, hydroxy C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl radical, R13Quilt C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl, or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group.
R3Can represent C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, halo C1-6Alkyl radical, substituted by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by R9Substituted C1-6Alkyl radical, by-NR10R11Substituted C1-6Alkyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -NR10R11Substituted C1-6Alkyl, C substituted by carboxyl1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12is-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkynyl, hydroxy C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl radical, R13Or by C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6An alkyl group.
In one embodiment, R3Represents C1-6An alkyl group. R3Can represent-CH3，-CH2CH3，-CH2CH2CH3or-CH2CH(CH3)2。
In one embodiment, R3Represents a hydroxyl group C1-6An alkyl group. R3Can represent-CH2CH2OH，-CH2CH2CH2OH，-CH2CHOHCH3，-CH2CHOHCH2CH3，-CH2CHOHCH(CH3)2，-CH2CH2C(OH)(CH3)2，-CH2CHOHCH2OH or-CH2C(CH3)2OH。R3Can represent-CD2CD2OH or-CD2CD2CD2OH。R3May represent-CH (CH)3)CH2OH。
In one embodiment, R3Represents halogeno C1-6An alkyl group. R3Can represent-CH2CH2CH2Cl or-CH2CH2CH2CH2Cl。R3Can represent-CH2CH2F or-CH2CH2I。
In one embodiment, R3represents-O-C (= O) -C1-6Alkyl-substituted halogeno C1-6An alkyl group. R3Can represent-CH2CH(CF3)-O-C(=O)CH3。
In one embodiment, R3Represents hydroxy halogeno C1-6Alkyl radicals, e.g. R3Can represent-CH2CHOHCF3。
In one embodiment, R3Represents a hydroxyl group C2-6Alkynyl, e.g. R3Can represent-CH2-C≡C-CH2OH or-CH2-C≡C-C(CH3)2OH。
In one embodiment, R3represents-C (= O) -C1-6Alkyl substituted C1-6Alkyl radicals, e.g. R3May represent CH3-C(=O)-CH2-，(CH3)2CH-C(=O)-CH2-。
In one embodiment, R3Represents C1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6Alkyl groups may be optionally substituted with one or two hydroxy groups. R3Can represent-CH2CH2OCH3，-CH2CH2OCH2CH3or-CH2CHOHCH2OCH3。
In one embodiment, R3Represents C1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted by one or two hydroxy groups or by-O-C (= O) -C1-6Alkyl substitution. R3Can represent-CH2CH(-O-C(=O)CH3)CH2OCH3。
In one embodiment, R3Is represented by R9Substituted C1-6An alkyl group.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents optionally substituted C3-8Cycloalkyl groups, such as cyclopropyl or cyclopentyl. R3Can represent-CH2-C3H5or-CH2C5H9。
In one embodiment, if C3-8Cycloalkyl is cyclopropyl, then it is interrupted by one hydroxy group C1-4Alkyl (e.g. -CH)2OH) substitution.
In one embodiment, if C3-8Cycloalkyl is cyclopropyl, it is substituted by a 6-membered aromatic monocyclic heterocyclyl group containing one nitrogen heteroatom, such as 4-pyridyl.
In another embodiment, if C3-8Cycloalkyl is cyclopropyl, then it is substituted by a C1-6alkyl-O-C (= O) -substitution, e.g. CH3CH2-O-C(=O)-。
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclic group containing nitrogen and oxygen heteroatoms, such as isoxazolyl. In one embodiment, the heterocyclyl is substituted with one or two C1-4Alkyl radicals such as-CH3And (4) substituting the group. R3Can represent 5-isoxazolyl (is-CH at the 3-position)3Substituted) or by 3-isoxazolyl (by-CH in position 5)3Substituted) substituted methyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted saturated 6-membered monocyclic heterocyclic group containing nitrogen and oxygen heteroatoms, such as morpholinyl. R3May represent ethyl or propyl substituted by 4-morpholinyl. R3May represent methyl substituted by 3-morpholinyl. R3May represent methyl substituted by 6-morpholinyl.
In one embodiment, the heterocyclyl is substituted with one or two C1-4Alkyl radicals such as-CH3And (4) substituting the group. R3May represent 4-morpholinyl (being-CH in positions 2 and 6)3Substituted) ethyl or propyl. R3May represent 3-morpholinyl (being two-CH in position 5)3Substituted) substituted methyl. R3May represent 6-morpholinyl (in position 4 by-CH (CH)3)2Substituted) substituted methyl. In one embodiment, the heterocyclyl is substituted with one C1-4Alkyl radicals such as-CH (CH)3)2And substitution. R3May represent 6-morpholinyl (being substituted in position 3)Replacement of O by-CH (CH) in position 43)2Substituted) substituted methyl.
In another embodiment, the heterocyclyl is substituted with phenyl C1-6Alkyl substituted, wherein phenyl is optionally substituted with R16Substituted, e.g. -CH2-C6H5。R3May represent 2-morpholinyl (in position 4 by-CH)2-C6H5Substituted) substituted methyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated or aromatic 3-, 4-, 5-or 6-membered monocyclic heterocyclic group containing one or two oxygen heteroatoms, such as ethylene oxide (oxetanyl), oxetane (oxetanyl), tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl or furanyl. R3May be methyl substituted with 2-tetrahydrofuranyl, 2-dioxolane, ethylene oxide, 2-furanyl or 4-tetrahydropyranyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted 4-membered heterocyclic radical containing one oxygen atom, e.g. oxetanyl, and is interrupted by a C1-4Alkyl radicals such as-CH3A substituted heterocyclic group. R3May be substituted by 3-oxetanyl (in position 3 by-CH)3Substituted) substituted methyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted 4-membered heterocyclic radical containing one oxygen atom, e.g. oxetanyl, and is interrupted by a C1-4Alkyl-substituted heterocyclic radical, in which C1-4Alkyl is-NR14R15Is substituted by radicals in which R14And R15One of them is hydrogen and the other is C1-4Alkyl radicals, e.g. -CH (CH)3)2。R3May be substituted by 3-oxetanyl (in position 3 by-CH)2NHCH(CH3)2Substituted) substituted methyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocycle containing one or two nitrogen heteroatoms, such as pyridyl or pyrazinyl. R3May represent methyl substituted by 3-pyridyl or 2-pyrazinyl. R3May represent propyl substituted by 4-pyridyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocycle containing two nitrogen heteroatoms, for example pyrimidinyl. R3May represent methyl or propyl substituted by 2-pyrimidinyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocyclyl group containing one nitrogen heteroatom, for example pyridyl substituted by one halogen, for example chlorine or bromine. R3May represent methyl substituted by 3-pyridyl (substituted by chlorine in position 6) or 2-pyridyl (substituted by bromine in position 6).
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocyclyl group containing one nitrogen heteroatom, for example pyridyl, which is substituted by:
(i) a C1-4Alkyl radicals, e.g. -CH3。R3May represent a 6-pyridyl group (in the 4 position by-CH)3Substituted) substituted propyl; or
(ii) A C1-4Alkoxy radicals, e.g. -OCH3。R3May represent a 2-pyridyl group (in position 3 by-OCH)3Substituted) propyl groups. R3May represent a 2-pyridyl group (in position 6 by-OCH)3Substituted) substituted methyl;
(iii) a is-NR14R15Substituted C1-4An alkyl group. In one embodiment, R14And R15Each represents hydrogen. R3May represent a 6-pyridyl group (in position 2 by-CH)2NH2Substituted) substituted methyl; or
(iv) One is-NR14R15. In one embodiment, R14And R15One of them represents hydrogen and the other represents C1-4Alkyl radicals, e.g. -CH3。R3Can represent 6-pyridyl (at the 2-position by-NHCH)3Substituted) substituted methyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocyclyl group containing two nitrogen heteroatoms, for example pyrimidinyl, which is substituted by:
(i) one or two C1-4Alkoxy radicals, e.g. -OCH3。R3Can represent a 2-pyrimidinyl radical (being-OCH in position 4)3Substituted) propyl groups. R3May represent 2-pyrimidinyl (substituted by-OCH in positions 4 and 6)3Substituted) substituted methyl;
(ii) one hydroxyl group, for example-OH. R3May represent propyl substituted by 2-pyrimidinyl (substituted in position 4 by-OH).
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted, saturated 6-membered monocyclic heterocyclyl group containing two nitrogen heteroatoms, for example piperazinyl. R3May represent methyl substituted by 3-piperazinyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted, saturated 6-membered monocyclic heterocyclic radical containing two nitrogen heteroatoms, e.g. by R13Substituted piperazinyl, e.g. said R13Represents a C1-4alkyl-C (= O) - (e.g. -C (= O) -CH3) A substituted piperidinyl group. R3May represent a 1-piperazinyl group (4-piperidinyl in the 4-position (C (= O) -CH in the 1-position)3Substituted) ethyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted saturated 6-membered monocyclic heterocyclyl radical containing two nitrogen heteroatoms, e.g. by C1-4Alkyl (by-C (= O) -NR)14R15Substituted) substituted piperazinyl. R3May represent a 1-piperazinyl group (in the 4 position by-CH)2C(=O)NHCH(CH3)2Substituted) ethyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a partially saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, which may be optionally substituted. R3May represent ethyl or propyl substituted by 1,2,3, 6-tetrahydropyridine.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted saturated 4-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as azetidinyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 4-membered monocyclic heterocyclyl group containing one nitrogen heteroatom, such as azetidinyl, and which heterocyclyl group is substituted by one or two halogens, such as fluorine. R3May represent propyl substituted by 1-azetidinyl (substituted in position 3 by two fluorines). In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 4-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as azetidinyl, and the heterocyclic group is substituted with one hydroxyl group. R3May represent propyl substituted by 1-azetidinyl (substituted in position 3 by one-OH).
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 5-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as pyrrolidinyl. R3May represent ethyl or propyl substituted by 1-pyrrolidinyl or 2-pyrrolidinyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 5-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as pyrrolidinyl, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclic group is substituted by:
a) one or two halogens, e.g. fluorine. R3May represent propyl substituted by 1-pyrrolidinyl (substituted by two fluorines in position 3) or 1-pyrrolidinyl (substituted by one fluorine in position 3);
b) a halogen radical C1-4Alkyl radicals, e.g. -CH2Cl。R3May represent 1-pyrrolidinyl (substituted in the 2-position by-CH)2Cl) substituted) propyl;
c) one hydroxyl group. R3May represent ethyl or propyl substituted by 1-pyrrolidinyl (substituted in position 3 with-OH);
d) group. R3May represent ethyl or propyl substituted by 1-pyrrolidinyl (substituted at position 2 with = O);
e) one-S (= O)2-C1-4Alkyl radical, C1-4The alkyl group may be-CH3。R3May represent 1-pyrrolidinyl (substituted in position 3 with-S (= O)2-CH3Substituted) substituted propyl;
f) one is-NR14R15A group. In one embodiment, R14And R15Each represents hydrogen. R3May represent 1-pyrrolidinyl (substituted by-NH in position 3)2Substituted) ethyl or propyl. In another embodiment, R14And R15Each independently representsC optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH3。R3May represent 1-pyrrolidinyl (substituted in the 3-position by-N (CH)3)2Substituted) ethyl. In another embodiment, R14And R15One of which is hydrogen and the other is C optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH3。R3May represent 1-pyrrolidinyl (substituted in position 3 by-NHCH)3Substituted) substituted propyl;
g) one or two C1-4Alkyl radicals, e.g. -CH3or-CH (CH)3)2。R3May represent 1-pyrrolidinyl (substituted in the 2-position by-CH)3Substituted), 1-pyrrolidinyl (substituted at the 2 and 5 positions with-CH)3Substituted) or 1-pyrrolidinyl (substituted in the 2-position by two-CH groups3Substituted) ethyl or propyl;
h) one carboxyl group. R3May represent an ethyl group substituted with 1-pyrrolidinyl (substituted at the 2-position with-C (= O) OH).
i) One hydroxyl group C1-4Alkyl radicals, e.g. -CH2OH，-C(CH3)2OH or-CH2CH2OH。R3May represent 1-pyrrolidinyl (substituted in the 2-position by-CH)2OH substituted) ethyl or propyl;
j) R13. In one embodiment, R13Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom. In another embodiment, R13Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen and one oxygen heteroatom. In a further embodiment, R13Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen and one oxygen heteroatom, which heterocyclic group is a substituted heterocyclic group, e.g. by two C1-6Alkyl (e.g. two-CH)3Group) substitution. R3May represent propyl substituted by 1-pyrrolidinyl (substituted in position 3 by 1-piperidinyl), or by 1-pyrrolidinyl (substituted in position 3 by 4-morpholinyl (substituted in positions 2 and 6 by-CH)3Substituted) propyl;
k) one cyano group. R3May represent ethyl or propyl substituted by 1-pyrrolidinyl (substituted in position 3 by-CN);
l) a cyano group C1-4Alkyl radicals, e.g. -CH2CN。R3May represent 1-pyrrolidinyl (substituted in the 2-position by-CH)2CN substituted) substituted propyl. R3May represent 1-pyrrolidinyl (substituted in the 2-position by-CH)2CN substituted) substituted ethyl;
m) one by-NH-S (= O)2-halo C1-4Alkyl substituted C1-4Alkyl radicals, e.g. -CH2NH-S(=O)2-CF3。R3May represent 1-pyrrolidinyl (substituted in the 2-position by-CH)2NH-S(=O)2-CF3Substituted) substituted propyl; or
n) one C1-6alkyl-O-C (= O) -, e.g. (CH)3)3C-O-C (= O) -or CH3-O-C(=O)-。R3May represent 2-pyrrolidinyl (substituted in position 1 with (CH)3)3C-O-C (= O) -substituted) or by 1-pyrrolidinyl (CH at position 2)3-O-C (= O) -substituted) methyl or ethyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 5-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as pyrrolidinyl, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclyl is substituted with a 6-membered aromatic monocyclic heterocyclyl containing one or two nitrogen heteroatoms, such as pyridyl or pyrimidinyl, and optionally R16And (4) substitution. In one embodiment, R16Represents C1-4Alkoxy radicals, e.g. -OCH3。R3May represent 3-pyrrolidinyl (substituted in position 1 by 2-pyridyl (substituted in position 3 by-OCH)3Substituted) methyl. R3May represent 3-pyrrolidinyl (substituted in position 1 by 2-pyrimidinyl (substituted in position 4 by-OCH)3Substituted) methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, for example piperidinyl. R3May represent methyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as a piperidyl group, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclic group is substituted by:
a) one or two halogens, e.g. fluorine. R3May represent ethyl substituted by 1-piperidinyl (substituted in the 4 position by two fluorines);
b) one hydroxyl group. R3May represent methyl or ethyl substituted by 1-piperidinyl (substituted in the 4 position by one-OH) or 4-piperidinyl (substituted in the 4 position by one-OH);
c) one is-NR14R15A group. In one embodiment, R14And R15Each represents hydrogen. R3May represent 1-piperidinyl (substituted by-NH in position 3 or 4)2Substituted) ethyl. In another embodiment, R14And R15Each independently represents C optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH3。R3Can represent 1-piperidinyl (in the 4 position by-N (CH)3)2Substituted) substituted ethyl;
d) one or two C1-4Alkyl radicals, e.g. -CH3or-CH (CH)3)2。R3May represent 1-piperidinyl (in the 2 position by-CH)3Substituted), 1-piperidinyl (substituted in the 2 and 6 positions by-CH)3Substituted), 4-piperidinyl (substituted in the 1-position by-CH (CH)3)2Substituted), 4-piperidinyl (substituted in the 1-position by-CH)3Substituted), 1-piperidinyl (substituted in the 3 and 5 positions by-CH)3Substituted) methyl, ethyl or propyl;
e) one hydroxyl group C1-4Alkyl radical, examplesSuch as-CH2OH，-C(CH3)2OH or-CH2CH2OH。R3Can represent 1-piperidinyl (in the 4 position by-C (CH)3)2OH-substituted), 1-piperidinyl (substituted in the 4-position by-CH)2CH2OH-substituted), 1-piperidinyl (substituted in the 4-position by-CH)2OH substituted) substituted ethyl;
f) one cyano group. R3May represent ethyl or propyl substituted by 1-piperidinyl (substituted in position 3 by-CN);
g) a C1-6alkyl-O-C (= O) -, e.g. CH3CH2-O-C(=O)-，(CH3)3C-O-C (= O) -or CH3-O-C(=O)-。R3May represent 1-piperidinyl (in the 4 position by CH)3CH2-O-C (= O) -substituted), 4-piperidinyl (substituted in position 1 with (CH)3)3C-O-C (= O) -substituted) methyl or ethyl;
h) a C1-6alkyl-O-C (= O) -, e.g. (CH)3)3C-O-C (= O) -, and one hydroxyl group. R3May represent 4-piperidinyl (substituted in the 4 position by-OH, in the 1 position by (CH)3)3C-O-C (= O) -substituted) methyl;
i) a C1-6alkyl-O-C (= O) -, e.g. (CH)3)3C-O-C (= O) -, and one C1-4Alkoxy radicals, e.g. -OCH3。R3May represent 4-piperidinyl (in the 4 position by-OCH)3Substituted, in position 1 by (CH)3)3C-O-C (= O) -substituted) methyl;
j) a C1-4Alkoxy radicals, e.g. -OCH3。R3Can represent 1-piperidinyl (in the 4 position by-OCH)3Substituted) or 4-piperidinyl (substituted in the 4-position by-OCH3Substituted) substituted methyl or ethyl;
k) a halogen radical C1-4Alkyl radicals, e.g. CF3。R3May represent 1-piperidinyl (in the 4 position by-CF)3Substituted) substituted propyl; or
l) one-C (= O) -NR14R15Wherein R is14And R15Both represent hydrogen. R3Can represent 1-piperidinyl (substituted in the 3-position by-C (= O) -NH)2Substituted) ethyl. R3Can represent 1-piperidinyl (substituted in the 2-position by-C (= O) -NH)2Substituted) ethyl or propyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as a piperidyl group, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclic group is substituted by:
a) R3May represent ethyl substituted by 1-piperidinyl (substituted by = O in the 4 position), or propyl substituted by 1-piperidinyl (substituted by = O in the 2 position);
b) a is-NR14R15Substituted C1-6Alkyl radical, wherein R14And R15Both represent hydrogen. R3May represent 1-piperidinyl (in the 4 position by-CH)2NH2Substituted) ethyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as a piperidyl group, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclyl is substituted with a 6-membered aromatic monocyclic heterocyclyl containing two nitrogen heteroatoms, e.g. pyrimidinyl, and optionally R16And (4) substitution. In one embodiment, R16Represents C1-4Alkoxy radicals, e.g. -OCH3。R3Can represent 4-piperidinyl (substituted in position 1 by 2-pyrimidinyl (substituted in position 4 by-OCH)3Substituted) methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a bicyclic heterocyclic group containing a benzene ring wherein the benzene ring is bonded to a ring containing 1,5-or 6-membered rings of 2 or 3 ring heteroatoms are fused. In one embodiment, the bicyclic heterocyclic group contains a benzene ring fused to a 5-membered ring containing 1 ring heteroatom. In one embodiment, the ring heteroatom is a nitrogen heteroatom. In one embodiment, the bicyclic heterocyclic group is substituted with two = O groups on a 5-membered ring containing one ring heteroatom. R3May represent ethyl, propyl or butyl substituted by isoindolyl-1, 3-dione (isoindolole-1, 3-dione), for example isoindol-2-yl-1, 3-dione, also known as phthalimido (phtalimidyl). R3May represent-CH (CH) substituted by isoindolyl-1, 3-dione (isoindolole-1, 3-dione)3)CH2-。
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl (e.g. ethyl or propyl), R9Represents an optionally substituted monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S. In one embodiment, R9Represents a 4,5 or 6 membered monocyclic saturated heterocyclic ring substituted by two substituents, which are attached to the same atom and taken together to form a 4 to 7 membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S; r3Represents C substituted by a 4,5 or 6 membered monocyclic saturated heterocycle1-6Alkyl (e.g., ethyl or propyl), wherein the monocyclic saturated heterocyclic ring is substituted with two substituents, both substituents being attached to the same atom and taken together to form a 4-to 7-membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S. For example, R3May represent 2-oxa-6-aza-spiro [3.3]]Ethyl substituted by heptane, or R3May represent ethyl substituted by 1-piperidinyl, the 1-piperidinyl group being substituted in the 4-position by 1, 4-dioxolane, e.g. to form 1, 4-dioxa-8-aza-spiro [4.5]]Decane.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclic group containing one sulfur heteroatom, for example thiophene. R3May represent methyl substituted by 2-thienyl. In one embodiment, an aromatic 5-membered monocyclic heterocyclyl containing one sulfur heteroatom is substituted with one chlorine. R3May represent methyl substituted by 2-thienyl (substituted in position 5 by chlorine).
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing one sulphur and one nitrogen heteroatom, for example thiazole. The 5-membered heterocyclic group may be substituted by, for example, a C1-4Alkyl (e.g. -CH)3) And (4) substitution. R3May represent a 4-thiazolyl group (in the 2 position by-CH)3Substituted) substituted methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing two nitrogen heteroatoms, such as piperazinyl. R3May represent ethyl or propyl substituted by 1-piperazinyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing two nitrogen heteroatoms, such as a piperazinyl group, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclic group is substituted by:
a) a C1-4alkyl-C (= O) -, e.g. CH3-C(=O)-。R3May represent a 1-piperazinyl group (in the 4 position by CH)3-C (= O) -substituted) ethyl;
b) one hydroxyl group C1-4Alkyl radicals, e.g. -CH2CH2OH。R3May represent a 1-piperazinyl group (in the 4 position by-CH)2CH2OH substituted) substituted ethyl;
c) one or two C1-4Alkyl radicals, e.g. -CH3。R3May represent a 1-piperazinyl group (substituted by-CH in the 3 and 5 positions)3Substituted) ethyl or propyl, or by 1-piperazinyl (substituted in the 4 position by-CH)3Substituted) ethyl or propyl；
d) R3May represent ethyl substituted by 1-piperazinyl (substituted at position 3 by = O); or
e) one-C (= O) -R13。R13May be C3-8Cycloalkyl groups, such as cyclopropyl. R3May represent a 1-piperazinyl group (substituted at the 4-position by-C (= O) -C3H5Substituted) ethyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing two nitrogen heteroatoms, such as a piperazinyl group, and the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclic group is substituted by two phenyl groups C1-6Alkyl substituted in which phenyl is substituted by R16And (4) substitution. R16Can represent C1-4Alkoxy radicals, e.g. CH3O-。R3May represent methyl substituted by 2-piperazinyl (substituted in the 1 and 4 positions by methylphenyl), wherein the phenyl group is substituted in the 4 position by CH3O-substitution.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an aromatic 5-membered monocyclic heterocyclic group containing four nitrogen heteroatoms, such as tetrazolyl. R3May represent ethyl substituted by 5-tetrazolyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an aromatic 5-membered monocyclic heterocyclic group containing one oxygen atom and two nitrogen heteroatoms, for example 1,3, 4-oxadiazolyl. The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group may be substituted by an-NR14R15Is substituted by radicals in which each R is14And R15Is hydrogen. Or, R14And R15One of which may be hydrogen and the other may represent C optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH2CH2OH。R3May represent 2- (1,3, 4-oxadiazolyl) (substituted in position 5 with-NH)2Substitution) Or 2- (1,3, 4-oxadiazolyl) (substituted in position 5 with-NH-CH)2CH2OH substituted) substituted methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing two nitrogen heteroatoms, for example pyrazolyl or imidazolyl. R3May represent methyl, ethyl or propyl substituted by 1-pyrazolyl or 2-imidazolyl. R3May represent methyl substituted by 3-pyrazolyl or 5-pyrazolyl. The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group may be substituted by one or two C1-4Alkyl (e.g. -CH)3or-CH2CH3) And (4) substitution. R3May represent a 1-imidazolyl group (in the 2-position by-CH)3Substituted), 3-pyrazolyl (substituted in the 1 and 5 positions by-CH)3Substituted), 1-imidazolyl (substituted by-CH at the 2 and 5 positions3Substituted), 1-imidazolyl (substituted by-CH at the 2 and 4 positions3Substituted), 2-imidazolyl (substituted in position 1 with-CH3Substituted) or 2-imidazolyl (substituted in position 1 by-CH)2CH3Substituted) methyl, ethyl or propyl. R3May represent a 2-imidazolyl group (in position 5 by-CH)3Substituted) substituted methyl. R3May represent 1-pyrazolyl (in position 3 by-CH)3Substituted) ethyl. R3May represent 4-pyrazolyl (in position 1 by-CH)3Substituted) substituted methyl. In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing two nitrogen heteroatoms, for example imidazolyl. The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group is substituted by a C1-4Alkyl (e.g. -CH)3) And one-S (= O)2-NR14R15And (4) substitution. R14And R15Can each represent C1-4Alkyl radicals, e.g. -CH3。R3Can represent a 2-imidazolyl group (substituted in the 3-position by-S (= O)2-N(CH3)2Substituted in position 1 by-CH3Substituted) substituted methyl.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing two nitrogen heteroatoms, for example pyrazolyl. The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group is substituted by R13And (4) substitution. R13May represent a saturated 6-membered monocyclic heterocyclic group containing one oxygen heteroatom. R3May represent methyl substituted by 5-pyrazolyl (substituted in position 2 by 2-tetrahydropyran). R3May represent methyl substituted by 3-pyrazolyl (substituted in position 1 by 2-tetrahydropyran).
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing two nitrogen heteroatoms, for example imidazolyl. The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group is substituted with-S (= O)2-NR14R15And (4) substitution. R14And R15May each represent C optionally substituted by a substituent selected from the group consisting of1-4Alkyl (e.g., -CH)3): hydroxy radical, C1-4Alkoxy, amino or mono-or di (C)1-4Alkyl) amino. R3Can represent a 2-imidazolyl group (substituted in the 1-position by-S (= O)2-N(CH3)2Substituted) substituted methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing three nitrogen heteroatoms, for example triazolyl. R3May represent a methyl group substituted by 4- (1,2, 3-triazolyl). The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group is substituted by:
a) one hydroxyl group C1-4Alkyl radicals, e.g. -CH2CH2OH。R3May represent 4- (1,2, 3-triazolyl) (substituted in position 1 by-CH2CH2OH-substituted) or 4- (1,2, 3-triazolyl) (substituted in position 2 with-CH2OH substituted) substituted methyl; or
b) A quilt C1-6C substituted by alkyl-O-C (= O) -groups1-4Alkyl radicals, e.g. -CH2-C(=O)-OCH2CH3。R3May represent 4- (1,2, 3-triazolyl) (substituted in position 1 by-CH2-C(=O)-OCH2CH3Substituted) substituted methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing three nitrogen heteroatoms, for example triazolyl. R3May represent ethyl substituted by 1- (1,2, 4-triazolyl). The heterocyclic group may be a substituted heterocyclic group. For example, the heterocyclic group is substituted by C1-4Alkyl (e.g. -CH)3) And (4) substitution. R3May represent 1- (1,2, 4-triazolyl) (substituted in position 3 by-CH3Substituted) ethyl or propyl. R3May represent 2- (1,2, 4-triazolyl) (substituted in position 3 by-CH3Substituted) ethyl or propyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 5-membered monocyclic heterocyclic group containing one nitrogen and one oxygen heteroatom, such as oxazolidinyl. The heterocyclyl group may be a substituted heterocyclyl group, for example, substituted with R3May represent ethyl or propyl substituted by 3-oxazolidinyl (substituted by = O at the 2 position). R3May represent methyl substituted by 5-oxazolidinyl (substituted by = O at the 2 position). The heterocyclyl group may be substituted heterocyclyl, e.g., substituted with and one C1-6Alkyl substitution. R3May represent 5-oxazolidinyl (substituted by = O at the 2-position and-CH (CH) at the 3-position3)2Substituted) substituted methyl.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocyclic group containing one nitrogen and one sulfur heteroatom, such as thiomorpholinyl. The heterocyclic group may be a substituted heterocyclic group, for example, in a thiaSubstituted on the atom by two = O groups. R3May represent propyl substituted with 4-thiomorpholinyl (substituted in position 1 with two = O groups).
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 7-membered monocyclic heterocyclic group containing two nitrogen heteroatoms, such as homopiperazinyl. R3May represent an ethyl group substituted by a 1-homopiperazinyl group.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents a saturated 7-membered monocyclic heterocyclic group containing one nitrogen and one oxygen heteroatom, such as homomorpholinyl. R3May represent ethyl substituted by a higher morpholinyl group.
In another embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents phenyl or naphthyl, especially phenyl. R3Can represent-CH2-C6H5. When R is9When representing a phenyl or naphthyl group (especially phenyl), the phenyl or naphthyl group may be substituted, for example, by a chloro group. R3May represent a methyl group substituted by a phenyl group (substituted by chlorine in position 2,3 or 4).
In one embodiment, R3Represents cyano group C1-6Alkyl radicals, e.g. -CH2CH2CN or-CH2CH2CH2CN。
In one embodiment, R3Represents hydroxy, halo or-NR10R11Substituted C1-6An alkyl group. In a further embodiment, R3Represents hydroxy or-NR10R11Substituted C1-6An alkyl group. In yet a further embodiment, R3Is represented by-NR10R11Substituted C1-6An alkyl group.
In one embodiment, R3Represents hydroxy, halo or-NR10R11Substituted C1-6Alkyl radical, wherein the C1-6Alkyl is a straight-chain alkyl group, such as 2-ethyl, n-propyl, n-butyl. In one embodiment, R3Is represented by-NR10R11Substituted C1-4An alkyl group. In one embodiment, R3Is represented by-NR10R11Substituted C1-4Alkyl radical, wherein the C1-4Alkyl is a straight-chain alkyl group, such as 2-ethyl, n-propyl, n-butyl. In one embodiment, R3Is represented by-NR10R11Substituted C1-4Alkyl radical, wherein the C1-4Alkyl is ethyl (-CH)2CH2-)。
In one embodiment, when R3Is represented by-NR10R11Substituted C1-6When alkyl, R10And R11Has the following meanings:
a) each R10And R11Represents hydrogen. R3Can represent-CH2CH2NH2，-CH2CH2CH2NH2or-CH2CH2CH2CH2NH2。R3Can represent-CH2CH(CH3)NH2，-CH(CH3)CH2NH2；
b) R10And R11One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3，-CH2CH3or-CH (CH)3)2。R3Can represent-CH2CH2NHCH3，-CH2CH2CH2NHCH3，-CH2CH2NHCH2CH3，-CH2CH2NHCH(CH3)2，-CD2-CD2-NHCH(CH3)2or-CH2CH2CH2NHCH(CH3)2。R3May represent-CH (CH)3)CH2NHCH(CH3)2；
c) Each R10And R11Independently represent C1-6Alkyl radicals, e.g. -CH2CH3or-CH (CH)3)2。R3Can represent-CH2CH2N(CH2CH3)2，-CH2CH2N(CH2CH3)(CH(CH3)2). Each R10And R11May independently represent C1-6Alkyl radicals, e.g. -CH3。R3Can represent-CH2CH2N(CH3)2or-CH2CH2N(CH3)CH(CH3)2；
d) R10And R11One of them represents hydrogen and the other represents halogeno C1-6Alkyl radicals, e.g. -CH2CF3，-CH2CHF2or-CH2CH2F。R3Can represent-CH2CH2CH2NHCH2CF3，-CH2CH2NHCH2CHF2or-CH2CH2NHCH2CH2F. Halogen substituted C1-6The alkyl group may be-C (CH)3)2CH2F。R3May represent-CH (CH)3)CH2NHCH2CF3，-CH2CH(CH3)NHCH2CF3，-CH2CH2NHCH2CF3，-CH2CH2CH2NHCH2CHF2-CH2CH2NHCH2CH2CF3，-CH2CH2CH2NHCH2CHF2，-CH2CH2CH2NHC(CH3)2CH2F，-CD2-CD2-CD2-NHCH2CF3；
e) R10And R11One represents hydrogen and the other represents-C (= O) C1-6Alkyl, for example-C (= O) -Me. R3Can be used forrepresents-CH2CH2NH-C(=O)-CH3；
f) R10And R11One represents hydrogen and the other represents-S (= O)2-C1-6Alkyl radicals, e.g., -S (= O)2-CH3，-S(=O)2-CH2CH3or-S (= O)2-CH(CH3)2。R3Can represent-CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH2CH3or-CH2CH2NH-S(=O)2-CH(CH3)2；
g) R10And R11One represents hydrogen and the other represents-S (= O)2-NR14R15Wherein R is14And R15Each represents C optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH3。R3Can represent-CH2CH2NH-S(=O)2-N(CH3)2or-CH2CH2CH2NH-S(=O)2-N(CH3)2；
h) R10And R11One of them represents hydrogen and the other represents a hydroxyl group C1-6Alkyl radicals, e.g. -CH2CH2OH。R3Can represent-CH2CH2NHCH2CH2OH；
i) R10And R11One of them represents hydrogen and the other represents-C (= O) -hydroxyhaloC1-6Alkyl radicals, e.g., -C (= O) -C (OH) (CH)3)CF3。R3Can represent-CH2CH2CH2NH-C(=O)-C(OH)(CH3)CF3or-CH2CH2NH-C(=O)-C(OH)(CH3)CF3；
j) R10And R11One of them represents hydrogen and the other represents hydrogenrepresents-C (= O) -R6。R6Can represent C3-8Cycloalkyl groups, such as cyclopropyl. R3Can represent-CH2CH2NH-C(=O)-C3H5. Or, R6May represent a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, for example piperidinyl. The heterocyclic group may be substituted heterocyclic group, e.g. by a C1-6Alkyl (e.g. -CH)3) And substituted to form an N-methylpiperidinyl group. R3Can represent-CH2CH2NH-C (= O) - (piperidin-3-yl), wherein the piperidinyl group is substituted at the 1-position with-CH3Substitution;
k) R10and R11One of them represents hydrogen and the other represents cyano group C1-6Alkyl radicals, e.g. -CH2CH2CN。R3Can represent-CH2CH2NHCH2CH2CN。R3Can represent-CH2CH2CH2NHCH2CH2CN；
l) R10And R11One of them represents hydrogen and the other represents R6。R6Can represent C3-8Cycloalkyl, e.g. cyclopropyl or cyclopentyl, or R6May represent a saturated 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom, for example piperidinyl. The heterocyclic group may be a substituted heterocyclic group, e.g. by four C1-6Alkyl (e.g. -CH)3) Substitution, for example, to form 2,2,6, 6-tetramethyl-piperidyl. R3Can represent-CH2CH2NHC3H5，-CH2CH2NHC5H9or-CH2CH2NH- (2,2,6, 6-tetramethyl-piperidin-4-yl). For example, the heterocyclic group may be substituted by one-S (= O)2NR14R15(e.g., -S (= O)2NH2) And (4) substitution. R3Can represent-CH2CH2NH- (piperidin-4-yl), wherein the piperidinyl group is substituted at the 1-position by-S (= O)2NH2Substitution;
m) R10and R11One of them represents hydrogen, andone is represented by R6Substituted C1-6An alkyl group. R6Can represent C3-8Cycloalkyl groups, such as cyclopropyl. R3Can represent-CH2CH2NHCH2C3H5. Or, R6May represent a saturated 5-membered monocyclic heterocyclic group containing one oxygen heteroatom. R3Can represent-CH2CH2NHCH2- (tetrahydrofuran-2-yl). Or, R6May represent an aromatic 6-membered monocyclic heterocyclic group containing one nitrogen heteroatom. R3Can represent-CH2CH2NHCH2- (pyridin-6-yl);
n) R10and R11One of them represents hydrogen and the other represents-C (= O) -halogeno-C1-6Alkyl radicals, e.g., -C (= O) -CF3。R3Can represent-CH2CH2NHC(=O)-CF3or-CH2CH2CH2NHC(=O)-CF3；
o) R10And R11One represents hydrogen and the other represents-Si (CH)3)3Substituted C1-6An alkyl group. R3Can represent-CH2CH2NHCH2Si(CH3)3(ii) a Or
p) R10And R11One of them represents C1-6Alkyl, the other being represented by R6Substituted C1-6An alkyl group. R6May represent a phenyl group. R6Can represent-NR14R15Substituted phenyl, wherein R14And R15Each represents hydrogen. In one embodiment, R10And R11One of them represents-CH3And the other represents-CH2-C6H5。R3Can represent-CH2CH2N(CH3)CH2-C6H5. In one embodiment, R10And R11One of them represents-CH (CH)3)2And the other represents-CH2-C6H5Wherein phenyl isAt position 4 by-NH2And (4) substitution.
In one embodiment, when R3Is represented by-NR10R11Substituted C1-6When alkyl, R10And R11Has the following meanings:
a) R10and R11One of them represents C1-6Alkyl radicals, e.g. -CH (CH)3)2And the other is represented by-NR14R15Substituted C1-6Alkyl radical, wherein R14And R15Each represents hydrogen. R3Can represent-CH2CH2N(CH(CH3)2)CH2CH2CH2NH2；
b) R10And R11One represents hydrogen and the other represents-C (= O) -NR14R15Substituted C1-6Alkyl radical, wherein R14And R15Each represents hydrogen. R3Can represent-CH2CH2CH2NHCH2C(=O)NH2or-CH2CH2NHCH2C(=O)NH2；
c) R10And R11One of them represents C1-6Alkyl radicals, e.g., -CH3The other represents C1-6Alkoxy radicals, e.g. -OCH3。R3Can represent-CH2CH2CH2N(CH3)-OCH3。
d) R10And R11One of them represents hydrogen and the other represents C1-6Alkoxy radicals, e.g. -OCH3。R3Can represent-CH2CH2NH-OCH3(ii) a Or
e) R10And R11One of them represents hydrogen and the other represents hydroxyhalogeno C1-6Alkyl radicals, e.g. -CH2CHOHCF3。R3Can represent-CH2CH2NHCH2CHOHCF3。
f) R10And R11One represents hydrogen and the other represents carboxyl (i.e., -C (= O) -OH); r3Can represent-CH2CH2CH2NHCOOH。
In one embodiment, R10Represents hydrogen or C1-6Alkyl radicals, e.g. hydrogen, -CH3，-CH2CH3or-CH (CH)3)2. In one embodiment, R10Is hydrogen.
In one embodiment, R11Represents hydrogen, C1-6Alkyl, halo C1-6Alkyl, -C (= O) -C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15Hydroxy radical C1-6Alkyl, -C (= O) -hydroxyhaloC1-6Alkyl, -C (= O) -R6Cyano group C1-6Alkyl radical, R6，-C(=O)-R6Is by R6Substituted C1-6Alkyl, -C (= O) -halo C1-6Alkyl, by-Si (CH)3)3Substituted C1-6An alkyl group.
In one embodiment, R11Represents hydrogen, -CH3，-CH2CH3or-CH (CH)3)2，-CH2CF3，-CH2CHF2or-CH2CH2F，-C(=O)-CH3，-S(=O)2-CH3，-S(=O)2-CH2CH3，-S(=O)2-CH(CH3)2，-S(=O)2-N(CH3)2，-CH2CH2OH，-C(=O)-C(OH)(CH3)CF3-C (= O) -cyclopropyl, -CH2CH2CN, cyclopropyl, cyclopentyl, 2,2,6, 6-tetramethyl-piperidinyl, -CH2C3H5，-CH2-tetrahydrofuranyl, -C (= O) - (1-methyl-piperidin-3-yl), -C (= O) -CF3，-CH2Si(CH3)3，-CH2-C6H5。
In one embodiment, R3represents-CH2CH2NH2，-CH2CH2CH2NH2，-CH2CH2CH2CH2NH2，-CH2CH2NHCH3，-CH2CH2CH2NHCH3，-CH2CH2NHCH2CH3，-CH2CH2NHCH(CH3)2，-CH2CH2CH2NHCH(CH3)2，-CH2CH2N(CH2CH3)2，-CH2CH2N(CH2CH3)(CH(CH3)2)，-CH2CH2CH2NHCH2CF3，-CH2CH2NHCH2CHF2or-CH2CH2NHCH2CH2F，-CH2CH2NH-C(=O)-CH3，-CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH2CH3，-CH2CH2NH-S(=O)2-CH(CH3)2，-CH2CH2NH-S(=O)2-N(CH3)2，-CH2CH2CH2NH-S(=O)2-N(CH3)2，-CH2CH2NHCH2CH2OH，-CH2CH2CH2NH-C(=O)-C(OH)(CH3)CF3，-CH2CH2NH-C(=O)-C(OH)(CH3)CF3，-CH2CH2NH-C(=O)-C3H5，-CH2CH2NHCH2CH2CN，CH2CH2NHC3H5，-CH2CH2NHC5H9，-CH2CH2-NHCO- (piperidin-3-yl) wherein the piperidin-3-yl is in position 1is-CH3,-CH2CH2NHCH2C3H5,-CH2CH2NHCH2(tetrahydrofuran-2-yl) -CH2CH2NHC(=O)-CF3，-CH2CH2CH2NHC(=O)-CF3，-CH2CH2NH- (2,2,6, 6-tetramethyl-piperidin-4-yl), -CH2CH2NHCH2Si(CH3)3，-CH2CH2N(CH3)CH2-C6H5And (4) substitution.
In one embodiment, R3Represents a substituted hydroxyl group and-NR10R11Substituted C1-6An alkyl group.
In one embodiment, when R3Represents a substituted hydroxyl group and-NR10R11Substituted C1-6When it is alkyl, each R10And R11Represents hydrogen. R3Can represent-CH2CHOHCH2NH2。
In one embodiment, when R3Represents a substituted hydroxyl group and-NR10R11Substituted C1-6When alkyl, R10And R11One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3，-CH(CH3)2。R3Can represent-CH2CHOHCH2NHCH3or-CH2CHOHCH2NHCH(CH3)2。
In one embodiment, when R3Represents a substituted hydroxyl group and-NR10R11Substituted C1-6When alkyl, R10And R11One of them represents hydrogen and the other represents halogeno C1-6Alkyl radicals, e.g. -CH2CF3。R3Can represent-CH2CHOHCH2NHCH2CF3。
In one embodiment, when R3Represents a substituted hydroxyl group and-NR10R11Substituted C1-6When alkyl, R10And R11One of them represents C1-6Alkyl radicals, e.g. -CH (CH)3)2And the other represents-C (= O) -halogeno-C1-6Alkyl radicals, e.g., -C (= O) -CH2Cl。R3Can represent-CH2CHOHCH2N(CH(CH3)2)-C(=O)CH2Cl。
In one embodiment, R3Represents a hydroxyl group C1-6Alkyl radical, wherein hydroxy C1-6Alkyl groups include-CD2CD2OH，-CH2CH2CH2OH，-CD2CD2CD2OH，-CH2CHOHCH3，-CH2CHOHCH2CH3，-CH2CHOHCH(CH3)2，-CH2CH2C(OH)(CH3)2，-CH2CHOHCH2OH or-CH2C(CH3)2OH。
In one embodiment, R3Represents one or two halogen atoms and-NR10R11Substituted C1-6An alkyl group. In one embodiment, each R is10And R11Represents hydrogen. R3Can represent-CH2CHFCH2NH2。
In one embodiment, R3Is represented by-C (= O) -O-C1-6Alkyl substituted C1-6An alkyl group. R3Can represent-CH2C(=O)-O-CH2CH3or-CH2CH2-C(=O)-O-CH2CH3，R3May represent-CH (CH)3)C(=O)-O-CH2CH3。
In one embodiment, R3Is represented by C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl (e.g., methyl). R3Can represent-CH2-C(=O)-CH2OCH3。
In one embodimentIn the scheme, R3Is represented by-C (= O) -NR10R11Substituted C1-6An alkyl group.
In one embodiment, when R3Is represented by-C (= O) -NR14R15Substituted C1-6When alkyl, the C1-6Alkyl is a straight chain alkyl, such as n-ethyl, n-propyl, n-butyl. In one embodiment, R3Is represented by-C (= O) -NR14R15Substituted C1-4An alkyl group. In one embodiment, when R3Is represented by-C (= O) -NR14R15Substituted C1-4When alkyl, the C1-4Alkyl is a straight chain alkyl, such as n-ethyl, n-propyl, n-butyl. In one embodiment, when R3Is represented by-C (= O) -NR14R15Substituted C1-6When alkyl, the C1-6Alkyl is ethyl (-CH)2CH2-)。
In one embodiment, when R3Is represented by-C (= O) -NR10R11Substituted C1-6When alkyl, R10And R11Has the following meanings:
a) R10and R11Each represents hydrogen. R3Can represent-CH2C(=O)NH2；
b) R10And R11One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3。R3Can represent-CH2C(=O)NHCH3；C1-6The alkyl group may be-CH (CH)3)2。R3Can represent-CH2C(=O)NHCH(CH3)2or-CH2CH2C(=O)NHCH(CH3)2；
c) R10And R11One of them represents hydrogen and the other represents C1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6Alkyl groups may be optionally substituted by one or two hydroxy groups, e.g. -CH2CH2OCH3。R3Can represent-CH2C(=O)-NHCH2CH2OCH3；
d) R10And R11One of them represents hydrogen and the other represents R6Substituted C1-6An alkyl group. R6It may be a saturated 5-membered monocyclic heterocycle containing one nitrogen heteroatom, such as pyrrolidinyl. Or R6An aromatic 5-membered monocyclic heterocycle containing two nitrogen heteroatoms, such as imidazolyl, is possible. R3Can represent-CH2C(=O)-NH-CH2CH2- (pyrrolidin-1-yl) or-CH2C(=O)-NH-CH2CH2- (imidazol-2-yl);
e) R10and R11One of them represents hydrogen and the other represents a hydroxyl group C1-6Alkyl radicals, e.g. -CH2CH2OH。R3Can represent-CH2C(=O)-NHCH2CH2OH; or
f) R10And R11One represents hydrogen and the other represents-NR14R15Substituted C1-6Alkyl radical, wherein R14And R15Both are hydrogen. R3Can represent-CH2C(=O)-NHCH2CH2NH2。
In one embodiment, when R3Is represented by-C (= O) -NR10R11Substituted C1-6When alkyl, R10And R11Has the following meanings:
a) R10and R11One of them represents hydrogen and the other represents halogeno C1-6Alkyl radicals, e.g. -CH2CF3。R3Can represent-CH2CH2C(=O)-NHCH2CF3；
b) R10And R11One of them represents C1-6Alkyl radicals, e.g., -CH3The other represents C1-6Alkoxy radicals, e.g. -OCH3。R3Can represent-CH2CH2C(=O)N(CH3)-OCH3。
c) R10And R11One of them represents hydrogen and the other represents R6。R6May be a C-containing radical containing one or two nitrogen atoms and optionally1-6Alkyl or C1-6Alkoxy-substituted 6-membered monocyclic heterocyclic group. R3Can represent-CH2C (= O) NH- (pyridin-2-yl), wherein the pyridin-2-yl is-OCH at the 3-position3Substituted, -CH2C (= O) NH- (pyridin-6-yl), wherein the pyridin-6-yl is substituted with-CH at the 4-position3Substituted, or-CH2C (= O) NH- (pyrimidin-2-yl), wherein the pyrimidin-2-yl group is-OCH at the 4-position3And (4) substitution. R3Can represent-CH2C (= O) NH- (pyridin-3-yl), -CH2C (= O) NH- (pyridin-6-yl) or-CH2C (= O) NH- (pyridin-4-yl).
In one embodiment, R3Represents C substituted by carboxyl1-6An alkyl group. R3Can represent-CH2C (= O) OH or-CH2CH2C(=O)OH。
In one embodiment, R3Is represented by-O-C (= O) -NR10R11Substituted C1-6An alkyl group. In one embodiment, R10And R11One of them represents hydrogen and the other represents C1-6Alkyl radicals, e.g. -CH3。R3Can represent-CH2CH2-O-C(=O)-NHCH3。
In one embodiment, R3Is represented by-NR12-S(=O)2-C1-6Alkyl substituted C1-6An alkyl group. In one embodiment, R12Represents hydrogen. R3Can represent-CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH(CH3)2or-CH2CH2NH-S(=O)2-CH2CH3。
In one embodiment, R3Is represented by-NR12-S(=O)2-NR14R15Substituted C1-6An alkyl group. In one embodiment, R12Represents hydrogen, R14And R15Each represents-CH3。R3Can represent-CH2CH2NH-S(=O)2-N(CH3)2or-CH2CH2CH2NH-S(=O)2-N(CH3)2。
In one embodiment, R3Is represented by R9Substituted and optionally substituted by-O-C (= O) -C1-6Alkyl substituted C1-6An alkyl group.
In one embodiment, when R3Is represented by R9Substituted and optionally substituted by-O-C (= O) -C1-6Alkyl substituted C1-6When alkyl, R9Represents a 5-membered unsaturated ring fused with a 6-membered unsaturated ring, for example, a furan ring fused with a pyridine ring, or an pyrrole ring fused with a pyridine ring, wherein the pyrrole ring is optionally substituted by one C1-4Alkyl radicals such as-CH3And (4) substitution. In one embodiment, R9Represents 1H-pyrrolo [3,2-b ]]Pyridyl, 1-methyl-1H-pyrrolo [3,2-b ]]Pyridyl or furo [3,2-b ]]A pyridyl group.
In one embodiment, R3Represents a substituted hydroxyl group and R9Substituted C1-6An alkyl group.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents a saturated 5-membered monocyclic heterocyclic group containing one nitrogen heteroatom, such as pyrrolidinyl. R3May represent propyl substituted by-OH and 1-pyrrolidinyl.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents a saturated 5-membered monocyclic heterocyclic group containing one nitrogen heteroatom, e.g. pyrrolidinylAnd the heterocyclic group is a substituted heterocyclic group. For example, the heterocyclic group is substituted by:
a) two halo groups, for example two fluoro groups. R3May represent propyl substituted by-OH and 1-pyrrolidinyl, wherein the 1-pyrrolidinyl is substituted at the 3-position by two fluoro; or
b) A cyano group. R3May represent propyl substituted by-OH and 1-pyrrolidinyl, wherein the 1-pyrrolidinyl is substituted by cyano in position 3.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocycle containing one nitrogen and one oxygen heteroatom, such as morpholinyl. R3May represent propyl substituted by-OH and 4-morpholinyl.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents a saturated 6-membered monocyclic heterocycle containing one nitrogen heteroatom, for example piperidinyl. R3May represent propyl substituted by-OH and 1-piperidinyl.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents an aromatic 5-membered monocyclic heterocycle containing three nitrogen heteroatoms, for example 1,2, 4-triazolyl. The heterocyclic ring may be substituted by a C1-4Alkyl radicals such as-CH3And (4) substitution. R3May represent-OH and 2- (1,2, 4-triazolyl) (in position 3 by-CH)3Substituted) propyl groups.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents an aromatic 5-membered monocyclic heterocycle containing two nitrogen heteroatoms, such as imidazolyl. The heterocyclic ring may be substituted by a C1-4Alkyl radicals such as-CH3And (4) substitution. R3May represent-OH and 1-imidazolyl (in the 2-position by-CH)3Substituted) propyl groups.
In one embodiment, when R3Represents a substituted hydroxyl group and R9Substituted C1-6When alkyl, R9Represents an optionally substituted bicyclic heterocyclic group containing one nitrogen heteroatom, which may be substituted, for example, by two = O groups. R3May represent a propyl group substituted by a hydroxyl group and an isoindole-1, 3-dione.
In one embodiment, R3represents-C1-6alkyl-C (R)12)=N-O-R12。R12May be independently selected from hydrogen and optionally C1-4Alkoxy-substituted C1-4Alkyl radicals, e.g. -CH3or-CH (CH)3)2。R3Can represent-CH2C(CH3)=N-O-H，-CH2C(CH2OCH3) = N-O-H or-CH2C(CH(CH3)2)=N-O-H。
In one embodiment, R3represents-S (= O)2-NR14R15Wherein R is14And R15May each be C1-4An alkyl group. R3May be-S (= O)2-N(CH3)2。
In one embodiment, R3Is represented by-S (= O)2-C1-6Alkyl substituted C1-6An alkyl group. R3May be-CH2CH2-S(=O)2-CH3。
In one embodiment, R3represents-C (= O) -R9Substituted C1-6An alkyl group. R9May represent a saturated 5-membered monocyclic heterocycle containing one nitrogen heteroatom, such as pyrrolidinyl. R3Can represent-CH2-C(=O)-R9，R9Is a 1-pyrrolidinyl group.
In one embodiment, R3Is represented by R9Substituted C2-6An alkenyl group. R9May represent an optionally substituted aromatic 6-membered monocyclic heterocycle containing one or two nitrogen heteroatoms, e.g. pyridyl or pyrimidineAnd (4) a base. The heterocyclic group may be substituted heterocyclic group, e.g. by a C1-4Alkyl or a C1-4Substituted by alkoxy substituents, e.g. -CH3or-OCH3。R3Can represent-CH2CH = CH- (2-pyrimidinyl), -CH2CH = CH- (2-pyrimidinyl), wherein the 2-pyrimidinyl is-OCH in position 43Substituted, -CH2CH = CH- (2-pyridyl), wherein the 2-pyridyl is-CH at the 4-position3Substituted, or-CH2CH = CH- (2-pyridyl), wherein the 2-pyridyl is-OCH at the 3-position3And (4) substitution.
In one embodiment, R3Is represented by R9Substituted C2-6Alkynyl. R9May represent an optionally substituted aromatic 5-membered monocyclic heterocycle containing two nitrogen heteroatoms, such as imidazolyl. The heterocyclic group may be substituted heterocyclic group, e.g. by a C1-4Substituted by alkyl substituents, e.g. -CH3。R3Can represent-CH2-C ≡ C- (2-imidazolyl), wherein the 2-imidazolyl group is substituted at the 1-position with-CH3Substituted, or-CH2-C ≡ C- (5-imidazolyl), wherein the 5-imidazolyl group is substituted at the 1-position with-CH3And (4) substitution.
In one embodiment, R3Is represented by R9Substituted C2-6Alkynyl.
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocycle containing one or two nitrogen heteroatoms, such as pyridyl, pyrimidinyl or pyrazinyl. R3Can represent-CH2-C ≡ C- (4-pyridyl), -CH2-C ≡ C- (3-pyridyl), -CH2-C ≡ C- (2-pyridyl), -CH2-C ≡ C- (2-pyrimidinyl), -CH2-C ≡ C- (6-pyrazinyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted aromatic 6-membered monocyclic heterocycle containing one or two nitrogen heteroatoms, e.g. pyridineA pyrimidinyl group or a pyrazinyl group, and the heterocyclic group may be a substituted heterocyclic group, for example, substituted with:
a) one hydroxyl group C1-4An alkyl group. R3May represent a-CH substituted at position 2 or 42OH-substituted-CH2-C ≡ C- (6-pyridyl);
b) a C1-4Alkoxy radicals, e.g. -OCH3，-OCH2CH3。R3Can represent
At position 6 by-OCH3substituted-CH2-C ≡ C- (4-pyridyl) substituted at the 3 or 5 position by-OCH3substituted-CH2-C ≡ C- (2-pyridyl) substituted in position 4 or 6 with-OCH3substituted-CH2-C.ident.C- (2-pyrimidinyl),
at position 2,4 or 5 by-OCH3substituted-CH2-C ≡ C- (6-pyridyl) substituted in the 4-position by-OCH3substituted-CH2-C.ident.C- (6-pyrimidinyl),
at position 6 by-OCH3substituted-CH2-C.ident.C- (5-pyrazinyl),
at position 6 by-OCH2CH3substituted-CH2-C.ident.C- (2-pyrimidinyl),
at position 4 by-OCH3substituted-C (CH)3)2-C ≡ C- (2-pyrimidinyl) substituted in position 4 with-OCH (CH)3)2substituted-CH2-C ≡ C- (2-pyrimidinyl);
c) one cyano group. R3May represent-CH substituted in the 2 or 4 position by cyano2-C ≡ C- (6-pyridyl), -CH substituted at the 5 or 6 position by cyano2-C ≡ C- (4-pyridyl);
d) one is-NR14R15。R3May represent a substituted radical-NH-in position 2 or 42substituted-CH2-C ≡ C- (6-pyridyl) substituted at the 2-position by-NH2substituted-CH2-C ≡ C- (6-pyrimidinyl) substituted at the 3-position by-NH2substituted-CH2-C≡C-(2-Pyridyl) substituted by-NH at the 6-position2substituted-CH2-C ≡ C- (3-pyrazinyl), at position 5 by-NHCH3substituted-CH2-C.ident.C- (6-pyridyl),
e) a C1-4Alkyl radicals, e.g. -CH3or-CH2CH3。R3May represent a-CH substituted at position 3 or 43substituted-CH2-C ≡ C- (6-pyridyl) substituted in position 3 with-CH3substituted-CH2-C ≡ C- (2-pyridyl) substituted at the 4-position by-CH3substituted-CH2-C ≡ C- (2-pyrimidinyl) substituted in position 6 with-CH2CH3substituted-CH2-C.ident.C- (2-pyrimidinyl),
f) a C1-4Alkyl radicals, e.g. -CH3And a-NR14R15E.g. -NH2。R3May represent a-CH at position 23Substituted and substituted in the 4-position by-NH2substituted-CH2-C ≡ C- (6-pyrimidinyl);
g) one halogen, e.g. -Cl, and one-NR14R15E.g. -NH2。R3May represent a substituted radical-NH at the 2-position2Substituted and-CH substituted in the 4-position by-Cl2-C.ident.C- (6-pyrimidinyl),
h) a halogen, such as-Br, -Cl or-F. R3May represent-CH substituted in position 3 by-Cl2-C ≡ C- (2-pyrazinyl), -CH substituted at the 5-position with-Cl2-C ≡ C- (3-pyrazinyl), or-CH substituted at position 3 with-F2-C ≡ C- (2-pyridyl), -CH substituted in position 6 with-Br2-C ≡ C- (5-pyridyl);
i) one-C (= O) -NR14R15。R3May represent a substituted radical of-C (= O) -NH at the 4-position2substituted-CH2-C ≡ C- (6-pyridyl);
j) a C1-4alkyl-O-C (= O) -. R3May represent a channel being CH at position 53-O-C (= O) -substituted-CH2-C ≡ C- (6-pyridyl) substituted by CH at position 63-O-C (= O) -substituted-CH2-C ≡ C- (2-pyrimidinyl);
k) a halogen radical C1-4An alkyl group. R3May represent a 3-bit by-CF3substituted-CH2-C ≡ C- (2-pyridyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing one nitrogen and one sulphur heteroatom, for example thiazolyl. R3Can represent-CH2-C.ident.C- (5-thiazolyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents optionally substituted phenyl. R3May be-CH2-C ≡ C- (phenyl). Phenyl may be substituted, e.g. by a C1-4Alkoxy substitution. R3Can represent-CH2-C ≡ C- (phenyl), wherein the phenyl is substituted in the 5-position by-OCH3And (4) substitution.
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted saturated 4-membered monocyclic heterocycle containing one nitrogen heteroatom, for example azetidinyl. The heterocyclic group may be substituted, for example, with the following:
a) one hydroxyl group and one C1-4alkyl-O-C (= O) -. R3Can represent a 1-bit is (CH)3)3-CH substituted by C-O-C (= O) -and substituted in position 3 by-OH2-C ≡ C- (3-azetidinyl);
b) one hydroxyl group. R3May represent-CH substituted in position 3 by-OH2-C ≡ C- (3-azetidinyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted saturated 5-membered monocyclic heterocycle containing one nitrogen heteroatom, for example pyrrolidinyl. The heterocyclic group may beTo be substituted, for example, by:
a) one hydroxyl group and one C1-4alkyl-O-C (= O) -. R3Can represent a 1-bit is (CH)3)3-CH substituted by C-O-C (= O) -and substituted in position 3 by-OH2-C ≡ C- (3-pyrrolidinyl);
b) one hydroxyl group. R3May represent-CH substituted in position 3 by-OH2-C ≡ C- (3-pyrrolidinyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted, saturated 6-membered monocyclic heterocycle containing one nitrogen heteroatom, for example piperidinyl. R3Can represent-CH2-C ≡ C- (4-piperidinyl). The heterocyclic group may be substituted, for example, with the following:
a) one hydroxyl group. R3May represent-CH substituted in the 4-position by-OH2-C ≡ C- (4-piperidinyl);
b) a C1-4alkyl-O-C (= O) -. R3Can represent a 1-bit is (CH)3)3C-O-C (= O) -substituted-CH2-C ≡ C- (4-piperidinyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted, saturated 5-membered monocyclic heterocycle containing one oxygen heteroatom, for example tetrahydrofuranyl. The heterocyclic group may be substituted, for example, with one hydroxy group. R3May represent-CH substituted in position 3 by-OH2-C ≡ C- (4-tetrahydrofuryl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents an optionally substituted, saturated 6-membered monocyclic heterocycle containing one oxygen heteroatom, for example tetrahydropyranyl. The heterocyclic group may be substituted, for example, with one hydroxy group. R3May represent-CH substituted in the 4-position by-OH2-C ≡ C- (4-tetrahydropyranyl).
In one embodiment, when R3Is represented by R9Substituted C2-6In the case of alkynyl, R9Represents C3-8Cycloalkyl radicals, such as cyclohexyl.
R3Can represent-CH2-C ≡ C- (cyclohexyl).
In one embodiment, R3Is represented by R9Substituted C2-6Alkynyl (e.g., -CH)2-C ≡ C-), wherein R is9Represents C3-8Cycloalkyl or a 3-to 12-membered monocyclic or bicyclic heterocyclic radical containing at least one heteroatom selected from N, O or S, said C3-8The cycloalkyl or 3 to 12 membered monocyclic or bicyclic heterocyclyl is each optionally and each independently substituted with 1,2,3, 4 or 5 substituents as defined herein.
In one embodiment, R3Is represented by R9Substituted C2-6Alkynyl (e.g., -CH)2-C ≡ C-), wherein R is9Represents an optionally substituted 4-to 8-membered monocyclic or bridged heterocyclic radical, e.g. R9Represents optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl or 2, 5-diaza-bicyclo [2.2.1]]A heptyl group.
In one embodiment, R3Is represented by R9Substituted C2-6Alkynyl (e.g., -CH)2-C ≡ C-), wherein R is9Represents
An optionally substituted aromatic 5-or 6-membered monocyclic heterocyclyl group, such as imidazolyl, thiazolyl, pyridyl, pyrimidinyl or pyrazinyl,
optionally substituted saturated 4,5 or 6 membered monocyclic heterocyclyl, for example azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,
an optionally substituted 6-to 8-membered bridged heterocyclyl group, for example a 2, 5-diaza-bicyclo [2.2.1] heptyl group,
C3-8cycloalkyl radicals, such as cyclohexyl.
In one embodiment, R3Is represented by R9Substituted C2-6Alkynyl (e.g., -CH)2-C ≡ C-), wherein R is9Represents
An optionally substituted aromatic 5-membered monocyclic heterocycle containing two nitrogen heteroatoms, such as imidazolyl,
an optionally substituted aromatic 6-membered monocyclic heterocycle containing one nitrogen heteroatom, for example pyridyl,
an optionally substituted aromatic 6-membered monocyclic heterocycle containing one or two nitrogen heteroatoms, such as pyridyl, pyrimidinyl or pyrazinyl,
an optionally substituted aromatic 5-membered monocyclic heterocyclyl group containing one nitrogen and one sulphur heteroatom, for example thiazolyl,
an optionally substituted saturated 4-membered monocyclic heterocycle containing one nitrogen heteroatom, such as azetidinyl,
an optionally substituted saturated 5-membered monocyclic heterocycle containing one nitrogen heteroatom, such as pyrrolidinyl,
an optionally substituted saturated 5-membered monocyclic heterocycle containing one oxygen heteroatom, for example tetrahydrofuranyl,
an optionally substituted saturated 6-membered monocyclic heterocycle containing one oxygen heteroatom, for example tetrahydropyranyl,
- C3-8cycloalkyl radicals, e.g. cyclohexyl, or
A 6-to 8-membered bridged heterocyclyl group, for example a 2, 5-diaza-bicyclo [2.2.1] heptyl group.
In one embodiment, when R3Is represented by R9Substituted C1-6When alkyl, R9Represents an optionally substituted 6-to 8-membered bridged heterocyclyl group, for example, 2 optionally substituted by-C (= O) -O-C4 alkyl,5-diaza-bicyclo [2.2.1]A heptyl group.
In one embodiment, R3Represents C1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6Alkyl groups may be optionally substituted with one or two hydroxy groups. R3Can represent-CH2CHOHCH2OCH3。
In one embodiment, R3Represents C2-6An alkenyl group. R3Can represent-CH2-CH=CH2。
In one embodiment, R3Represents C2-6Alkynyl. R3Can represent-CH2-C≡C-H。R3Can represent-C (CH)3)2-C≡C-H。
In one embodiment, R3Represents R13。
In one embodiment, when R3Represents R13When R is13Represents a saturated 4-membered monocyclic heterocycle containing one oxygen heteroatom. R3May represent a 3-oxetanyl group.
In another embodiment, when R3Represents R13When R is13Represents optionally substituted C3-8A cycloalkyl group. E.g. C3-8Cycloalkyl radicals may be substituted by one NR14R15Is substituted in which R14And R15One of which represents hydrogen and the other represents C optionally substituted by hydroxy1-4Alkyl radicals, e.g. -CH (CH)3)2。R3May represent a residue substituted in position 4 by-NH-CH (CH)3)2A substituted cyclohexane group.
In one embodiment of the invention, R3Is represented by R9Substituted C1-6Alkyl radical, wherein R9Is by R13Substituted saturated heterocyclic radical, wherein R13Is an optionally substituted saturated heterocyclic radical, e.g. substituted by-C (= O) -C1-6Alkyl substitution. In one embodiment, R9Is a quiltR13Substituted piperazinyl wherein R13Is represented by-C (= O) -C1-6Alkyl-substituted piperidinyl.
In one embodiment of the invention, R3represents-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group. R3Can represent-CH2CH2P(=O)(OCH2CH3)2。
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2NHCH(CH3)2。
In a further embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2-CH2-NHCH2CF3。
In a further embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH2。
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g.CH3O-，R3Is represented by-R9Substituted C2-6Alkynyl, e.g. -CH2-C ≡ C- (2-pyridyl).
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-R9Substituted C2-6Alkynyl, e.g. by-OCH in the 3 position3substituted-CH2-C ≡ C- (2-pyridyl).
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CD3O-，R3Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. R3Can represent-CD2-CD2-NHCH(CH3)2。
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-R9Substituted C2-6Alkynyl, e.g. by-NH in position 22substituted-CH2-C ≡ C- (6-pyridyl).
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-R9Substituted C2-6Alkynyl, e.g. by-OCH at the 4 position3substituted-CH2-C ≡ C- (2-pyrimidinyl).
In one embodiment of the inventionIn the scheme, R1Represents C1-6Alkyl radicals, e.g. -CH (CH)3)2Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CD3O-，R3Is represented by-R9Substituted C2-6Alkynyl, e.g., -CH2-C ≡ C- (4-pyridyl).
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH (CH)3)2Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Represents C1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted by one or two hydroxy groups or by-O-C (= O) -C1-6Alkyl substitution, e.g., -CH2CHOHCH2OCH3。
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-R9Substituted C2-6Alkynyl, e.g. by-CH in the 4-position3substituted-CH2-C ≡ C- (6-pyridyl).
In one embodiment of the invention, R1Is represented by-NR4R5Substituted C1-6Alkyl radicals, e.g. -CH2CH2CH2NH2Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Represents hydroxy halogeno C1-6Alkyl radicals, e.g. -CH2CHOHCF3。
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 4, two R' s2Represents C1-4Alkoxy radicals, e.g. CH3O-, two R2Represents halogen, e.g. F, R3Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g., -CH2CH2NH(CH(CH3)2)。
In one embodiment of the invention, R1Represents C1-6Alkyl radicals, e.g. -CH3Each R1aRepresents hydrogen, n represents an integer equal to 2, each R represents2Represents C1-4Alkoxy radicals, e.g. CH3O-，R3Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2CH2NH2。
In a further embodiment, the compound of formula (I) as defined herein is selected from the following compounds or is one of the following compounds:
n- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (Compound 84)
3- {4- [3- (4- {7- [ (cyclopropylmethyl) (3, 5-dimethoxyphenyl) amino ] quinoxalin-2-yl } -1H-pyrazol-1-yl) propyl ] piperazin-1-yl } propan-1-ol or its HCl salt (Compound 130)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (Compound 4)
2- [4- (7- { (cyclopropylmethyl) [3- (2-hydroxyethoxy) -5-methoxyphenyl ] amino } quinoxalin-2-yl) -1H-pyrazol-1-yl ] ethanol or its HCl salt (Compound 131)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-imidazol-2-yl) prop-2-yn-1-yl ] -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 300)
1- (3- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } propyl) pyrrolidin-2-one (Compound 132)
(3S) -1- (2- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } ethyl) pyrrolidine-3-carbonitrile (Compound 133)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] -N' - (2,2, 2-trifluoroethyl) propane-1, 3-diamine (Compound 5)
2- (4- {7- [ (3, 5-dimethoxyphenyl) {2- [ (1-methylethyl) amino ] ethyl } amino ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -N-methylacetamide or its HCl salt (Compound 134)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-ethyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] -N' - (1-methylethyl) ethane-1, 2-diamine or the HCl salt thereof (Compound 135)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- {3- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-pyrazol-4-yl ] quinoxalin-6-yl } ethane-1, 2-diamine or its HCl salt (Compound 136)
(2S) -3- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } propane-1, 2-diol (Compound 98)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine or its HCl salt (Compound 137)
N- (3, 5-Dimethoxyphenyl) -N- (1H-imidazol-2-ylmethyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 99)
3- { (Cyclopropylmethyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -5-fluoro-N-methylbenzamide (Compound 138)
1- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -3- [ (2,2, 2-trifluoroethyl) amino ] propan-2-ol (Compound 139)
3- [ (2- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } ethyl) amino ] propionitrile (Compound 140)
4- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -2-methylbutan-2-ol (Compound 141)
(2S) -1- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -3- [ (2,2, 2-trifluoroethyl) amino ] propan-2-ol (Compound 142)
N- [2- (4-acetylpiperazin-1-yl) ethyl ] -N- (3, 5-dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 143)
4- (2- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } ethyl) piperazin-2-one (Compound 144)
(2S) -1- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -3- [ (1-methylethyl) amino ] propan-2-ol or its HCl salt (Compound 145)
N- (3, 5-Dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -N- (pyrazin-2-ylmethyl) quinoxalin-6-amine (Compound 146)
N- (3, 5-Dimethoxyphenyl) -N- {3- [1- (1-methylethyl) -1H-pyrazol-4-yl ] quinoxalin-6-yl } -N' - (2,2, 2-trifluoroethyl) propane-1, 3-diamine or the HCl salt thereof (Compound 147)
(2R x) -3- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -1,1, 1-trifluoropropan-2-ol (relative stereochemistry) (Compound 148)
(2S) -3- { (3, 5-Dimethoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] amino } -1,1, 1-trifluoropropan-2-ol (relative stereochemistry) (compound 149);
an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
In a further embodiment, the compound of formula (I) as defined herein is selected from the following compounds or is one of the following compounds:
n- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] -N' - (2,2, 2-trifluoroethyl) propane-1, 3-diamine (Compound 5)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (Compound 4)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (Compound 84)
N- (3, 5-Dimethoxyphenyl) -N- {3- [1- (1-methylethyl) -1H-pyrazol-4-yl ] quinoxalin-6-yl } -N' - (2,2, 2-trifluoroethyl) propane-1, 3-diamine or the HCl salt thereof (Compound 147)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine or its HCl salt (Compound 137)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- {3- [1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-pyrazol-4-yl ] quinoxalin-6-yl } ethane-1, 2-diamine or its HCl salt (Compound 136)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-ethyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] -N' - (1-methylethyl) ethane-1, 2-diamine or the HCl salt thereof (Compound 135)
2- (4- {7- [ (3, 5-dimethoxyphenyl) {2- [ (1-methylethyl) amino ] ethyl } amino ] quinoxalin-2-yl } -1H-pyrazol-1-yl) -N-methylacetamide or its HCl salt (Compound 134)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-imidazol-2-yl) prop-2-yn-1-yl ] -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 300);
an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
In a further embodiment, the compound of formula (I) as defined herein is selected from the following compounds or is one of the following compounds:
n- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] -N' - (2,2, 2-trifluoroethyl) propane-1, 3-diamine (Compound 5)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (Compound 4)
N- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (Compound 84);
an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
In a further embodiment, the compound of formula (I) as defined herein is selected from the following compounds or is one of the following compounds:
n- (3, 5-Dimethoxyphenyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] propane-1, 3-diamine (Compound 93)
2- (4- {7- [ (3, 5-Dimethoxyphenyl) {2- [ (1-methylethyl) amino ] ethyl } amino ] quinoxalin-2-yl } -1H-pyrazol-1-yl) ethanol (Compound 691)
N- (3, 5-Dimethoxyphenyl) -N' - (1-methylethyl) -N- (3- {1- [2- (methylsulfonyl) ethyl ] -1H-pyrazol-4-yl } quinoxalin-6-yl) ethane-1, 2-diamine (Compound 678)
N- (3, 5-Dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -N- (3-pyridin-2-ylprop-2-yn-1-yl) quinoxalin-6-amine (Compound 691)
N- (3, 5-Dimethoxyphenyl) -N- [3- (3-methoxypyridin-2-yl) prop-2-yn-1-yl ] -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 652)
N- {3, 5-bis [ (II) ((III))2H3) Methoxy radical]Phenyl } -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl](2H4) Ethane-1, 2-diamine (Compound 618)
N- [3- (6-Aminopyridin-2-yl) prop-2-yn-1-yl ] -N- (3, 5-dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 689)
N- (3, 5-Dimethoxyphenyl) -N- [3- (4-methoxypyrimidin-2-yl) prop-2-yn-1-yl ] -3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-amine (Compound 688)
N- {3, 5-bis [ (II) ((III))2H3) Methoxy radical]Phenyl } -3- [1- (1-methylethyl) -1H-pyrazol-4-yl]-N- (3-pyridin-4-ylprop-2-yn-1-yl) quinoxalin-6-amine (compound 653)
1- [ (3, 5-dimethoxyphenyl) {3- [1- (1-methylethyl) -1H-pyrazol-4-yl ] quinoxalin-6-yl } amino ] -3-methoxypropan-2-ol; or its hydrochloride (compound 657)
N- (3, 5-Dimethoxyphenyl) -3- (1-methyl-1H-pyrazol-4-yl) -N- [3- (4-methylpyridin-2-yl) prop-2-yn-1-yl ] quinoxalin-6-amine (Compound 634)
3- [ {3- [1- (3-aminopropyl) -1H-pyrazol-4-yl ] quinoxalin-6-yl } (3, 5-dimethoxyphenyl) amino ] -1,1, 1-trifluoropropan-2-ol; or an enantiomer thereof (Compounds 660 and 661)
N- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine (compound 687);
an N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
According to one aspect of the present invention, there is provided a compound of formula (I):
(I)
including any tautomeric or stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, C1-6Alkyl radical, C2-4Alkenyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, cyano C1-4Alkyl radical, each of which is C1-6The alkyl radical mayWith C optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, or by-Si (CH)3)3Substituted C1-6An alkyl group;
each R1aIndependently selected from hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl radical, di (C)1-4Alkyl) amino-substituted C1-4Alkyl, and C substituted by one or more fluorine atoms1-4An alkyl group;
each R2Independently selected from hydroxy, halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13Is being NR7R8Substituted C1-4Alkyl radical, by NR7R8Substituted C1-4Alkoxy, -NR7R8and-C (= O) -NR7R8(ii) a Or when two R are2When groups are attached to adjacent carbon atoms, they may be joined together to form a compound of the formula-O- (C (R)17)2)p-O-wherein R is17Represents hydrogen or fluorine, p represents 1 or 2;
R3represents C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, hydroxy C2-6Alkynyl, halo C1-6Alkyl, optionally substituted by-O-C (= O) -C1-6Alkyl-substituted halogeno C1-6Alkyl radical, substituted by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted by one or two hydroxy groups or by-O-C (= O) -C1-6Alkyl substituted C1-6Alkoxy radical C1-6Alkyl radical, by R9Substituted C1-6Alkyl radical, by-NR10R11Substituted C1-6Alkyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl, C substituted by carboxyl1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, by R9Substituted and optionally substituted by-O-C (= O) -C1-6Alkyl substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12，-S(=O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkenyl radical, by R9Substituted C2-6Alkynyl, hydroxy C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl radical, R13Or by C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl, or substituted by-P (= O) (OC)1-6Alkyl radical)2Substituted C1-6An alkyl group;
R4and R5Each independently represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-6Alkyl radical, R13Or by R13Substituted C1-6An alkyl group;
R6represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C is3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4-to 7-membered monocyclic heterocyclyl, optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: cyano radicals, C1-6Alkyl, cyano C1-6Alkyl, hydroxy, carboxyl, hydroxy C1-6Alkyl, halogen, halogeno C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-O-C (= O) -, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R7and R8Each independently represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl or C1-6Alkoxy radical C1-6An alkyl group;
R9represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, naphthyl, or a 3-to 12-membered monocyclic or bicyclic heterocyclic group containing at least one heteroatom selected from N, O or S, said C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, naphthyl, or 3-to 12-membered monocyclic or bicyclic heterocyclyl are each optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: = O, C1-4Alkyl, hydroxy, carboxyl, hydroxy C1-4Alkyl, cyano C1-4Alkyl radical, C1-4alkyl-O-C (= O) -, by C1-4alkyl-O-C (= O) -substituted C1-4Alkyl radical, C1-4alkyl-C (= O) -, in which each C is1-4C wherein alkyl may be optionally substituted by one or two hydroxy groups1-4Alkoxy radical C1-4Alkyl, halogen, halogeno C1-4Alkyl, hydroxy-halogeno-C1-4Alkyl, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-4Alkyl radical, by-C (= O) -NR14R15Substituted C1-4Alkyl radical, C1-4Alkoxy, -S (= O)2-C1-4Alkyl, -S (= O)2-halo C1-4Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-NR14R15Substituted C1-4Alkyl radical, by-NH-S (= O)2-C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-halo C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-4Alkyl radical, R13，-C(=O)-R13Is by R13Substituted C1-4Alkyl, optionally substituted by R16Substituted phenyl, wherein phenyl is optionally substituted with R16Substituted phenyl radicals C1-6Alkyl, a 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl is optionally substituted by R16Substitution;
or when R is9When the two substituents of (a) are attached to the same atom, they may be taken together to form a 4-to 7-membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S;
R10and R11Each independently represents hydrogen, C1-6Alkyl, cyano C1-6Alkyl radical, by-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl, -C (= O) -R6，-C(=O)-C1-6Alkyl, -C (= O) -hydroxy C1-6Alkyl, -C (= O) -halo C1-6Alkyl, -C (= O) -hydroxyhaloC1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radicalquilt-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R12represents hydrogen or optionally substituted by C1-4Alkoxy-substituted C1-4An alkyl group;
R13represents C3-8Cycloalkyl or a saturated 4-to 6-membered monocyclic heterocyclyl group containing at least one heteroatom selected from N, O or S, wherein said C is3-8The cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1,2 or 3 substituents each independently selected from halogen, hydroxy, C1-6Alkyl, -C (= O) -C1-6Alkyl radical, C1-6Alkoxy or-NR14R15；
R14And R15Each independently represents hydrogen, or halogeno C1-4Alkyl, or C optionally substituted by a substituent selected from the group consisting of1-4Alkyl groups: hydroxy radical, C1-4Alkoxy, amino or mono-or di (C)1-4Alkyl) amino;
R16represents hydroxy, halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, -NR14R15or-C (= O) NR14R15；
An N-oxide thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
In one embodiment, there is provided formula (I)0) The compound of (1):
(I0)
including any stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, C1-6Alkyl radical, C2-4Alkenyl, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, or by-Si (CH)3)3Substituted C1-6An alkyl group;
each R2Independently selected from halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13Is being NR7R8Substituted C1-4Alkyl radical, by NR7R8Substituted C1-4Alkoxy, -NR7R8or-C (= O) -NR7R8；
R3Represents C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl, halo C1-6Alkyl radical, substituted by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted with one or two hydroxyl groupsSubstituted C1-6Alkoxy radical C1-6Alkyl radical, by R9Substituted C1-6Alkyl radical, by-NR10R11Substituted C1-6Alkyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl, C substituted by carboxyl1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12is-C (= O) -NR10R11Substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkynyl, hydroxy C1-6Alkoxy radical, C2-6Alkenyl radical, C2-6Alkynyl radical, R13Or by C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6An alkyl group;
R4and R5Independently represent hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl radicalSubstituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-6Alkyl radical, R13Or by R13Substituted C1-6An alkyl group;
R6represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4,5,6 or 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C is3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl, 4,5,6, or 7 membered monocyclic heterocyclyl is optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: cyano radicals, C1-6Alkyl, cyano C1-6Alkyl, hydroxy, carboxyl, hydroxy C1-6Alkyl, halogen, halogeno C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6alkyl-O-C (= O) -, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R7and R8Independently represent hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl or C1-6Alkoxy radical C1-6An alkyl group;
R9represents C3-8Cycloalkyl radical, C3-8Cycloalkenyl, phenyl or a 3-to 12-membered monocyclic or bicyclic heterocyclic radical containing at least one heteroatom selected from N, O or S, C3-8Cycloalkyl radical, C3-8The cycloalkenyl group, aryl group, or 3-to 12-membered monocyclic or bicyclic heterocyclic group is each optionally and each independently substituted with 1 to 5 substituents, each substituent independently selected from: = O, C1-4Alkyl, hydroxy, carboxyl, hydroxy C1-4Alkyl, cyano C1-4Alkyl radical, C1-4alkyl-O-C (= O) -, by C1-6alkyl-O-C (= O) -substituted C1-4Alkyl radical, C1-4alkyl-C (= O) -, in which each C is1-4C wherein alkyl may be optionally substituted by one or two hydroxy groups1-4Alkoxy radical C1-4Alkyl, halogen, halogeno C1-4Alkyl, hydroxy-halogeno-C1-4Alkyl, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-4Alkyl radical, by-C (= O) -NR14R15Substituted C1-4Alkyl radical, C1-4Alkoxy, -S (= O)2-C1-4Alkyl, -S (= O)2-halo C1-4Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-NR14R15Substituted C1-4Alkyl radical, by-NH-S (= O)2-C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-halo C1-4Alkyl substituted C1-4Alkyl radical, by-NH-S (= O)2-NR14R15Substituted C1-4Alkyl radical, R13，-C(=O)-R13Is by R13Substituted C1-4Alkyl, optionally substituted by R16Substituted phenyl, wherein phenyl is optionally substituted with R16Substituted phenyl radicals C1-6Alkyl, a 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said heterocyclyl is optionally substituted by R16Substitution;
or when R is9When two substituents of (a) are attached to the same atom, they may be taken together to form a 4-, 5-, 6-or 7-membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S;
R10and R11Each independently represents hydrogen, C1-6Alkyl, cyano C1-6Alkyl radical, by-NR14R15Substituted C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy-halogeno-C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl, -C (= O) -R6，-C(=O)-C1-6Alkyl, -C (= O) -hydroxy C1-6Alkyl, -C (= O) -halo C1-6Alkyl, -C (= O) -hydroxyhaloC1-6Alkyl, by-Si (CH)3)3Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-halo C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl radical, is substituted by-S (= O)2-NR14R15Substituted C1-6Alkyl radical, by-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NH-S (= O)2-halo C1-6Alkyl substituted C1-6Alkyl, or substituted by-NH-S (= O)2-NR14R15Substituted C1-6An alkyl group;
R12represents hydrogen or optionally substituted by C1-4Alkoxy-substituted C1-4An alkyl group;
R13represents C3-8Cycloalkyl or a saturated 4-to 6-membered monocyclic heterocyclyl group containing at least one heteroatom selected from N, O or S, wherein said C is3-8The cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1,2 or 3 substituents each independently selected from halogen, hydroxyBase, C1-6Alkyl, -C (= O) -C1-6Alkyl radical, C1-6Alkoxy or-NR14R15；
R14And R15Each independently represents hydrogen, or halogeno C1-4Alkyl, or C optionally substituted by a substituent selected from the group consisting of1-4Alkyl groups: hydroxy radical, C1-4Alkoxy, amino or mono-or di (C)1-4Alkyl) amino;
R16represents hydroxy, halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, -NR14R15or-C (= O) NR14R15；
And N-oxides, pharmaceutically acceptable salts, or solvates thereof.
In one embodiment, there is provided formula (I)0) The compound of (1):
(I0)
including any stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, and is selected from the group consisting of,
C1-6alkyl radicals, e.g. -CH3，-CD3，-CH2CH3，-CH2CH2CH3，-CH2CH(CH3)2，-CH(CH3)2，-CH2CH(CH3)2，
C2-4Alkenyl radicals, e.g. CH2-CH=CH2，
Hydroxy radical C1-6Alkyl radicals, e.g. -CH2CH2OH，-CH2C(CH3)2OH or CH2CHOHCH2OH，
Halogen substituted C1-6Alkyl radicals, e.g. -CH2CH2F，CH2CH2CH2Cl or CH2CH2Br，
Wherein each C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radicals, e.g. -CH2CH2OCH3，
Is represented by-NR4R5Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH2or-CH2CH2CH2NH2，-CH2CH2NHCH3，-CH2CH2NHS(=O)2N(CH3)2，-CH2CH2NHS(=O)2CH3，
by-C (= O) -NR4R5Substituted C1-6Alkyl radicals, e.g. -CH2C(=O)N(CH3)2，-CH2C(=O)NHCH3or-C (CH)3)2C(=O)NHCH3，-C(CH3)2C(=O)NHCH2CH2OH or-CH2C(=O)NHCH2CH2OH，-CH2C(=O)NHCH2CH2OCH3or-C (CH)3)2C(=O)NHCH2CH2OCH3，-CH2-C(=O)-NH-CH2-CH2- (pyrrolidin-1-yl), -CH2CH2CH2NHCH2CH2-S(=O)2-CH3，
-S(=O)2-C1-6Alkyl radicals, e.g., -S (= O)2-CH3，
-S(=O)2-NR14R15For example-S (= O)2-N(CH3)2，
quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g.-CH2CH2S(=O)2-CH3，
is-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2CH2NHS(=O)2-CH3，
R6E.g. 4-piperidinyl, 2-tetrahydropyranyl or 4-tetrahydropyranyl, 4-tetrahydrofuranyl, in position 1 by-CH2CH2OH-substituted 3-azetidinyl substituted on the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperidinyl substituted on the nitrogen by-S (= O)2CH3Substituted 4-piperidinyl radicals substituted on the nitrogen atom by-CH3A substituted 4-piperidinyl group which is substituted,
by R6Substituted C1-6Alkyl, for example methyl or ethyl, each substituted by 4-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl or 4-tetrahydropyranyl; propyl substituted with morpholinyl, wherein the morpholinyl is attached to the propyl through an N heteroatom; methyl, ethyl or propyl each substituted by: at the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperidinyl substituted on the nitrogen by-CH3Substituted 4-piperidinyl radicals substituted on the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperazinyl substituted on the nitrogen by-CH2CH24-piperazinyl substituted by-CH on the nitrogen atom2CH2CH24-piperazinyl substituted by OH, 1-piperidinyl substituted by-OH in position 1, by-O-CH in position 13Substituted 1-piperidinyl, methyl substituted with 2-thienyl, wherein the 2-thienyl is substituted with chloro at the 5-position; methyl substituted by 4-piperidinyl, wherein the 4-piperidinyl group is substituted on the nitrogen atom by (CH)3)3C-O-C (= O) -substituted and substituted with-OH at the 4-position,
is represented by-C (= O) -R6Substituted C1-6Alkyl radicals, e.g., -C (CH)3)2-C (= O) - (piperazin-4-yl) substituted at the 1-position on the nitrogen atom with (CH)3)3C-O-C (= O) -substituted-C (CH)3)2-C (= O) - (piperazin-4-yl), -CH substituted at the 3-position with-OH2-C (= O) - (pyrrolidin-1-yl),
by R6Substituted hydroxy radical C1-6Alkyl radicals, e.g. 1-piperidinyl-substituted-CH2CHOHCH2-，
is-Si (CH)3)3Substituted C1-6Alkyl radicals, e.g. -CH2Si(CH3)3Or is or
Cyano group C1-4Alkyl radicals, e.g. -CH2CH2CN；
Each R2Independently selected from:
a hydroxyl group(s),
halogen, such as fluorine, chlorine or bromine,
the cyano group(s),
C1-4alkyl radicals, e.g. -CH3，
C2-4Alkenyl, e.g. -CH = CH2，
C1-4Alkoxy radicals, e.g. CH3O-，(CH3)2CHO-，CH3CH2O-，CD3O-，
Hydroxy radical C1-4Alkyl radicals, e.g. -CH2OH，
Hydroxy radical C1-4Alkoxy radicals, e.g. -OCH2CH2OH，
Halogen substituted C1-4Alkyl radicals, e.g. CF3，
Halogen substituted C1-4Alkoxy radicals, e.g. -OCH2CH2F，CHF2O-or-OCF3，
C1-4Alkoxy radical C1-4Alkyl radicals, e.g. -CH2CH2OCH3，
R13For example, a 2-dioxolanyl group,
by R13Substituted C1-4Alkoxy radicals, e.g. -OCH2C3H5，
-C(=O)-R13For example-C (= O) - (1-pyrrolidinyl),
by NR7R8Substituted C1-4Alkyl radicals, e.g. -CH2N(CH2CH3)2，-CH2N(CH3)2or-CH2N(CH2CH3)(CH3)，
By NR7R8Substituted C1-4Alkoxy radicals, e.g. -OCH2CH2NH2，
-NR7R8For example-NHCH3or-N (CH)3)2，
-C(=O)-NR7R8(ii) a For example-C (= O) -NHCH3Or is or
Two R2The radicals being bound to adjacent carbon atoms to form, together, a radical of the formula-O- (C (R)17)2)p-Radical of O-, wherein R17Represents hydrogen, p represents 1;
R3represents
C1-6Alkyl radicals, e.g. -CH3，-CH2CH3，-CH2CH2CH3or-CH2CH(CH3)2，
Hydroxy radical C1-6Alkyl radicals, e.g. -CH2CH2OH，-CH2CH2CH2OH，-CH2CHOHCH3，-CH2CHOHCH2CH3，-CH2CHOHCH(CH3)2，-CH2CH2C(OH)(CH3)2，-CH2CHOHCH2OH，-CH2C(CH3)2OH，-CD2CD2OH，-CD2CD2CD2OH, or-CH (CH)3)CH2OH，
Hydroxy halogeno C1-6Alkyl radicals, e.g. -CH2CHOHCF3，
Halogen substituted C1-6Alkyl radicals, e.g. -CH2CH2CH2Cl，-CH2CH2CH2CH2Cl，-CH2CH2F or-CH2CH2I，
Optionally substituted by-O-C (= O) -C1-6Alkyl-substituted halogeno C1-6Alkyl radicals, e.g. -CH2CH(CF3)-O-C(=O)CH3Hydroxy radical C2-6Alkynyl, e.g. -CH2-C≡C-CH2OH or-CH2-C≡C-C(CH3)2OH，
Is represented by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radicals, e.g. CH3-C(=O)-CH2-，(CH3)2CH-C(=O)-CH2-，
Wherein each C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radicals, e.g. -CH2CH2OCH3，-CH2CH2OCH2CH3or-CH2CHOHCH2OCH3，
Wherein each C1-6The alkyl group may optionally be substituted by one or two hydroxy groups or by-O-C (= O) -C1-6Alkyl substituted C1-6Alkoxy radical C1-6Alkyl radicals, e.g. -CH2CH(-O-C(=O)CH3)CH2OCH3，
By R9Substituted C1-6Alkyl radicals, e.g.
-CH2-C3H5or-CH2C5H9，
C substituted by cyclopropyl1-6Alkyl radical, whereinCyclopropyl quilt-CH2OH、CH3CH2-O-C (= O) -4-pyridyl substitution,
methyl substituted by 5-isoxazolyl, 5-isoxazolyl being substituted in position 3 by-CH3And (4) substitution. Or methyl substituted by 3-isoxazolyl, wherein 3-isoxazolyl is substituted in the 5-position by-CH3The substitution is carried out by the following steps,
ethyl or propyl substituted with 4-morpholinyl, methyl substituted with 3-morpholinyl, methyl substituted with 6-morpholinyl,
by 4-morpholinyl (by-CH in positions 2 and 6)3Substituted) ethyl or propyl groups substituted with (i) a,
by 2-morpholinyl (in position 4 by-CH)2-C6H5Substituted) methyl, by 3-morpholinyl (by two-CH in position 5)3Substituted) methyl, by 6-morpholinyl (in position 4 by-CH (CH)3)2Substituted) by 6-morpholinyl (substituted at position 3 with = O, at position 4 with-CH (CH)3)2Substituted) methyl, by 2-morpholinyl (by-CH in position 4)2-C6H5Substituted) methyl, methyl substituted with 2-tetrahydrofuranyl, 2-dioxolane, ethylene oxide, 2-furyl, or 4-tetrahydropyranyl,
by 3-oxetanyl (in the 3-position by-CH)3Substituted) methyl, 3-oxetanyl (in position 3 by-CH)2NHCH(CH3)2Substituted) with a substituted methyl group, or a substituted methyl group,
methyl substituted by 3-pyridyl or 2-pyrazinyl, or propyl substituted by 4-pyridyl,
methyl or propyl substituted by 2-pyrimidinyl,
methyl substituted by 3-pyridyl (substituted by chlorine at the 6-position) or methyl substituted by 2-pyridyl (substituted by bromine at the 6-position),
by 6-pyridyl (by-CH at the 4-position)3Substituted) propyl, substituted by 6-pyridyl (substituted in position 3 by-OCH3Substituted) of a substituted propyl group,by 2-pyridyl (in position 6 by-OCH)3Substituted) methyl, by 6-pyridyl (by-CH at the 2-position2NH2Substituted) methyl, by 6-pyridyl (by-NHCH at position 2)3Substituted) with a substituted methyl group, or a substituted methyl group,
is 2-pyrimidinyl (in the 4-position by-OCH)3Substituted) propyl, substituted by 2-pyrimidinyl (by-OCH in the 4 and 6 positions)3Substituted) methyl, propyl substituted with 2-pyrimidinyl (substituted with-OH at the 4-position),
a methyl group substituted by a 3-piperazinyl group,
ethyl substituted by 1-piperazinyl, wherein 1-piperazinyl is substituted at the 4-position by 4-piperidinyl and 4-piperidinyl is substituted at the 1-position by-C (= O) -CH3Substituted by 1-piperazinyl (substituted in the 4-position by-CH)2C(=O)NHCH(CH3)2Substituted) with a substituted ethyl group, or a substituted ethyl group,
ethyl or propyl substituted with 1,2,3, 6-tetrahydropyridine,
c substituted by azetidinyl1-6An alkyl group, a carboxyl group,
propyl substituted with 1-azetidinyl (substituted with two fluorines at the 3 position),
propyl substituted with 1-azetidinyl (substituted at the 3-position with one-OH),
ethyl or propyl substituted by 1-pyrrolidinyl or 2-pyrrolidinyl,
propyl substituted with 1-pyrrolidinyl (substituted with two fluorines at the 3-position), or propyl substituted with 1-pyrrolidinyl (substituted with one fluorine at the 3-position),
by 1-pyrrolidinyl (in the 2-position by-CH)2Cl) is substituted) with a substituted propyl group,
ethyl or propyl substituted with 1-pyrrolidinyl (substituted at the 3-position with-OH),
ethyl or propyl substituted with 1-pyrrolidinyl (substituted with = O at the 2-position),
by 1-pyrrolidinyl(in position 3 by-S (= O)2-CH3Substituted) of a substituted propyl group,
by 1-pyrrolidinyl (by-NH in position 3)2Substituted) ethyl or propyl groups substituted with (i) a,
by 1-pyrrolidinyl (by-N (CH) in position 33)2Substituted) ethyl, substituted by 1-pyrrolidinyl (substituted at the 3-position by-NHCH3Substituted) of a substituted propyl group,
ethyl or propyl substituted by: a) at position 2 by-CH3Substituted 1-pyrrolidinyl; b) at positions 2 and 5 by-CH3Substituted 1-pyrrolidinyl; or c) is substituted by two-CH at position 23A substituted 1-pyrrolidinyl group having a substituent,
ethyl substituted by 1-pyrrolidinyl (substituted at the 2-position by-C (= O) OH),
by 1-pyrrolidinyl (in the 2-position by-CH)2OH-substituted) or by pyrrolidinyl (by-C (CH)3)2OH or-CH2CH2OH substituted) substituted ethyl or propyl,
propyl substituted by: a) 1-pyrrolidinyl substituted at the 3-position with 1-piperidinyl; b) by 4-morpholinyl in position 3 (by-CH in positions 2 and 6)3Substituted) substituted 1-pyrrolidinyl groups,
ethyl or propyl substituted with 1-pyrrolidinyl (substituted at the 3-position with-CN),
by 1-pyrrolidinyl (in the 2-position by-CH)2CN) or by 1-pyrrolidinyl (substituted in the 2-position by-CH)2CN-substituted) substituted ethyl group,
by 1-pyrrolidinyl (in the 2-position by-CH)2NH-S(=O)2-CF3Substituted) of a substituted propyl group,
methyl or ethyl substituted by: a) at position 1 is (CH)3)3C-O-C (= O) -substituted 2-pyrrolidinyl, or b) substituted at the 2-position with CH3-O-C (= O) -substituted 1-pyrrolidinyl, substituted 3-pyrrolidinyl (substituted 2-pyridyl in position 1 (substituted-OCH in position 3)3Substitution) ofOr by 3-pyrrolidinyl (by 2-pyrimidinyl in position 1 (by-OCH in position 4)3Substituted) methyl groups,
methyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl,
ethyl substituted with 1-piperidinyl (substituted in the 4 position with two fluorines),
methyl or ethyl substituted by: a) 1-piperidinyl substituted in the 4 position by an-OH group, or b) 4-piperidinyl substituted in the 4 position by an-OH group,
by 1-piperidinyl (in position 3 or 4 by-NH)2Substituted) with a substituted ethyl group, or a substituted ethyl group,
by 1-piperidinyl (in the 4 position by-N (CH)3)2Substituted) with a substituted ethyl group, or a substituted ethyl group,
methyl, ethyl or propyl substituted by: a) at position 2 by-CH3Substituted 1-piperidinyl, b) substituted in the 2 and 6 positions by-CH3Substituted 1-piperidinyl, c) substituted in position 1 with-CH (CH)3)2Substituted 4-piperidinyl, d) substituted in position 1 by-CH3Substituted 4-piperidinyl radicals, e) substituted in the 3 and 5 positions by-CH3(ii) a substituted 1-piperidinyl group,
ethyl substituted by: a) at position 4 by-C (CH)3)2OH-substituted 1-piperidinyl, b) substituted in the 4-position by-CH2CH2OH-substituted 1-piperidinyl, c) substituted in the 4-position by-CH2An OH-substituted 1-piperidinyl group,
ethyl or propyl substituted with 1-piperidinyl (substituted in the 3-position with-CN),
methyl or ethyl substituted by: a) at position 4 by CH3CH2-O-C (= O) -substituted 1-piperidinyl, or b) substituted in the 1-position with (CH)3)3C-O-C (= O) -substituted 4-piperidinyl,
by 4-piperidinyl (substituted in the 4-position by-OH, in the 1-position by (CH)3)3C-O-C (= O) -substituted) methyl,
is substituted by 4-piperidinyl (in 4)Bit is-OCH3Substituted, in position 1 by (CH)3)3C-O-C (= O) -substituted) methyl,
methyl or ethyl substituted by: a) at position 4 by-OCH3Substituted 1-piperidinyl, or b) substituted in the 4-position by-OCH3A substituted 4-piperidinyl group which is substituted,
by 1-piperidinyl (in the 4 position by-CF)3Substituted) of a substituted propyl group,
is substituted by 1-piperidinyl (in position 3 by-C (= O) -NH)2Substituted) ethyl, substituted by 1-piperidinyl (substituted in the 2 position by-C (= O) -NH)2Substituted) ethyl or propyl, ethyl substituted with 1-piperidinyl (substituted with = O in the 4 position), or propyl substituted with 1-piperidinyl (substituted with = O in the 2 position),
by 1-piperidinyl (in the 4 position by-CH)2NH2Substituted) with a substituted ethyl group, or a substituted ethyl group,
is substituted by 4-piperidinyl (substituted in position 1 by 2-pyrimidinyl (substituted in position 4 by-OCH)3Substituted) methyl groups,
ethyl, propyl or butyl substituted by isoindole-1,3-dione, -CH (CH) substituted by isoindolyl-1, 3-dione (isoindolole-1, 3-dione)3)CH2-，
Ethyl substituted with 2-oxa-6-aza-spiro [3.3] heptane,
ethyl substituted by 1, 4-dioxa-8-aza-spiro [4.5] decane,
a methyl group substituted by a 2-thienyl group,
methyl substituted by 2-thienyl (which is substituted at the 5-position by chlorine),
by 4-thiazolyl (which is substituted by-CH at the 2-position)3Substituted) with a substituted methyl group, or a substituted methyl group,
ethyl or propyl substituted by a 1-piperazinyl group,
by 1-piperazinyl (which is CH at the 4-position)3-C (= O) -substituted) ethyl,
by 1-piperazinyl (which is substituted by-CH at the 4-position)2CH2OH-substituted) substituted ethyl groups,
ethyl or propyl substituted by: a) at positions 3 and 5 by-CH3Substituted 1-piperazinyl, or b) substituted in the 4-position by-CH3A substituted 1-piperazinyl group selected from the group consisting of,
ethyl substituted with 1-piperazinyl substituted at the 3 position with = O,
by 1-piperazinyl which is-C (= O) -C at the 4-position3H5Substituted) with a substituted ethyl group, or a substituted ethyl group,
by 2-piperazinyl (substituted in the 1 and 4 positions by methylphenyl, wherein the phenyl group is substituted in the 4 position by CH3O-substituted), ethyl substituted with 5-tetrazolyl,
methyl substituted by: at position 5 by-NH2Substituted 2- (1,3, 4-oxadiazolyl), or b) substituted in position 5 with-NH-CH2CH2OH-substituted 2- (1,3, 4-oxadiazolyl),
methyl, ethyl or propyl substituted by 1-pyrazolyl or 2-imidazolyl, methyl substituted by 3-pyrazolyl or 5-pyrazolyl,
methyl, ethyl or propyl substituted by: a) at position 2 by-CH3Substituted 1-imidazolyl, b) substituted by-CH in the 1 and 5 positions3Substituted 3-pyrazolyl, c) substituted in the 2 and 5 positions by-CH3Substituted 1-imidazolyl, d) substituted by-CH in the 2 and 4 positions3Substituted 1-imidazolyl, e) substituted in position 1 by-CH3Substituted 2-imidazolyl, or f) substituted in position 1 by-CH2CH3Substituted 2-imidazolyl, substituted 2-imidazolyl (substituted in position 5 by-CH)3Substituted) with a substituted methyl group, or a substituted methyl group,
by 1-pyrazolyl (by-CH at the 3-position)3Substituted) with a substituted ethyl group, or a substituted ethyl group,
by 4-pyrazolyl (by-CH in position 1)3Substituted) methyl, by 2-imidazolyl (by-S (= O) at position 3)2-N(CH3)2Substituted in position 5 by-CH3Substituted) methyl, by 5-pyridineMethyl substituted in the 2-position by 2-tetrahydropyran, or methyl substituted in the 1-position by 3-pyrazolyl substituted in the 1-position by 2-tetrahydropyran, by 2-imidazolyl substituted in the 1-position by-S (= O)2-N(CH3)2Substituted) with a substituted methyl group, or a substituted methyl group,
methyl substituted by 4- (1,2, 3-triazolyl),
methyl substituted by: a) at position 1 by-CH2CH2OH-substituted 4- (1,2, 3-triazolyl), or b) substituted in the 2-position by-CH2OH-substituted 4- (1,2, 3-triazolyl),
by 4- (1,2, 3-triazolyl) (which is substituted by-CH in position 1)2C(=O)-OCH2CH3Substituted) with a substituted methyl group, or a substituted methyl group,
ethyl substituted by 1- (1,2, 4-triazolyl),
by 1- (1,2, 4-triazolyl) (in position 3 by-CH3Substituted) ethyl or propyl groups substituted with (i) a,
by 2- (1,2, 4-triazolyl) (by-CH in position 3)3Substituted) ethyl or propyl groups substituted with (i) a,
ethyl or propyl substituted with 3-oxazolidinyl (which is substituted with = O at the 2-position), methyl substituted with 5-oxazolidinyl (substituted with = O at the 2-position), 5-oxazolidinyl (substituted with = O at the 2-position, with-CH (CH) at the 3-position3)2Substituted) with a substituted methyl group, or a substituted methyl group,
propyl substituted with 4-thiomorpholinyl (which is substituted at the 1-position with two = O groups),
an ethyl group substituted with a 1-homopiperazinyl group,
an ethyl group substituted with a homomorpholinyl group,
-CH2-C6H5，
methyl substituted by phenyl (which is substituted in position 2,3 or 4 by chlorine), cyano C1-6Alkyl radicals, e.g. -CH2CH2CN or-CH2CH2CH2CN，
Is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH2，-CH2CH2CH2NH2，-CH2CH2CH2CH2NH2，-CH2CH(CH3)NH2，-CH(CH3)CH2NH2，
-CH2CH2NHCH3，-CH2CH2CH2NHCH3，-CH2CH2NHCH2CH3，-CH2CH2NHCH(CH3)2，-CD2-CD2-NHCH(CH3)2，-CH2CH2CH2NHCH(CH3)2，-CH(CH3)CH2NHCH(CH3)2，
-CH2CH2N(CH2CH3)2，-CH2CH2N(CH2CH3)(CH(CH3)2)，
-CH2CH2N(CH3)2or-CH2CH2N(CH3)CH(CH3)2，
-CH2CH2CH2NHCH2CF3，-CH2CH2NHCH2CHF2or-CH2CH2NHCH2CH2F，-CH(CH3)CH2NHCH2CF3，-CH2CH(CH3)NHCH2CF3，-CH2CH2NHCH2CF3，-CH2CH2CH2NHCH2CHF2-CH2CH2NHCH2CH2CF3，-CH2CH2CH2NHCH2CHF2，-CH2CH2CH2NHC(CH3)2CH2F，-CD2-CD2-CD2-NHCH2CF3，
-CH2CH2NH-C(=O)-CH3，
-CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH2CH3or-CH2CH2NH-S(=O)2-CH(CH3)2，
-CH2CH2NH-S(=O)2-N(CH3)2or-CH2CH2CH2NH-S(=O)2-N(CH3)2，
-CH2CH2NHCH2CH2OH，
-CH2CH2CH2NH-C(=O)-C(OH)(CH3)CF3or-CH2CH2NH-C(=O)-C(OH)(CH3)CF3，
-CH2CH2NH-C(=O)-C3H5，
-CH2CH2NH-C (= O) - (piperidin-3-yl), wherein the piperidinyl group is substituted at the 1-position with-CH3The substitution is carried out by the following steps,
-CH2CH2NHCH2CH2CN，-CH2CH2CH2NHCH2CH2CN，
-CH2CH2NHC3H5，-CH2CH2NHC5H9or-CH2CH2NH- (2,2,6, 6-tetramethyl-piperidin-4-yl)
-CH2CH2NH- (piperidin-4-yl), wherein the piperidinyl group is substituted at the 1-position by-S (= O)2NH2The substitution is carried out by the following steps,
-CH2CH2NHCH2C3H5，-CH2CH2NHCH2- (tetrahydrofuran-2-yl), -CH2CH2NHCH2- (pyridin-6-yl),
-CH2CH2NHC(=O)-CF3or-CH2CH2CH2NHC(=O)-CF3；
-CH2CH2NHCH2Si(CH3)3，
-CH2CH2N(CH3)CH2-C6H5。
R10And R11One of them represents-CH (CH)3)2And the other represents-CH2-C6H5Wherein the phenyl group is substituted in the 4-position by-NH2The substitution is carried out by the following steps,
-CH2CH2N(CH(CH3)2)CH2CH2CH2NH2，
-CH2CH2CH2NHCH2C(=O)NH2or-CH2CH2NHCH2C(=O)NH2，
-CH2CH2CH2N(CH3)-OCH3，
-CH2CH2NH-OCH3Or is or
-CH2CH2NHCH2CHOHCF3；
-CH2CH2CH2NHCOOH。
By hydroxy and-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CHOHCH2NH2，-CH2CHOHCH2NHCH3or-CH2CHOHCH2NHCH(CH3)2，-CH2CHOHCH2NHCH2CF3，-CH2CHOHCH2N(CH(CH3)2)-C(=O)CH2Cl，
By one or two halogens and-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CHFCH2NH2，
Is represented by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2-C(=O)-O-CH2CH3or-CH2CH2-C(=O)-O-CH2CH3，-CH(CH3)C(=O)-O-CH2CH3，
Quilt C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl radicals (e.g. methyl), e.g. -CH2-C(=O)-CH2OCH3，
by-O-C (= O) -NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2-C(=O)NH2，-CH2-C(=O)NHCH3，-CH2C(=O)NHCH(CH3)2or-CH2CH2C(=O)NHCH(CH3)2，-CH2-C(=O)-NHCH2CH2OCH3，-CH2-C(=O)-NH-CH2CH2- (pyrrolidin-1-yl) or-CH2-C(=O)-NH-CH2CH2- (imidazol-2-yl), -CH2-C(=O)-NHCH2CH2OH，-CH2-C(=O)-NHCH2CH2NH2，-CH2CH2C(=O)-NHCH2CF3-CH2CH2C(=O)N(CH3)-OCH3，-CH2C (= O) NH- (pyridin-2-yl), wherein the pyridin-2-yl is-OCH at the 3-position3Substituted, -CH2C (= O) NH- (pyridin-6-yl), wherein the pyridin-6-yl is substituted with-CH at the 4-position3Substituted, or-CH2C (= O) NH- (pyrimidin-2-yl)) Wherein the pyrimidin-2-yl group is-OCH at the 4-position3Substituted, -CH2C (= O) NH- (pyridin-3-yl), -CH2C (= O) NH- (pyridin-6-yl) or-CH2C (= O) NH- (pyridin-4-yl),
c substituted by carboxyl1-6Alkyl radicals, e.g. -CH2C (= O) OH or-CH2CH2C(=O)OH，
by-O-C (= O) -NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2-O-C(=O)-NHCH3，
Is represented by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH(CH3)2or-CH2CH2NH-S(=O)2-CH2CH3，
Is represented by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH-S(=O)2-N(CH3)2or-CH2CH2CH2NH-S(=O)2-N(CH3)2，
By R9Substituted and optionally substituted by-O-C (= O) -C1-6Alkyl substituted C1-6Alkyl radical, R9Represents 1H-pyrrolo [3,2-b ]]Pyridyl, 1-methyl-1H-pyrrolo [3,2-b ]]Pyridyl or furo [3,2-b ]]A pyridyl group, a carboxyl group,
by hydroxy and R9Substituted C1-6Alkyl radicals, e.g.
Propyl substituted by-OH and 1-pyrrolidinyl,
propyl substituted with-OH and 1-pyrrolidinyl, wherein the 1-pyrrolidinyl is substituted at the 3-position with two fluorines,
propyl substituted with-OH and 1-pyrrolidinyl, wherein the 1-pyrrolidinyl is substituted at the 3-position with cyano,
propyl substituted by-OH and 4-morpholinyl,
propyl substituted by-OH and 1-piperidinyl,
by-OH and 2- (1,2, 4-triazolyl) (in position 3 by-CH3Substituted) of a substituted propyl group,
by-OH and 1-imidazolyl (by-CH in position 2)3Substituted) of a substituted propyl group,
propyl substituted by-OH and isoindole-1,3-dione,
-C1-6alkyl-C (R)12)=N-O-R12E.g. -CH2C(CH3)=N-O-H，-CH2C(CH2OCH3) = N-O-H or-CH2C(CH(CH3)2)=N-O-H-S(=O)2-NR14R15For example-S (= O)2-N(CH3)2quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2CH2-S(=O)2-CH3，
by-C (= O) -NR10R11Substituted C1-6Alkyl radicals, e.g.
-CH2C(=O)NH2，
-CH2C(=O)NHCH3，
-CH2C(=O)-NHCH2CH2OCH3，
-CH2C(=O)-NH-CH2CH2- (pyrrolidin-1-yl), or-CH2C(=O)-NH-CH2CH2- (imidazol-2-yl), -CH2C(=O)-NHCH2CH2OH，-CH2C(=O)-NHCH2CH2NH2，
Is represented by-C (= O) -R9Substituted byC1-6Alkyl radicals, e.g. -CH2C(=O)-R9，R9Is a 1-pyrrolidinyl group having a structure,
by R9Substituted C2-6Alkenyl radicals, e.g. CH2CH = CH- (2-pyrimidinyl), -CH2CH = CH- (2-pyrimidinyl) wherein the 2-pyrimidinyl is-OCH in position 43Substituted, -CH2CH = CH- (2-pyridyl) wherein the 2-pyridyl group is-CH at the 4-position3Substituted, or-CH2CH = CH- (2-pyridyl) wherein the 2-pyridyl group is-OCH at the 3-position3The substitution is carried out by the following steps,
by R9Substituted C2-6Alkynyl radicals, e.g.
-CH2-C ≡ C- (2-imidazolyl), wherein the 2-imidazolyl group is substituted at the 1-position with-CH3Substituted, or-CH2-C ≡ C- (5-imidazolyl), wherein the 5-imidazolyl group is substituted at the 1-position with-CH3Substituted, -CH2-C ≡ C- (4-pyridyl), -CH2-C ≡ C- (3-pyridyl), -CH2-C ≡ C- (2-pyridyl), -CH2-C ≡ C- (2-pyrimidinyl), -CH2-C.ident.C- (6-pyrazinyl) in position 2 or 4 by-CH2OH-substituted-CH2-C.ident.C- (6-pyridyl),
at position 6 by-OCH3substituted-CH2-C ≡ C- (4-pyridyl) substituted at the 3 or 5 position by-OCH3substituted-CH2-C.ident.C- (2-pyridyl),
at position 4 or 6 by-OCH3substituted-CH2-C.ident.C- (2-pyrimidinyl),
at position 2,4 or 5 by-OCH3substituted-CH2-C.ident.C- (6-pyridyl),
at position 4 by-OCH3substituted-CH2-C.ident.C- (6-pyrimidinyl),
at position 6 by-OCH3substituted-CH2-C.ident.C- (5-pyrazinyl),
at position 6 by-OCH2CH3substituted-CH2-C.ident.C- (2-pyrimidinyl),
at position 4 by-OCH3substituted-C (CH)3)2-C.ident.C- (2-pyrimidinyl),
at position 4 by-OCH (CH)3)2substituted-CH2-C ≡ C- (2-pyrimidinyl);
-CH substituted in position 2 or 4 by cyano2-C ≡ C- (6-pyridyl), -CH substituted at the 5 or 6 position by cyano2-C ≡ C- (4-pyridyl);
at position 2 or 4 by-NH2substituted-CH2-C ≡ C- (6-pyridyl) substituted at the 2-position by-NH2substituted-CH2-C ≡ C- (6-pyrimidinyl) substituted at the 3-position by-NH2substituted-CH2-C ≡ C- (2-pyridyl) substituted at the 6-position by-NH2substituted-CH2-C ≡ C- (3-pyrazinyl), at position 5 by-NHCH3substituted-CH2-C.ident.C- (6-pyridyl),
at position 3 or 4 by-CH3substituted-CH2-C ≡ C- (6-pyridyl) substituted in position 3 with-CH3substituted-CH2-C ≡ C- (2-pyridyl) substituted at the 4-position by-CH3substituted-CH2-C ≡ C- (2-pyrimidinyl) substituted in position 6 with-CH2CH3substituted-CH2-C.ident.C- (2-pyrimidinyl),
at position 2 by-CH3Substituted and substituted in the 4-position by-NH2substituted-CH2-C.ident.C- (6-pyrimidinyl),
at position 2 by-NH2Substituted and-CH substituted in the 4-position by-Cl2-C.ident.C- (6-pyrimidinyl),
-CH substituted in position 3 by-Cl2-C ≡ C- (2-pyrazinyl), -CH substituted at the 5-position with-Cl2-C ≡ C- (3-pyrazinyl), or-CH substituted at position 3 with-F2-C ≡ C- (2-pyridyl), -CH substituted in position 6 with-Br2-C.ident.C- (5-pyridyl),
at position 4 by-C (= O) -NH2substituted-CH2-C ≡ C- (6-pyridyl);
at position 5 by CH3-O-C (= O) -substituted-CH2-C ≡ C- (6-pyridyl) substituted by CH at position 63-O-C (= O) -substituted-CH2-C ≡ C- (2-pyrimidinyl);
at position 3 by-CF3substituted-CH2-C.ident.C- (2-pyridyl),
-CH2-C.ident.C- (5-thiazolyl),
-CH2-C.ident.C- (phenyl),
-CH2-C ≡ C- (phenyl), wherein the phenyl group is-OCH in the 5-position3The substitution is carried out by the following steps,
at position 1 by C (CH)3)3-CH substituted by-O-C (= O) and substituted at position 3 with-OH2-C.ident.C- (3-azetidinyl),
-CH substituted in position 3 by-OH2-C.ident.C- (3-azetidinyl),
at position 1 by C (CH)3)3--CH substituted with O-C (= O) and substituted at position 3 with-OH2-C.ident.C- (3-pyrrolidinyl),
-CH substituted in position 3 by-OH2-C.ident.C- (3-pyrrolidinyl),
-CH2-C.ident.C- (4-piperidinyl),
-CH substituted in the 4-position by-OH2-C.ident.C- (4-piperidinyl),
at position 1 by C (CH)3)3-O-C (= O) -substituted-CH2-C.ident.C- (4-piperidinyl),
-CH substituted in position 3 by-OH2-C.ident.C- (4-tetrahydrofuryl),
-CH substituted in the 4-position by-OH2-C.ident.C- (4-tetrahydropyranyl),
-CH2-C.ident.C- (cyclohexyl),
by R9Substituted C1-6Alkyl radical, R9Represents 6 toAn 8-membered bridged heterocyclyl group, e.g. optionally substituted by-C (= O) -O-C4Alkyl-substituted 2, 5-diaza-bicyclo [2.2.1]Heptyl radical, wherein each C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radicals, e.g. -CH2CHOHCH2OCH3，
C2-6Alkenyl radicals, e.g. CH2-CH=CH2，
C2-6Alkynyl, e.g. -CH2-C ≡ C-H or-C (CH)3)2-C≡C-H，
Quilt C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl radicals, e.g. -CH2-C(=O)-CH2OCH3Or is or
R13For example 3-oxetanyl, in the 4-position by-NH-CH (CH)3)2A substituted cyclohexane group,
by R9Substituted C1-6Alkyl radical, wherein R9Is by R13Substituted saturated heterocyclic radical, wherein R13Is an optionally substituted saturated heterocyclic radical, e.g. substituted by-C (= O) -C1-6Alkyl substitution. In one embodiment, R9Is by R13Substituted piperazinyl wherein R13Is represented by-C (= O) -C1-6An alkyl-substituted piperidinyl group which is substituted with an alkyl group,
by R9Substituted C1-6Alkyl radical, wherein R9Is by R13Substituted saturated heterocyclic radical, wherein R13Is an optionally substituted saturated heterocyclic radical, e.g. substituted by-C (= O) -C1-6Alkyl substitution. In one embodiment, R9Is by R13Substituted piperazinyl wherein R13Is represented by-C (= O) -C1-6Alkyl-substituted piperidinyl.
In one embodiment, there is provided formula (I)0) The compound of (1):
(I0)
including any stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2 or 3;
R1represents hydrogen, and is selected from the group consisting of,
C1-6alkyl radicals, e.g. -CH3，-CD3，-CH2CH3，-CH2CH2CH3，-CH2CH(CH3)2，-CH(CH3)2，-CH2CH(CH3)2，
C2-4Alkenyl radicals, e.g. CH2-CH=CH2，
Hydroxy radical C1-6Alkyl radicals, e.g. -CH2CH2OH，-CH2C(CH3)2OH or CH2CHOHCH2OH，
Halogen substituted C1-6Alkyl radicals, e.g. -CH2CH2F，CH2CH2CH2Cl or CH2CH2Br，
Wherein each C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radicals, e.g. -CH2CH2OCH3，
Is represented by-NR4R5Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH2or-CH2CH2CH2NH2，-CH2CH2NHCH3，-CH2CH2NHS(=O)2N(CH3)2，-CH2CH2NHS(=O)2N(CH3)2，
by-C (= O) -NR4R5Substituted C1-6Alkyl radicals, e.g. -CH2C(=O)N(CH3)2，-CH2C(=O)NHCH3or-C (CH)3)2C(=O)NHCH3-C(CH3)2C(=O)NHCH2CH2OH or-CH2C(=O)NHCH2CH2OH，-CH2C(=O)NHCH2CH2OCH3or-C (CH)3)2C(=O)NHCH2CH2OCH3，-CH2-C(=O)-NH-CH2-CH2- (pyrrolidin-1-yl), -CH2CH2CH2NHCH2CH2-S(=O)2-CH3，
-S(=O)2-C1-6Alkyl radicals, e.g., -S (= O)2-CH3，
-S(=O)2-NR14R15For example-S (= O)2-N(CH3)2，
quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2CH2S(=O)2-CH3，
is-NH-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2CH2NHS(=O)2-CH3，
R6E.g. 2-tetrahydropyranyl, being substituted in position 1 by-CH2CH2OH-substituted 3-azetidinyl substituted on the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperidinyl substituted on the nitrogen by-S (= O)2CH3A substituted 4-piperidinyl group which is substituted,
by R6Substituted C1-6Alkyl, for example methyl or ethyl, each substituted by 4-piperidinyl, 4-piperazinyl, 1-pyrrolidinyl or 4-tetrahydropyranyl; propyl substituted with morpholinyl, wherein the morpholinyl is attached to the propyl through an N heteroatom; methyl, ethyl or propyl each substituted by: at the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperidinyl substituted on the nitrogen by-CH3Substituted 4-piperidinyl radicals substituted on the nitrogen atom by (CH)3)3C-O-C (= O) -substituted 4-piperazinyl substituted on the nitrogen by-CH2CH24-piperazinyl substituted by-CH on the nitrogen atom2CH2CH24-piperazinyl substituted by OH, 1-piperidinyl substituted by-OH in position 1, by-O-CH in position 13Substituted 1-piperidinyl, methyl substituted with 2-thienyl, wherein the 2-thienyl is substituted with chloro at the 5-position; methyl substituted by 4-piperidinyl, wherein the 4-piperidinyl group is substituted on the nitrogen atom by (CH)3)3C-O-C (= O) -substituted and substituted with-OH at the 4-position,
is represented by-C (= O) -R6Substituted C1-6Alkyl radicals, e.g. -C (CH)3)2-C (= O) - (piperazin-4-yl) substituted at the 1-position on the nitrogen atom by C (CH)3)3-O-C (= O) -substituted-C (CH)3)2-C (= O) - (piperazin-4-yl), -CH substituted at the 3-position with-OH2-C (= O) - (pyrrolidin-1-yl),
by R6Substituted hydroxy radical C1-6Alkyl radicals, e.g. 1-piperidinyl-substituted-CH2CHOHCH2-; or
is-Si (CH)3)3Substituted C1-6Alkyl radicals, e.g. -CH2Si(CH3)3；
Each R2Independently selected from:
halogen, such as fluorine, chlorine or bromine,
the cyano group(s),
C1-4alkyl radicals, e.g. -CH3，
C2-4Alkenyl, e.g. -CH = CH2，
C1-4Alkoxy radicals, e.g. CH3O-，(CH3)2CHO-，CH3CH2O-，CD3O-，
Hydroxy radical C1-4Alkyl radicals, e.g. -CH2OH，
Hydroxy radical C1-4Alkoxy radicals, e.g. -OCH2CH2OH，
Halogen substituted C1-4Alkoxy radicals, e.g. -OCH2CH2F or CHF2O-，
C1-4Alkoxy radical C1-4Alkyl radicals, e.g. -CH2CH2OCH3，
R13For example, a 2-dioxolanyl group,
by R13Substituted C1-4Alkoxy radicals, e.g. -OCH2C3H5，
-C(=O)-R13For example-C (= O) - (1-pyrrolidinyl),
by NR7R8Substituted C1-4Alkyl radicals, e.g. -CH2N(CH2CH3)2，-CH2N(CH3)2or-CH2N(CH2CH3)(CH3)，
By NR7R8Substituted C1-4Alkoxy radicals, e.g. -OCH2CH2NH2，
-NR7R8For example-NHCH3Or is or
-C(=O)-NR7R8(ii) a For example-C (= O) -NHCH3；
R3Represents
C1-6Alkyl radicals, e.g. -CH3，-CH2CH3，-CH2CH2CH3or-CH2CH(CH3)2，
Hydroxy radical C1-6Alkyl radicals, e.g. -CH2CH2OH，-CH2CH2CH2OH，-CH2CHOHCH3，-CH2CHOHCH2CH3，-CH2CHOHCH(CH3)2，-CH2CH2C(OH)(CH3)2，-CH2CHOHCH2OH or-CH2C(CH3)2OH，
Hydroxy halogeno C1-6Alkyl radicals, e.g. -CH2CHOHCF3，
Halogen substituted C1-6Alkyl radicals, e.g. -CH2CH2CH2Cl or-CH2CH2CH2CH2Cl，
Is represented by-C (= O) -C1-6Alkyl substituted C1-6Alkyl radicals, e.g. CH3-C(=O)-CH2-，(CH3)2CH-C(=O)-CH2-，
Wherein each C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl radicals, e.g. -CH2CH2OCH3，-CH2CH2OCH2CH3or-CH2CHOHCH2OCH3，
By R9Substituted C1-6Alkyl radicals, e.g.
-CH2-C3H5or-CH2C5H9，
C substituted by cyclopropyl1-6Alkyl, wherein cyclopropyl is-CH2OH or CH3CH2-O-C (= O) -substitution,
methyl substituted by 5-isoxazolyl, 5-isoxazolyl being substituted in position 3 by-CH3Methyl substituted or substituted by 3-isoxazolyl, wherein 3-isoxazolyl is substituted in position 5 by-CH3The substitution is carried out by the following steps,
ethyl or propyl substituted by 4-morpholinyl
By 4-morpholinyl (which is substituted by-CH at positions 2 and 6)3Substituted) ethyl or propyl
By 2-morpholinyl (which is substituted at position 4 by-CH)2-C6H5Substituted) substituted methyl group
Methyl substituted by 2-tetrahydrofuryl, 2-dioxolane, ethylene oxide, 2-furanyl or 4-tetrahydropyranyl,
by 3-oxetanyl (which is substituted in the 3-position by-CH)3Substituted) substituted methyl.
Methyl substituted by 3-pyridyl or 2-pyrazinyl.
Methyl substituted by 3-pyridyl (substituted by chlorine at the 6-position) or methyl substituted by 2-pyridyl (substituted by bromine at the 6-position),
ethyl substituted by 1-piperazinyl, wherein 1-piperazinyl is substituted at the 4-position by-piperidinyl and 4-piperidinyl is substituted at the 1-position by-C (= O) -CH3The substitution is carried out by the following steps,
ethyl or propyl substituted with 1,2,3, 6-tetrahydropyridine,
c substituted by azetidinyl1-6An alkyl group, a carboxyl group,
propyl substituted with 1-azetidinyl (which is substituted at the 3-position with two fluorines), propyl substituted with 1-azetidinyl (which is substituted at the 3-position with one-OH),
ethyl or propyl substituted by 1-pyrrolidinyl or 2-pyrrolidinyl,
propyl substituted with 1-pyrrolidinyl (substituted with two fluorines at the 3-position), or propyl substituted with 1-pyrrolidinyl (substituted with one fluorine at the 3-position),
by 1-pyrrolidinyl (in the 2-position by-CH)2Cl) is substituted) with a substituted propyl group,
ethyl or propyl substituted with 1-pyrrolidinyl (substituted at the 3-position with-OH),
ethyl or propyl substituted with 1-pyrrolidinyl (substituted with = O at the 2-position),
by 1-pyrrolidinyl (by-S (= O) in position 3)2-CH3Substituted) of a substituted propyl group,
by 1-pyrrolidinyl (which is substituted by-NH at the 3-position)2Substituted) ethyl or propyl, by 1-pyrrolidinyl (which is substituted in position 3 by-N (CH)3)2Substituted) ethyl, substituted by 1-pyrrolidinyl (which is substituted at the 3-position by-NHCH3Substituted) of a substituted propyl group,
ethyl or propyl substituted by: a) at position 2 by-CH3Substituted 1-pyrrolidinyl; b) at positions 2 and 5 by-CH3Substituted 1-pyrrolidinyl; or c) is substituted by two-CH at position 23A substituted 1-pyrrolidinyl group having a substituent,
ethyl substituted by 1-pyrrolidinyl (substituted at the 2-position by-C (= O) OH),
by 1-pyrrolidinyl (in the 2-position by-CH)2OH-substituted) or by pyrrolidinyl (by-C (CH)3)2OH or-CH2CH2OH substituted) substituted ethyl or propyl,
propyl substituted by: a) 1-pyrrolidinyl substituted in position 3 with 1-piperidinyl, or b) 4-morpholinyl in position 3 (with-CH in positions 2 and 6)3Substituted) substituted 1-pyrrolidinyl groups,
ethyl or propyl substituted by 1-pyrrolidinyl (substituted in position 3 by-CN), by 1-pyrrolidinyl (substituted in position 2 by-CH)2CN substitution) of a substituted propyl group,
by 1-pyrrolidinyl (in the 2-position by-CH)2NH-S(=O)2-CF3Substituted) of a substituted propyl group,
methyl or ethyl substituted by: a) at position 1 is (CH)3)3C-O-C (= O) -substituted 2-pyrrolidinyl, or b) substituted at the 2-position with CH3-O-C (= O) -substituted 1-pyrrolidinyl,
methyl, ethyl or propyl substituted by 4-piperidinyl or 1-piperidinyl,
ethyl substituted with 1-piperidinyl (substituted in the 4 position with two fluorines),
methyl or ethyl substituted by: a) 1-piperidinyl substituted in the 4 position by an-OH group, or b) 4-piperidinyl substituted in the 4 position by an-OH group,
by 1-piperidinyl (in position 3 or 4 by-NH)2Substituted) with a substituted ethyl group, or a substituted ethyl group,
by 1-piperidinyl (in the 4 position by-N (CH)3)2Substituted) with a substituted ethyl group, or a substituted ethyl group,
methyl, ethyl or propyl substituted by: a) at position 2 by-CH3Substituted 1-piperidinyl, b) substituted in the 2 and 6 positions by-CH3Substituted 1-piperidinyl, c) substituted in position 1 with-CH (CH)3)2Substituted 4-piperidinyl, d) substituted in position 1 by-CH3Substituted 4-piperidinyl radicals, e) substituted in the 3 and 5 positions by-CH3(ii) a substituted 1-piperidinyl group,
ethyl substituted by: a) at position 4 by-C (CH)3)2OH-substituted 1-piperidinyl, b) substituted in the 4-position by-CH2CH2OH-substituted 1-piperidinyl, c) substituted in the 4-position by-CH2An OH-substituted 1-piperidinyl group,
ethyl or propyl substituted with 1-piperidinyl (substituted in the 3-position with-CN),
methyl or ethyl substituted by: a) at position 4 by CH3CH2-O-C (= O) -substituted 1-piperidinyl, or b) substituted in the 1-position with (CH)3)3C-O-C (= O) -substituted 4-piperidinyl,
by 4-piperidinyl (substituted in the 4-position by-OH, in the 1-position by (CH)3)3C-O-C (= O) -substituted) methyl,
is substituted by 4-piperidinyl (in the 4 position by-OCH)3Substituted, in position 1 by (CH)3)3C-O-C (= O) -substituted) methyl,
methyl or ethyl substituted by: a) at position 4 by-OCH3Substituted 1-piperidinyl, or b) in4-position quilt-OCH3A substituted 4-piperidinyl group which is substituted,
by 1-piperidinyl (in the 4 position by-CF)3Substituted) of a substituted propyl group,
is substituted by 1-piperidinyl (in position 3 by-C (= O) -NH)2Substituted) with a substituted ethyl group, or a substituted ethyl group,
ethyl, propyl or butyl substituted by isoindole-1,3-dione,
ethyl substituted with 2-oxa-6-aza-spiro [3.3] heptane,
ethyl substituted by 1, 4-dioxa-8-aza-spiro [4.5] decane,
a methyl group substituted by a 2-thienyl group,
methyl substituted by 2-thienyl (which is substituted in position 5 by chlorine), by 4-thiazolyl (which is substituted in position 2 by-CH)3Substituted) with a substituted methyl group, or a substituted methyl group,
ethyl or propyl substituted by a 1-piperazinyl group,
by 1-piperazinyl (which is CH at the 4-position)3-C (= O) -substituted) ethyl,
by 1-piperazinyl (which is substituted by-CH at the 4-position)2CH2OH-substituted) substituted ethyl groups,
ethyl or propyl substituted by: a) at positions 3 and 5 by-CH3Substituted 1-piperazinyl, or b) substituted in the 4-position by-CH3A substituted 1-piperazinyl group selected from the group consisting of,
ethyl substituted with 1-piperazinyl substituted at the 3 position with = O,
by 1-piperazinyl which is-C (= O) -C at the 4-position3H5Substituted) with a substituted ethyl group, or a substituted ethyl group,
an ethyl group substituted with a 5-tetrazolyl group,
methyl substituted by: a) at position 5 by-NH2Substituted 2- (1,3, 4-oxadiazolyl), or b) substituted in position 5 with-NH-CH2CH2OH-substituted 2- (1,3, 4-oxadiazolyl),
methyl, ethyl or propyl substituted by 1-pyrazolyl or 2-imidazolyl,
methyl, ethyl or propyl substituted by: a) at position 2 by-CH3Substituted 1-imidazolyl, b) substituted by-CH in the 1 and 5 positions3Substituted 3-pyrazolyl, c) substituted in the 2 and 5 positions by-CH3Substituted 1-imidazolyl, d) substituted by-CH in the 2 and 4 positions3Substituted 1-imidazolyl, e) substituted in position 1 by-CH3Substituted 2-imidazolyl, or f) substituted in position 1 by-CH2CH3Substituted 2-imidazolyl substituted by 2-imidazolyl which is substituted in the 1-position by-S (= O)2-N(CH3)2Substituted) with a substituted methyl group, or a substituted methyl group,
methyl substituted by 4- (1,2, 3-triazolyl),
methyl substituted by: a) at position 1 by-CH2CH2OH-substituted 4- (1,2, 3-triazolyl), or b) substituted in the 2-position by-CH2OH-substituted 4- (1,2, 3-triazolyl),
by 4- (1,2, 3-triazolyl) (which is substituted by-CH in position 1)2C(=O)-OCH2CH3Substituted) with a substituted methyl group, or a substituted methyl group,
ethyl or propyl substituted with 3-oxazolidinyl (which is substituted with = O at the 2 position),
propyl substituted with 4-thiomorpholinyl (which is substituted at the 1-position with two = O groups),
an ethyl group substituted with a 1-homopiperazinyl group,
-CH2-C6H5，
methyl substituted by phenyl which is substituted in the 2,3 or 4 position by chlorine,
is represented by-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH2，-CH2CH2CH2NH2or-CH2CH2CH2CH2NH2，-CH2CH2NHCH3，-CH2CH2CH2NHCH3，-CH2CH2NHCH2CH3，-CH2CH2NHCH(CH3)2or-CH2CH2CH2NHCH(CH3)2，-CH2CH2N(CH2CH3)2，-CH2CH2N(CH2CH3)(CH(CH3)2)，-CH2CH2CH2NHCH2CF3，-CH2CH2NHCH2CHF2or-CH2CH2NHCH2CH2F，-CH2CH2NH-C(=O)-CH3，-CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH2CH3or-CH2CH2NH-S(=O)2-CH(CH3)2-CH2CH2NH-S(=O)2-N(CH3)2or-CH2CH2CH2NH-S(=O)2-N(CH3)2-CH2CH2NHCH2CH2OH，-CH2CH2CH2NH-C(=O)-C(OH)(CH3)CF3or-CH2CH2NH-C(=O)-C(OH)(CH3)CF3-CH2CH2NH-C(=O)-C3H5-CH2CH2NH-C (= O) - (piperidin-3-yl), wherein the piperidinyl group is substituted at the 1-position with-CH3Substitution; -CH2CH2NHCH2CH2CN-CH2CH2NHC3H5，-CH2CH2NHC5H9or-CH2CH2NH- (2,2,6, 6-tetramethyl-piperidin-4-yl), -CH2CH2NHCH2C3H5，-CH2CH2NHCH2- (tetrahydrofuran-2-yl), -CH2CH2NHC(=O)-CF3or-CH2CH2CH2NHC(=O)-CF3，-CH2CH2NHCH2Si(CH3)3，-CH2CH2N(CH3)CH2-C6H5，-CH2CH2NH- (piperidin-4-yl), wherein the piperidinyl group is substituted at the 1-position by-S (= O)2NH2The substitution is carried out by the following steps,
by hydroxy and-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CHOHCH2NH2，-CH2CHOHCH2NHCH3or-CH2CHOHCH2NHCH(CH3)2，-CH2CHOHCH2NHCH2CF3，
By one or two halogens and-NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CHFCH2NH2，
Is represented by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. CH2-C(=O)-O-CH2CH3or-CH2CH2-C(=O)-O-CH2CH3，
by-O-C (= O) -NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2-C(=O)NH2，-CH2-C(=O)NHCH3，-CH2-C(=O)-NHCH2CH2OCH3，-CH2-C(=O)-NH-CH2CH2- (pyrrolidin-1-yl) or-CH2-C(=O)-NH-CH2CH2- (imidazol-2-yl), -CH2-C(=O)-NHCH2CH2OH，-CH2-C(=O)-NHCH2CH2NH2，
C substituted by carboxyl1-6Alkyl radicals, e.g. -CH2C (= O) OH or-CH2CH2C(=O)OH，
by-O-C (= O) -NR10R11Substituted C1-6Alkyl radicals, e.g. -CH2CH2-O-C(=O)-NHCH3，
Is represented by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radicals, e.g. -CH2CH2NH-S(=O)2-CH3，-CH2CH2CH2NH-S(=O)2-CH3，-CH2CH2NH-S(=O)2-CH(CH3)2or-CH2CH2NH-S(=O)2-CH2CH3，
Is represented by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radicals, e.g. -CH2CH2NH-S(=O)2-N(CH3)2or-CH2CH2CH2NH-S(=O)2-N(CH3)2，
By hydroxy and R9Substituted C1-6Alkyl radicals, e.g.
Propyl substituted by-OH and 1-pyrrolidinyl,
propyl substituted with-OH and 1-pyrrolidinyl, wherein the 1-pyrrolidinyl is substituted at the 3-position with two fluorines,
propyl substituted with-OH and 1-pyrrolidinyl, wherein the 1-pyrrolidinyl is substituted at the 3-position with cyano,
propyl substituted by-OH and 4-morpholinyl,
propyl substituted by-OH and 1-piperidinyl,
propyl substituted by-OH and isoindole-1,3-dione,
-C1-6alkyl-C (R)12)=N-O-R12E.g. -CH2C(CH3)=N-O-H，-CH2C(CH2OCH3) = N-O-H or-CH2C(CH(CH3)2)=N-O-H
by-C (= O) -NR10R11Substituted C1-6Alkyl radicalE.g. of
-CH2C(=O)NH2，
-CH2C(=O)NHCH3，
-CH2C(=O)-NHCH2CH2OCH3，
-CH2C(=O)-NH-CH2CH2- (pyrrolidin-1-yl), or-CH2C(=O)-NH-CH2CH2- (imidazol-2-yl), -CH2C(=O)-NHCH2CH2OH，-CH2C(=O)-NHCH2CH2NH2，
Is represented by-C (= O) -R9Substituted C1-6Alkyl radicals, e.g., -CH2C(=O)-R9，R9Is a 1-pyrrolidinyl group having a structure,
by R9Substituted C2-6Alkynyl, e.g. -CH2-C ≡ C- (2-imidazolyl), wherein the 2-imidazolyl group is substituted at the 1-position with-CH3Substituted, or-CH2-C ≡ C- (5-imidazolyl), wherein the 5-imidazolyl group is substituted at the 1-position with-CH3The substitution is carried out by the following steps,
C2-6alkenyl radicals, e.g. CH2-CH=CH2，
C2-6Alkynyl, e.g. -CH2-C≡C-H，
Quilt C1-6Alkoxy radical C1-6alkyl-C (= O) -substituted C1-6Alkyl radicals, e.g. -CH2-C(=O)-CH2OCH3Or R is13。
In one embodiment, formula (I) or formula (I)0) The compound of formula (I)0') of:
(I0’)
including any stereochemically isomeric form thereof;
and N-oxides, pharmaceutically acceptable salts or solvates thereof, wherein N, R2And R3As defined herein.
In one embodiment, formula (I) or formula (I)0) The compound of formula (I)0'') of:
(I0'')
including any stereochemically isomeric form thereof;
and N-oxides, pharmaceutically acceptable salts or solvates thereof, wherein R2And R3As defined herein.
In one embodiment, formula (I) or formula (I)0) The compound of formula (I)0' ' ') of:
(I0''')
including any stereochemically isomeric form thereof;
and N-oxides, pharmaceutically acceptable salts or solvates thereof, wherein R3As defined herein.
In one embodiment, there is provided formula (I)0'' '') wherein R is3As defined in any of the embodiments above, and particularly as defined in open english text line 86, line 20 to page 92, line 17.
In one embodiment, the compound of formula (I) is a compound wherein one R is1aSelected from hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino or-NH (C)3-8Cycloalkyl) substituted C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl and C substituted by one or more fluorine atoms1-4An alkyl group; another R1aIs selected from C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino or-NH (C)3-8Cycloalkyl) substituted C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl and C substituted by one or more fluorine atoms1-4An alkyl group; wherein n and R1、R2And R3As defined herein.
In one embodiment, the compound of formula (I) is a compound wherein each R is1aIndependently selected from C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino or-NH (C)3-8Cycloalkyl) substituted C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl and C substituted by one or more fluorine atoms1-4An alkyl group; another R1aIs selected from C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino or-NH (C)3-8Cycloalkyl) substituted C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl and C substituted by one or more fluorine atoms1-4An alkyl group; wherein n and R1、R2And R3As defined herein.
In one embodiment, the compound of formula (I) is a compound wherein each R is1aIs hydrogen; wherein n and R1、R2And R3As defined herein.
In one embodiment, at R3Within the definition, each alkyl group is C1-4An alkyl group.
In one embodiment, at R3Within the definition, each alkyl group is a straight chain C1-6Alkyl, especially straight-chain C1-4An alkyl group.
In one embodiment, the compound of formula (I) is a compound of formula (Γ):
(I’)
including any stereochemically isomeric form thereof;
and N-oxides, pharmaceutically acceptable salts or solvates thereof, wherein N, R1a、R2And R3As defined herein.
In one embodiment, the compound of formula (I) is a compound of formula (I '')
(I'')
Including any stereochemically isomeric form thereof;
and N-oxides, pharmaceutically acceptable salts or solvates thereof, wherein R1a、R2And R3As defined herein.
In one embodiment, the compound of formula (I) is a compound of formula (I ' ' ')
(I''')
Including any stereochemically isomeric form thereof;
and N-oxides, pharmaceutically acceptable salts or solvates thereof, wherein R1aAnd R3As defined herein.
In one embodiment, provided are compounds of formula (I), (I ' ' '), (I)0)、(I0')、(I0'') or (I)0' ' ') a compound ofIn R3Each alkyl within the definition is a straight chain C1-6An alkyl group. In one embodiment, provided are compounds of formula (I), (I ' ' '), (I)0)、(I0')、(I0'') or (I)0'' '') wherein R is3Each alkyl within the definition is C1-4An alkyl group. In one embodiment, provided are compounds of formula (I), (I ' ' '), (I)0)、(I0')、(I0'') or (I)0'' '') wherein R is3Each alkyl within the definition is a straight chain C1-4An alkyl group.
For the avoidance of doubt, it is to be understood that each of the conventional and specific preferences, embodiments and examples for a substituent may be combined with the conventional and specific preferences, embodiments and examples for one or more substituents (preferably, all other substituents) as defined herein, and that all such embodiments are included herein.
Process for the preparation of compounds of formula (I)
In this section, as in all other sections of this application, formula (I) also includes all other subgroups thereof and embodiments thereof as defined herein, unless the context indicates otherwise.
In general, the compounds of formula (I) can be prepared according to the following scheme 1.
Reaction scheme 1
In scheme 1, intermediates of formula (IV) are prepared as follows: an intermediate of formula (II) wherein W is W in the presence of a suitable catalyst (e.g. tetrakis (triphenylphosphine) palladium (0) or palladium (II) acetate), a suitable base (e.g. sodium carbonate), a suitable ligand (e.g. triphenylphosphine) and a suitable solvent or solvent mixture (e.g. ethylene glycol dimethyl ether and water)1And W2Each independently represents a suitable leaving group, e.g. halogen, such as chlorine or bromine, etc., with an intermediate of formula (III). An intermediate of formula (II) wherein W1Is chlorine, W2Is bromine, and can be prepared as follows: 7-bromo-2 (1H) -quinoxalinone is reacted with phosphorus oxychloride in a suitable solvent, for example, toluene, or with thionyl chloride and N, N-dimethylformamide. The intermediates of formula (IV) can also be prepared as follows: 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline and intermediate W10-R1Reaction of in which W10Represents a suitable leaving group such as halogen, e.g. bromine, and the like. An intermediate of formula (IV) wherein R1The substituents bearing suitable protecting groups may be prepared according to the same scheme, but wherein 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline is coupled with intermediate W10-R1-P reaction, wherein P represents a suitable protecting group, such as-C (= O) -O-C (CH)3)3. Then, in the presence of a suitable catalyst (e.g., palladium (II) acetate), a suitable base (e.g., sodium tert-butoxide or Cs)2CO3) Suitable ligands (e.g. 1,1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) And in the presence of a suitable solvent or solvent mixture (e.g. dioxane or ethylene glycol dimethyl ether and water), the intermediate of formula (IV) is further reacted in the next step with the intermediate of formula (V) to give the intermediate of formula (VI). The intermediate of formula (VI) may then be reacted with an intermediate of formula (VII) in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide or N, N-dimethylacetamide), wherein W is3Represents a suitable leaving group, e.g. halogen, e.g. bromine, wherein RxAnd RyRepresents C1-4Alkyl radical, RzRepresents C1-4Alkyl or phenyl, e.g. RxAnd RyRepresents CH3，RzRepresents C (CH)3)3Or phenyl to give an intermediate of formula (VIII). An intermediate of formula (VIII) or wherein R1Intermediates of formula (VIII) wherein the substituents bear suitable protecting groups may also be prepared as follows: in the presence of a suitable catalyst (e.g. palladium (II) acetate), a suitable ligand (e.g. racemic-2, 2 '-bis (diphenylphosphino) -1,1' -binaphthyl), a suitable ligandAlkali (e.g. Cs)2CO3) And a suitable solvent (e.g. 1, 2-dimethoxyethane), an intermediate of formula (IV) or wherein R1Reaction of an intermediate of formula (IV) wherein the substituents bear suitable protecting groups with an intermediate of formula (XXIII'), wherein R3a' represents-C1-6alkyl-O-Si (R)x)(Ry)(Rz). Intermediates of formula (VIII) can be converted to compounds of formula (I) wherein R is3represents-C1-6alkyl-OH, said compound being represented by formula (I-a) or by wherein R1Compounds of formula (I-a) wherein the substituents bear suitable protecting groups. Such reactions may also be carried out in the presence of a suitable acid (e.g. acetic acid or HCl) and a suitable solvent (e.g. tetrahydrofuran or dioxane). Alternatively, an intermediate of formula (VI) may be reacted with an intermediate of formula (VII') wherein W is in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide or N, N-dimethylacetamide)3Represents a suitable leaving group, e.g. halogen, such as bromine and the like, to give an intermediate of formula (XXV), which is then deprotected in the presence of a suitable acid (e.g. HCl) and a suitable solvent (e.g. an alcohol such as methanol or isopropanol) to give a compound of formula (I-a). A compound of formula (I-a) or wherein R is a compound of formula (I-a) wherein R is methyl or ethyl acetate, in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine or N, N-dimethyl-4-aminopyridine) and a suitable solvent (e.g. dichloromethane or tetrahydrofuran)1Compounds of formula (I-a) wherein the substituents bear suitable protecting groups may be reacted with methanesulfonyl chloride to give an intermediate of formula (IX) (a mesylate derivative) or an intermediate of formula (IX ') (a chloride derivative), or an intermediate of formula (IX) or (IX'), wherein R is1The substituents bear suitable protecting groups. The intermediate of formula (IX) or (IX') may then be reacted with an intermediate of formula (X) to obtain a compound of formula (I), wherein R3Is represented by NR10R11Substituted C1-6Alkyl, said compound being represented by formula (I-b), or wherein R1Compounds of formula (I-b) wherein the substituents bear suitable protecting groups. The reaction may optionally be carried out inSuitable bases (e.g. triethylamine, K)2CO3、Na2CO3Or sodium hydride) and optionally a suitable solvent (e.g., acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide, 1-methyl-pyrrolidone), a suitable alcohol (e.g., 1-butanol), and the like. Such reactions may also be carried out with a suitable salt of the intermediate of formula (X), for example, the HCl salt of the intermediate of formula (X), or may be carried out in the presence of potassium iodide. In this way, R can be obtained3Represents iodo C1-6Alkyl compounds. A compound of formula (I-b), wherein R1The substituents carrying suitable protecting groups may be converted to compounds of formula (I-b) by reaction with a suitable acid, for example trifluoroacetic acid, in the presence of a suitable solvent, for example dichloromethane.
In the presence of a suitable solvent (e.g. acetonitrile, 1-methyl-2-pyrrolidone or an alcohol such as 1-butanol), optionally in the presence of potassium iodide or a suitable base (e.g. Na)2CO3、K2CO3Or triethylamine), the intermediate of formula (IX) may also be reacted with a suitable nitrogen-containing ring (at R)9Within the definition of (XXI) or a suitable salt of an intermediate of formula (XXI) to give a compound of formula (I-d). Intermediates of formula (IX) may also be reacted with intermediates of formula (X-a) wherein P represents a suitable protecting group, for example-C (= O) -O-C (CH), in the presence of a suitable base, for example sodium hydride, and a suitable solvent, for example dimethylacetamide3)3To give an intermediate of formula (XXX), which may be deprotected in the presence of a suitable acid (e.g. HCl or trifluoroacetic acid) and a suitable solvent (e.g. dichloromethane or an alcohol, e.g. methanol) to give a compound of formula (I-b-1). Intermediates of formula (XXX) may also be prepared as follows: the intermediate of formula (VI) is reacted with a compound of formula W in the presence of a suitable base, such as sodium hydride, and a suitable solvent, such as N, N-dimethylformamide or N, N-dimethylacetamide6-C1-6alkyl-NR10Intermediate of P (wherein W6Represents a suitable leaving group, e.g. halogen, such as bromine, etc., or-O-S (= O)2-CH3P is as described above). Or, formula (II)The compound of (1-d) or (1-b-1) can also be prepared as follows: intermediates of formula (VI) are each independently of formula W6-C1-6alkyl-N-rings or W6-C1-6alkyl-NHR10In which W is6As described above.
In the presence of a suitable base (e.g. sodium hydride or Cs)2CO3) And a suitable solvent (e.g. N, N-dimethylformamide, N-dimethylacetamide or acetonitrile), the intermediate of formula (VI) may be reacted with W6-R3aReaction of in which W6Represents a suitable leaving group, for example halogen, such as bromine, etc., or-O-S (= O)2-CH3，R3aRepresents optionally substituted C1-6Alkyl radicals, e.g. -CH2-C3H5To obtain the compound of formula (I-c). In this way, compounds of formula (I-c) (wherein R is3represents-S (= O)2-N(CH3)2) It can also be prepared as follows: the intermediate of formula (VI) is reacted with dimethylsulfamoyl chloride in the presence of a suitable base, such as NaH, and a suitable solvent, such as N, N-dimethylformamide.
A compound of formula (I-c), wherein R3arepresents-CH2-C (OH) (R ') (R' '), wherein R' represents optionally substituted C1-4Alkyl, R' represents hydrogen or optionally substituted C1-4An alkyl group, the compound represented by formula (I-c-1), can be prepared as follows: in the presence of a suitable base (e.g. sodium hydride, Cs)2CO3Or potassium hydroxide) and a suitable solvent (e.g., N-dimethylformamide, N-dimethylacetamide, acetonitrile or water) with an intermediate of formula (VI).
The intermediate of formula (IV) may also be reacted with an intermediate of formula (XXIII) in the presence of a suitable catalyst (e.g. palladium (II) acetate or tris (dibenzylideneacetone) dipalladium (0)), a suitable base (e.g. sodium tert-butoxide), a suitable ligand (e.g. 1,1'- [1, 1' -binaphthyl ] -2,2 '-diylbis [1, 1-diphenylphosphine ] or 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl) and a suitable solvent (e.g. dioxane) to give a compound of formula (I-c).
A compound of formula (I-b), wherein R11Is C substituted by amino1-6Alkyl group, which is represented by formula (I-b-2), can also be prepared according to the following reaction scheme 1A.
Reaction scheme 1A
In scheme 1A, a compound of formula (I-b-1) is reacted with N- (3-bromopropyl) phthalimide (phtalimide) in the presence of a suitable base (e.g., potassium carbonate) and a suitable solvent (e.g., acetonitrile) to give an intermediate of formula (XXXVI), which can be converted to a compound of formula (I-b-2) by reacting with hydrazine in the presence of a suitable solvent (e.g., an alcohol, such as ethanol).
A compound of formula (I-b), wherein R1Is hydrogen, represented by formula (I-b-3), can be prepared according to scheme 1A 1.
Reaction scheme 1A1
In scheme 1A1, an intermediate of formula (I-a-1) is reacted with methanesulfonyl chloride in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane) to give an intermediate of formula (IX-1), wherein Rurepresents-O-S (= O)2-CH3The intermediate of formula (IX-1) is reacted with the intermediate of formula (X) in the presence of a suitable solvent, such as acetonitrile, to convert to the compound of formula (I-b-3).
Recognition of the conditions and R in the reactions of scheme 1a and scheme 1a11aSuitable protecting groups for carrying out the reaction are considered to be within the knowledge of those skilled in the art. For example,r may be partially protected with a t-butyldimethylsilyl group1aA hydroxyl group within the definition of (1); can be replaced by-C (= O) -O-C (CH)3)3Radical protection of R1aNH group within the definition of (1).
Suitable deprotection reactions are also considered to be within the purview of those skilled in the art.
A compound of formula (I) wherein R3Represents optionally substituted C2-6Alkynyl, represented by formula (I-k), can be prepared according to scheme 1B.
Reaction scheme 1B
In scheme 1B, an intermediate of formula (VI) is reacted with a compound of formula W in the presence of a suitable base (e.g., NaH) and a suitable solvent (e.g., N-dimethylformamide)11-R3bWherein R is3bRepresents optionally substituted C2-6Alkynyl, W11Represents a suitable leaving group, for example halogen, such as chlorine, or-O-S (= O)2-CH3. Intermediate W11-R3bWherein W is11represents-O-S (= O)2-CH3It can be prepared as follows: the corresponding alcohol derivative is reacted with methanesulfonyl chloride in the presence of a suitable base (e.g., triethylamine or 4-dimethylaminopyridine) and a suitable solvent (e.g., dichloromethane).
A compound of formula (I-k), wherein R3bRepresents C substituted by hydroxy2-6Alkynyl, represented by formula (I-k-1), can be prepared according to the following scheme 1C.
Reaction scheme 1C
In scheme 1C, an intermediate of formula (VI) is reacted with an intermediate of formula (XXXVIII) in the presence of a suitable base (e.g. NaH) and a suitable solvent (e.g. N, N-dimethylformamide) to give an intermediate of formula (VIII'), which is converted to a compound of formula (I-k-1) by reaction with a suitable acid (e.g. trifluoroacetic acid) in the presence of a suitable solvent (e.g. tetrahydrofuran).
A compound of formula (I-k), wherein R3bRepresents C2-6Alkynyl, represented by formula (I-k-2), can be prepared according to the following scheme 1D.
Reaction scheme 1D
In scheme 1D, compounds of formula (I-k-2) are prepared as follows: in the presence of a suitable base (e.g. K)2CO3) And a suitable solvent (e.g., an alcohol, such as methanol, and the like), deprotecting the intermediate of formula (xxxxxii). The intermediates of formula (xxxxxii) can be prepared as follows: the intermediate of formula (VI) is reacted with W in the presence of a suitable base (e.g., NaH) and a suitable solvent (e.g., N-dimethylformamide)13-C2-6alkynyl-Si (CH)3)3And (4) reacting.
A compound of formula (I) wherein R3represents-P (= O) (OC)1-6Alkyl radical)2Substituted ethyl groups, represented by formula (I-l), can be prepared according to scheme 1E below.
Reaction scheme 1E
In scheme 1E, a compound of formula (VI) is reacted in the presence of a suitable catalyst (e.g., tri-N-butylphosphine) and a suitable solvent (e.g., acetonitrile)(VI) intermediate with bis (C) vinylphosphonic acid1-6Alkyl) esters to give compounds of formula (I-l).
The intermediates of formula (VI) can also be prepared according to scheme 2 below.
Reaction scheme 2
In scheme 2, intermediates of formula (XII) are prepared as follows: in the presence of a suitable catalyst (e.g., tetrakis (triphenylphosphine) palladium (0)), a suitable base (e.g., Na)2CO3) And a suitable solvent or solvent mixture (e.g. ethylene glycol dimethyl ether and water), wherein W is1Represents a suitable leaving group, such as halogen, e.g. chloro and the like, with an intermediate of formula (III). In the next step, the intermediate of formula (XII) is hydrogenated to the intermediate of formula (XIII) in the presence of a suitable catalyst (e.g. nickel) and a suitable solvent (e.g. an alcohol such as methanol, or tetrahydrofuran, or mixtures thereof).
The intermediates of formula (XIII) can also be prepared as follows: in Cu2In the presence of O, an intermediate of formula (IV) and NH4And (4) OH reaction. In the next step, in the presence of a suitable catalyst (e.g. palladium (II) acetate), a suitable base (e.g. sodium tert-butoxide), a suitable ligand (e.g. 1,1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) And a suitable solvent (e.g. ethylene glycol dimethyl ether or dioxane), with an intermediate of formula (XIII) wherein W is5Represents a suitable leaving group, e.g. bromo etc., to give an intermediate of formula (VI). The reaction can also be carried out in Pd2(dba)3(as a catalyst), Xphos (as a ligand), a suitable base (e.g., Cs)2CO3) And in the presence of a suitable solvent (e.g., an alcohol, such as butanol).
An intermediate of formula (IV) wherein R1Is hydrogen in a suitable base (e.g. NaH)And a suitable solvent (e.g. N, N-dimethylformamide) by reaction with W14-R1' (wherein W14Is a suitable leaving group, e.g. halogen, e.g. bromine), may be converted to an intermediate of formula (IV) wherein R is1Not hydrogen, said R1From R1' represents.
Intermediates of formula (VI) can also be prepared according to scheme 3 below.
Reaction scheme 3
In scheme 3, in the presence of a suitable catalyst (e.g. palladium (II) acetate), a suitable base (e.g. sodium tert-butoxide), a suitable ligand (e.g. 1,1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) And a suitable solvent (e.g. ethylene glycol dimethyl ether) to react the intermediate of formula (XV) with the intermediate of formula (V) to give the intermediate of formula (XVI). In the next step, the intermediate of formula (XVI) is reacted with P (= O) Cl3Or chlorosuccinimide reaction, optionally in the presence of a solvent such as acetonitrile, to give an intermediate of formula (XVII) in the presence of a suitable catalyst such as tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium (0), a suitable base such as Na2CO3Or K3PO4) Optionally in the presence of a suitable ligand (e.g. 2-dicyclohexylphosphino-2 ',6' dimethoxybiphenyl) and a suitable solvent (e.g. ethylene glycol dimethyl ether), the intermediate of formula (XVII) is reacted with the intermediate of formula (III) to convert to the intermediate of formula (VI).
In the above reaction, the intermediate of formula (III) may be reacted in its protected form, e.g.. The resulting protected intermediate of formula (VI) may be converted by reaction with tetrabutylammonium fluoride in the presence of a suitable solvent, such as tetrahydrofuranTo deprotected-C1-6An alkyl-OH intermediate. said-C1-6alkyl-OH can be converted to-C as follows1-6alkyl-NH2: first, in the presence of a suitable base (e.g., triethylamine) and a suitable solvent (e.g., dichloromethane), -C1-6alkyl-OH is reacted with methanesulfonyl chloride, and then the obtained intermediate is reacted with di-tert-butyl-iminoformate in the presence of a suitable base (e.g. NaH) and a suitable solvent (e.g. N, N-dimethylformamide), and then reacted with a suitable acid, e.g. trifluoroacetic acid, in a suitable solvent (e.g. dichloromethane).
The intermediates of formula (VIII) can also be prepared according to scheme 4 below.
Reaction scheme 4
In scheme 4, an intermediate of formula (XVII) is reacted with an intermediate of formula (VII) in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide) to give an intermediate of formula (XVIII). Then, in a suitable catalyst (e.g. Pd)2(dba)3) A suitable base (e.g. K)3PO4) The intermediate of formula (XVIII) is reacted with the intermediate of formula (III) in the presence of a suitable ligand (e.g. 2-dicyclohexylphosphino-2 ',6' -dimethoxy-biphenyl or S-Phos) and a suitable solvent (e.g. dioxane or water or mixtures thereof).
Intermediates of formula (VIII') can also be prepared according to scheme 4A below.
Reaction scheme 4A
In scheme 4A, an intermediate of formula (XVIII) is reacted with an intermediate of formula (XXXVII) in the presence of a suitable catalyst, e.g. tetrakis (triphenylphosphine) palladium (0), and a suitable solvent, e.g. toluene.
The intermediate of formula (VIII') can be further reacted according to scheme 4B below.
Reaction scheme 4B
In scheme 4B, intermediates of formula (VIII'), wherein R1Represents hydrogen, said intermediate being represented by formula (VIII' -a), with W in the presence of a suitable base (e.g. NaH) and a suitable solvent (e.g. N, N-dimethylformamide)12-C1-6Alkyl-halogen (wherein W12Represents a suitable leaving group, e.g. halogen, e.g. chlorine), may be converted into an intermediate of formula (VIII'), wherein R1Represents halogeno C1-6An alkyl group, said intermediate being represented by formula (VIII' -b). In the presence of a suitable base (e.g. K)2CO3) And a suitable solvent (e.g. acetonitrile), with an optionally substituted R6Can be converted into an intermediate of formula (VIII' -c), wherein R1Represents optionally substituted R6. R in the intermediate of formula (VIII' -c)6With a hydroxy group (as with the intermediates of formula (VIII' -C-1)), by reaction with C in the presence of a suitable base (e.g. triethylamine, 4-dimethylaminopyridine) and a suitable solvent (e.g. dichloromethane)1-6alkyl-C (= O) -W12Reaction, the hydroxyl group may be protected by a suitable protecting group P, for example-O-C (= O) -C1-6Alkyl to give an intermediate of formula (VIII' -c-2) which can be converted to an intermediate of formula (XXXIX) by reaction with tetrabutylammonium fluoride in the presence of a suitable solvent such as tetrahydrofuran. Said intermediate of formula (XXXIX) can be converted into an intermediate of formula (XXXX) by reaction with methanesulfonyl chloride in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane), by reaction with a compound of formula (X)The intermediates may be converted to intermediates of formula (XXXXI) by reaction in a suitable solvent, for example acetonitrile. Then, in a suitable base (e.g. K)2CO3) And a suitable solvent (e.g., an alcohol, such as methanol, and the like) to obtain a compound of formula (I-b-4).
The intermediates of formula (VIII') may also be reacted to prepare the compounds of the present invention according to the same reaction scheme as scheme 1. It will be appreciated within the knowledge of one skilled in the art that suitable conditions and R for carrying out the reaction are1aDefinition of protecting group. For example, R may be protected with a t-butyldimethylsilyl moiety1aA hydroxyl group within the definition of (1); can be replaced by-C (= O) -O-C (CH)3)3Radical protection of R1aNH group within the definition of (1).
Suitable deprotection reactions are also considered to be within the purview of those skilled in the art.
A compound of formula (I) wherein R3Represents optionally substituted C1-6Alkyl, said compounds being represented by formula (I-c), can also be prepared according to scheme 5.
Reaction scheme 5
In scheme 5, an intermediate of formula (XVII) is reacted with W in the presence of a suitable base, e.g. sodium hydride, and a suitable solvent, e.g. N, N-dimethylformamide6-R3aReaction of in which W6Represents a suitable leaving group, e.g. halogen, e.g. bromine, etc., R3aRepresents optionally substituted C1-6Alkyl radicals, e.g. -CH2-C3H5To give an intermediate of formula (XIX). In the next step, in a suitable catalyst (e.g. palladium or Pd tetrakis (triphenyl) phosphine)2(dba)3(tris (dibenzylideneacetone) dipalladium (0))), suitable ligands (e.g., 2-bicyclicHexylphosphino-2 ',6' -dimethoxybiphenyl), a suitable base (e.g., Na)2CO3Or K3PO4) And a suitable solvent (e.g. ethylene glycol dimethyl ether or dioxane or water) to react the intermediate of formula (XIX) with the intermediate of formula (III).
The compound of formula (I-c) can also be prepared according to the following reaction scheme 6.
Reaction scheme 6
In scheme 6, in the presence of a suitable catalyst (e.g., palladium (II) acetate), a suitable base (e.g., sodium tert-butoxide) and a suitable ligand (e.g., 1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) In the presence of (A), reacting an intermediate of formula (IV) with R3a-NH2Reaction to give an intermediate of formula (XX), in a next step, in a suitable catalyst (e.g. palladium (II) acetate or Pd2(dba)3(tris (dibenzylideneacetone) dipalladium (0))), suitable ligands (e.g. 2-dicyclohexylphosphino-tri-isopropyl-biphenyl or 1,1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) The intermediate of formula (XX) is reacted with the intermediate of formula (XIV) in the presence of a suitable base (e.g. sodium tert-butoxide) and a suitable solvent (e.g. ethylene glycol dimethyl ether).
A compound of formula (I) wherein R3Is C substituted by 5-amino-1, 3, 4-oxadiazolyl1-6Alkyl groups, can be prepared according to scheme 7 below.
Reaction scheme 7
In scheme 7, a compound of formula (I-h) is reacted with NH in the presence of a suitable solvent, e.g. an alcohol, e.g. ethanol2-NH2Reaction to give an intermediate of formula (XXXI) which is then, in a further step, in a suitable base (e.g. NaHCO)3) And a suitable solvent (e.g. water or dioxane) with W8-CN reaction, wherein W8Represents a suitable leaving group, for example halogen, for example bromine.
A compound of formula (I) wherein R3Is C substituted by 3, 3-dimethyl-morpholine1-6Alkyl groups, can be prepared according to scheme 7A below.
Reaction scheme 7A
In scheme 7A, a compound of formula (I-j ") is reacted with 2-amino-2-methyl-1-propanol in the presence of a suitable base (e.g., NaH) and in the presence of a suitable solvent (e.g., N-dimethylformamide) to yield NH2Partially protected with a suitable protecting group P (e.g., -C (= O) -O-C (CH)3)3) Protected intermediate of formula (XXXII) in a suitable solvent (e.g. dioxane) and a suitable base (e.g. NaHCO)3) With, for example, di-tert-butyl dicarbonate in the presence of (A) to give an intermediate of formula (XXXIII). In the next step, the intermediate is reacted with methanesulfonyl chloride in the presence of a suitable solvent (e.g. dichloromethane) and a suitable base (e.g. triethylamine) to give an intermediate of formula (XXXIV), which is converted to an intermediate of formula (XXXV) by reaction with a suitable acid (e.g. trifluoroacetic acid) in the presence of a suitable solvent (e.g. dichloromethane). The intermediate of formula (XXXV) is converted to a compound of formula (I-j') by reaction with a suitable base, such as N, N-diisopropylethylamine and triethylamine, in the presence of a suitable solvent, such as an alcohol, e.g. methanol.
As indicated above, the compounds of formula (I) or some of the above intermediates may be prepared by deprotecting the corresponding protected compounds. Other protection-deprotection reactions are shown in scheme 8 below.
Reaction scheme 8
In scheme 8, compounds of formula (I), wherein R1Represents a hydroxyl group C1-6An alkyl group, the compound represented by formula (I-e), may be prepared as follows: intermediates of formula (XXVI) are deprotected in the presence of a suitable acid (e.g. HCl or trifluoroacetic acid) or a suitable de-silylating agent (e.g. tetrabutylammonium fluoride) and a suitable solvent (e.g. an alcohol, such as methanol, or tetrahydrofuran). Intermediates of formula (XXVI) can be prepared as follows: in a suitable base (e.g. sodium hydride or K)2CO3) And a suitable solvent (e.g. N, N-dimethylformamide or acetonitrile), in the presence of a compound of formula (I) wherein R is1Is hydrogen, said compound being represented by (I-f), with an intermediate of formula (XXIV), wherein W is9Represents a suitable leaving group, e.g. halogen, such as bromine and the like, P represents a suitable protecting group, e.g. -O-Si (CH)3)2(C(CH3)3) Or)。
A compound of formula (I) wherein R1represents-C (= O) -R6Substituted C1-6Alkyl radical, wherein R6Is a suitable nitrogen-containing ring attached to the C (= O) moiety through a nitrogen atom, which compound is represented by formula (I-g) and may be prepared as follows: the intermediate of formula (XXIX) is reacted with the intermediate of formula (XXI) in the presence of suitable peptide coupling reagents (e.g., 1-hydroxy-benzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl). Intermediates of formula (XXIX) can be prepared as follows: the intermediate of formula (XXVIII) is reacted with LiOH in the presence of a suitable solvent, such as tetrahydrofuran or water. Intermediates of formula (XXVIII) can be prepared as follows: in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylFormamide) with an intermediate of the formula (XXVII), in which W is9As defined above.
The compounds of formula (I-I) can be prepared as follows: starting from an intermediate of formula (XXIX), with NHR in the presence of a suitable peptide coupling reagent (e.g. 1-hydroxy-benzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl) and a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane)4R5And (4) reacting.
Further, protection-deprotection reactions can also be used according to the method outlined in scheme 9 below.
Reaction scheme 9
In scheme 9, the following reaction conditions apply:
a: in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide).
B: in the presence of a suitable catalyst (e.g. palladium (II) acetate), a suitable base (e.g. sodium tert-butoxide), a suitable ligand (e.g. 1,1' - [1, 1' -binaphthyl ] -2,2' -diylbis [1, 1-diphenylphosphine ]) and a suitable solvent (e.g. dioxane or ethylene glycol dimethyl ether).
C: in the presence of a suitable catalyst (e.g. palladium (II) acetate), a suitable base (e.g. sodium tert-butoxide), a suitable ligand (e.g. 1,1' - [1, 1' -binaphthyl ] -2,2' -diylbis [1, 1-diphenylphosphine ]) and a suitable solvent (e.g. dioxane or ethylene glycol dimethyl ether).
D: in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane).
E: in the presence of a suitable base (e.g. K)2CO3) And a suitable solvent (e.g. 1-methyl-2-pyri-dine)Pyrrolidone).
F: in the presence of hydrazine monohydrate and a suitable solvent (e.g., an alcohol, such as ethanol).
G: in the presence of a suitable base (e.g. K)2CO3) And in the presence of a suitable solvent, such as tetrahydrofuran.
It is recognized that it is within the knowledge of one skilled in the art under which conditions and on which parts of the molecule suitable protecting groups may be present. For example, R1Protecting groups on substituents or on pyrazole moieties, or R3On a substituent or R2A protecting group on a substituent, or a combination thereof. It is also believed that the skilled person will be able to recognise the most suitable protecting group, for example-C (= O) -O-C1-4Alkyl orOr O-Si (CH)3)2(C(CH3)3) or-CH2-O-CH2CH2-O-CH3。
The invention also includes deuterated compounds. These deuterated compounds can be prepared during the synthetic process using suitable deuterated intermediates. For example, by reaction with methyl iodide-D in the presence of a suitable base (e.g., cesium carbonate) and a suitable solvent (e.g., acetonitrile)3Reaction of an intermediate of formula (IV-a)Can be converted into an intermediate of formula (IV-b)。
The compounds of formula (I) may also be interconverted with each other by reactions or functional group transformation methods known in the art.
For example, compounds of formula (I) wherein R is in the presence of a suitable solvent (e.g., dichloromethane, dioxane or an alcohol, e.g., methanol, isopropanol, etc.)1Represents tetrahydroPyranyl, which can be converted to compounds of formula (I) by reaction with a suitable acid, such as HCl or trifluoroacetic acid, wherein R1Represents hydrogen.
A compound of formula (I) wherein R1Or R3Represents a monohaloalkyl group, by reaction with an intermediate of formula (XXI), optionally in the presence of a suitable base (e.g. triethylamine or K)2CO3Or sodium hydride), optionally in the presence of a suitable solvent (e.g. acetonitrile, N-dimethylformamide or 1-methyl-2-pyrrolidone), may be converted into a compound of formula (I) wherein R is1Or R3Represents C substituted by the ring moiety as defined for the intermediate of formula (XXI) above1-6Alkyl and through a nitrogen atom with C1-6The alkyl moiety is attached.
A compound of formula (I) wherein R1Or R3Represents C1-6alkyl-OH, in the presence of a suitable solvent (e.g. dichloromethane), in the presence of a catalytic amount of an alcohol (e.g. ethanol), can be converted by reaction with diethylaminosulfur trifluoride into a compound of formula (I) wherein R is1Or R3Represents C1-6alkyl-F. Also, compounds of formula (I) wherein R1Or R3Is represented by R6Or R9Substituted C1-6Alkyl, wherein R is6Or R9Substituted by OH, in the presence of a suitable solvent, for example dichloromethane, by reaction with diethylaminosulfur trifluoride, it can be converted into compounds of the formula (I) in which R is1Or R3Is represented by R6Or R9Substituted C1-6Alkyl, wherein R is6Or R9Is substituted by F.
A compound of formula (I) wherein R1Or R3Is represented by R6Or R9Substituted C1-6Alkyl, wherein R is6Or R9Is represented by-C (= O) -O-C1-6Alkyl substitution by reaction with LiAlH in the presence of a suitable solvent, such as tetrahydrofuran4Can be converted into a compound of the formula (I) in which R1Or R3Is represented by R6Or R9Substituted C1-6Alkyl, wherein R is6Or R9is-CH2-OH substitution.
A compound of formula (I) wherein R3Represents C substituted by 1, 3-dioxo-2H-isoindol-2-yl1-6Alkyl groups, by reaction with hydrazine monohydrate in the presence of a suitable solvent (e.g. an alcohol, such as ethanol), may be converted to compounds of formula (I) wherein R is3Represents C substituted by amino1-6An alkyl group.
A compound of formula (I) wherein R1Or R3Represents C substituted by amino1-6Alkyl by reaction with Cl-S (= O) in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane)2-C1-6Alkyl groups, which may be converted to compounds of formula (I) wherein R1Or R3Is represented by-NH-S (= O)2-C1-6Alkyl substituted C1-6An alkyl group.
A compound of formula (I) wherein R1Or R3Represents C substituted by halogeno1-6Alkyl, using a large excess of amino groups or in a suitable base (e.g. K)2CO3) And a suitable solvent (e.g. acetonitrile, N-dimethylacetamide or 1-methyl-pyrrolidone) by reaction with NHR4R5Or NHR10R11Can be converted into a compound of the formula (I) in which R1Or R3Is represented by NR4R5Or NR10R11Substituted C1-6An alkyl group.
A compound of formula (I) wherein R1Represents hydrogen in a suitable base (e.g. sodium hydride or K)2CO3Or triethylamine or 4-dimethylamino-pyridine or diisopropylamine) and a suitable solvent (e.g. N, N-dimethylformamide or acetonitrile or dichloromethane) by reaction with a polyhalo C1-6alkyl-W or polyhydroxy-C1-6alkyl-W or C1-6alkyl-W or W-S (= O)2-NR14R15Or W-S (= O)2-C1-6Alkyl reactions in which W represents a suitable leaving group, e.g. halo, e.g. bromo and the like, may be converted to compounds of formula (I) in which R1Represents polyhalogenated C1-6Alkyl or polyhydroxy C1-6Alkyl or C1-6Alkyl or-S (= O)2-NR14R15or-S (= O)2-C1-6An alkyl group.
A compound of formula (I) wherein R1Represents hydrogen by reaction with W-C in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide)1-6alkyl-O-Si (CH)3)2(C(CH3)3) Can also be converted into compounds of the formula (I), in which R1Represents C1-6alkyl-OH.
A compound of formula (I) wherein R1Represents hydrogen by reaction with C in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. an alcohol, e.g. methanol)1-6Alkyl-vinylsulfones, or by reaction with C in the presence of a suitable deprotonating agent (e.g. NaH) and a suitable solvent (e.g. dimethylformamide)1-6Alkyl-2-bromoethylsulfone, which may also be converted to compounds of formula (I) wherein R1Is represented by-S (= O)2-C1-6Alkyl substituted ethyl.
A compound of formula (I) wherein R1Represents hydrogen by reaction with a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide)Reaction of whereinRepresents R6Suitable nitrogen-containing rings within the definition, compounds of formula (I) are also possible, wherein R1represents-CH2-CHOH-CH2。
A compound of formula (I) wherein R1Is represented by R6Substituted C1-6Alkyl, wherein R is6Is represented by-C (= O) -O-C1-6Alkyl or-S (= O)2-NR14R15Substituted, or wherein R3Is represented by R9Substituted C1-6Alkyl, wherein R is9Is represented by-C (= O) -O-C1-6Alkyl or-S (= O)2-NR14R15The substitution, by reaction with a suitable acid (e.g. HCl) in a suitable solvent (e.g. dioxane, acetonitrile or an alcohol, e.g. isopropanol), may be converted to a compound of formula (I) wherein R is6Or R9Is unsubstituted. A compound of formula (I) wherein R1Is represented by R6Substituted C1-6Alkyl, wherein R is6Is a nitrogen atom-containing cyclic moiety which is substituted by-CH2-OH is substituted, or wherein R is3Is represented by R9Substituted C1-6Alkyl, wherein R is9Is a nitrogen atom-containing cyclic moiety which is substituted by-CH2-OH substitution, in the presence of a suitable solvent (e.g. tetrahydrofuran), by reaction with sodium hydroxide, may be converted into a compound of formula (I) wherein R6Or R9Is unsubstituted.
A compound of formula (I) wherein R1Is represented by R6Substituted C1-6Alkyl, or R3Is represented by R9Substituted C1-6Alkyl, wherein R is6Or R9Unsubstituted, by reaction with W-C in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide)1-6Alkyl reaction, wherein W is as defined above, may be converted to a compound of formula (I), wherein R is6Or said R9Quilt C1-6Alkyl substitution.
A compound of formula (I) wherein R1Or R3Represents a hydroxyl group C1-6Alkyl groups can be converted to the corresponding carbonyl compounds by reaction with dess-Martin-periodinane (dessimutan oxidant) in the presence of a suitable solvent, such as dichloromethane.
A compound of formula (I) wherein R1Is represented by R6Substituted C1-6Alkyl, or R3Is represented by R9Substituted C1-6Alkyl, wherein R is6Or said R9Quilt C1-6Alkyl-halo substitution may be converted to compounds of formula (I) wherein R is R by reaction with sodium cyanide in the presence of a suitable solvent such as water or an alcohol such as ethanol6Or said R9Quilt C1-6alkyl-CN substitution.
A compound of formula (I) wherein R1Is represented by R6Substituted C1-6Alkyl, wherein R is6Is unsubstituted, or wherein R is3Is represented by R9Substituted C1-6Alkyl, wherein R is9Unsubstituted, by reaction with formaldehyde or acetone and NaBH in the presence of a suitable solvent, e.g. tetrahydrofuran or an alcohol, e.g. methanol3CN, which can be converted into a compound of formula (I) wherein R6Or R9is-CH3or-CH (CH)3)2And (4) substitution.
A compound of formula (I) wherein R1Containing R substituted by OH6A substituent, or wherein R3Containing R substituted by OH9By reacting with W-C in the presence of a suitable base (e.g. sodium hydride) and a suitable solvent (e.g. N, N-dimethylformamide)1-6Alkyl groups, which may be converted to compounds of formula (I) wherein R6Or R9Substituent group is represented by C1-6Alkoxy substitution.
A compound of formula (I) wherein R1Inclusion quilt C1-6Alkoxy substituted R6A substituent, or wherein R3Inclusion quilt C1-6Alkoxy substituted R9The substituents, by reaction with a suitable acid, e.g. hydrochloric acid, may be converted into compounds of formula (I) wherein R6Or R9The substituents are substituted with-OH.
A compound of formula (I) wherein R1Comprising substitution by halogenR of (A) to (B)6A substituent, or wherein R3Comprising R substituted by halogen9Substituents, in a suitable solvent (e.g. 1-methyl-pyrrolidone), by reaction with NHR14R15Can be converted into a compound of the formula (I) in which R6Or R9The substituent being represented by-NR14R15And (4) substitution.
A compound of formula (I) wherein R3Is represented by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl groups, by reaction with LiOH in the presence of a suitable solvent (e.g. tetrahydrofuran), may be converted to compounds of formula (I) wherein R is3Represents C substituted by COOH1-6An alkyl group. The compound of formula (I), wherein R3Represents C substituted by COOH1-6Alkyl groups are prepared by reaction with NH (Si (CH) in the presence of a suitable peptide coupling reagent (e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl and 1-hydroxybenzotriazole), a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane or N, N-dimethylformamide)3)3)2Or MeNH3 +Cl-or NHR10R11Can be converted into a compound of the formula (I) in which R3represents-C (= O) -NH2or-C (= O) -NHCH3or-C (= O) NR10R11Substituted C1-6An alkyl group. A compound of formula (I) wherein R3Is represented by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl groups, in the presence of suitable solvents (e.g. toluene and heptane), may also be converted to compounds of formula (I) by reaction with ethylenediamine and trimethylaluminum under nitrogen atmosphere, wherein R3Represents C substituted by 2-imidazolyl1-6An alkyl group. The compound of formula (I), wherein R3Represents C substituted by 2-imidazolyl1-6Alkyl, which can be converted into compounds of the formula (I) by reaction with sodium hydroxide, wherein R3Is represented by-C (= O) -NH- (CH)2)2-NH2Substituted C1-6An alkyl group. A compound of formula (I) wherein R3Represents C substituted by COOH1-6Alkyl in carbonyldiimidazole and suitable solvents (e.g. dichloromethane)Can also be converted into compounds of the formula (I) by reaction with dimethylhydroxylamine in the presence of (A), in which R is3Is represented by-C (= O) -NH- (CH)3)(OCH3) Substituted C1-6An alkyl group.
A compound of formula (I) wherein R3Is represented bySubstituted C1-6Alkyl groups, in a suitable solvent (e.g. dioxane or water), may be converted to compounds of formula (I) wherein R is3Represents C substituted by 2 OH1-6An alkyl group. These compounds of the formula (I), in which R3Is represented bySubstituted C1-6Alkyl, optionally in a suitable base (e.g. sodium hydride or Na)2CO3Or triethylamine or KI) in the presence of a suitable solvent (e.g. N, N-dimethylformamide or an alcohol, e.g. 1-butanol or ethanol) by reaction with NH2R10R11(optionally in salt form, e.g. NHR10R11+Cl-) Reacted, also converted into compounds of formula (I) wherein R3Is represented by OH and NR10R11Substituted C1-6An alkyl group.
A compound of formula (I) wherein R3Is represented by-C (= O) -O-C1-6Alkyl substituted C1-3Alkyl groups, by reaction with methyl iodide and Mg powder in the presence of a suitable solvent (e.g. diethyl ether or tetrahydrofuran), may be converted to compounds of formula (I) wherein R is3Is represented by-C (CH)3)2-OH substituted C1-3An alkyl group.
A compound of formula (I) wherein R3Is represented by-C (= O) -O-C1-6Alkyl substituted C1-5Alkyl groups, in a suitable solvent (e.g. tetrahydrofuran), by reaction with LiAlH4Can be converted into a compound of the formula (I) in which R3Is represented by the formula-OHSubstituted C1-6An alkyl group.
A compound of formula (I) wherein R3Represents C substituted by-OH1-5Alkyl groups by reaction with Cl-C (= O) -C in the presence of a suitable base (e.g. NaH) and a suitable solvent (e.g. tetrahydrofuran)1-6Alkyl groups, which may be converted to compounds of formula (I) wherein R3represents-O-C (= O) -C1-6Alkyl substituted C1-5An alkyl group.
A compound of formula (I) wherein R3represents-CH2-CH=CH2Can be converted into compounds of the formula (I) in which R is the same as R, by reaction with potassium permanganate in a suitable solvent, for example acetone or water3represents-CH2-CHOH-CH2-OH。
A compound of formula (I) wherein R3represents-C (= O) -C1-4Alkyl substituted C1-6Alkyl groups, which can be converted to compounds of formula (I) by reaction with hydroxylamine in the presence of a suitable base (e.g. pyridine) and a suitable solvent (e.g. an alcohol, e.g. ethanol), wherein R3Is represented by-C (C)1-4Alkyl) = N-OH substituted C1-6An alkyl group.
A compound of formula (I) wherein R3Is represented by NH2Substituted C1-6Alkyl groups, by reaction with the corresponding COOH analogue (e.g. R) in the presence of a suitable peptide coupling reagent (e.g. 1-hydroxy-benzotriazole and 1- (3-dimethylamino) propyl) carbodiimide), optionally in the presence of a suitable base (e.g. triethylamine)6-COOH or CF3-C(CH3) (OH) -COOH, etc.) which can be converted into compounds of formula (I) wherein R is3represents-NH-C (= O) -R6Or by-NH-C (= O) -C1-6Alkyl or by-NH-C (= O) -polyhydroxy C1-6Alkyl or by-NH-C (= O) -polyhaloC1-6Alkyl or C substituted by-NH-C (= O) -polyhydroxy polyhalogenated Cv alkyl1-6An alkyl group. The compound of formula (I), wherein R3Is represented by NH2Substituted C1-6Alkyl radicals in a suitable base (e.g. triethylamine) and a suitable solvent (e.g. tetrahydrofuran)Can also be converted into compounds of the formula (I) in which R is3Is represented by NH-C (= O) -CF3Substituted C1-6An alkyl group. The compound of formula (I), wherein R3Is represented by NH2Substituted C1-6Alkyl in a suitable base (e.g. K)2CO3) And a suitable solvent (e.g. N, N-dimethylformamide or dioxane) by reaction with a polyhalogenated C1-6alkyl-W (W is as defined above, e.g. iodo-2-fluoroethane) reaction, may also be converted to compounds of formula (I) wherein R is3represents-NH-polyhalogenated C1-6Alkyl (e.g. -NH-CH)2-CH2-F) substituted C1-6An alkyl group.
A compound of formula (I) wherein R3Represents C substituted by cyano1-6Alkyl groups by reaction with sodium azide and NH in the presence of a suitable solvent (e.g. N, N-dimethylformamide)4 +Cl-Can be converted into a compound of the formula (I) in which R3Represents C substituted by tetrazolyl1-6An alkyl group.
A compound of formula (I) wherein R3RepresentsMay be converted to a compound of formula (I) by reaction with ethyl azidoacetate in the presence of CuI and a suitable base (e.g. diisopropylamine) and a suitable solvent (e.g. tetrahydrofuran), wherein R is3Represents。
A compound of formula (I) wherein R3RepresentsIn a suitable catalyst (e.g. CuSO)4And sodium ascorbate), a suitable acid (e.g. acetic acid) and a suitable solvent (e.g. dioxane) by reaction with sodium azide and formaldehydeA compound of formula (I) wherein R3Represents。
A compound of formula (I) wherein R3Represents C2-6Alkynyl groups are prepared by reaction with W-R in the presence of a suitable catalyst (e.g., dichlorobis (triphenylphosphine) palladium), a suitable cocatalyst (e.g., CuI), a suitable base (e.g., triethylamine) and a suitable solvent (e.g., dimethyl sulfoxide)9Reactions in which W is as defined above, may be converted to compounds of formula (I) in which R is3Is represented by R9Substituted C2-6Alkynyl.
A compound of formula (I) wherein R3Comprising R substituted by halo9By reaction with NHR in the presence of a suitable solvent, such as 1-methyl-2-pyrrolidone14R15Can be converted into a compound of the formula (I) in which R3Containing by-NR14R15Substituted R9。
A compound of formula (I) wherein R3Comprising C2-6Alkynyl groups, in the presence of a suitable catalyst (e.g. palladium on charcoal) and a suitable solvent (e.g. ethyl acetate), may be hydrogenated to compounds of formula (I) wherein R3Comprising C2-6An alkyl group.
A compound of formula (I) wherein R3Comprising C2-6The alkynyl group, in the presence of a suitable catalyst (e.g., Lindlar catalyst) and a suitable solvent (e.g., ethyl acetate), may be hydrogenated to a compound of formula (I) wherein R3Comprising C2-6An alkenyl group.
A compound of formula (I) wherein R3represents-C (= O) (OC)1-6Alkyl radical)2Substituted C1-6Alkyl groups may be converted to compounds of formula (I) wherein R is3Is represented by-P (= O) (OH)2Substituted C1-6An alkyl group.
A compound of formula (I) wherein R9The substituent is substituted with = O in a suitable solvent (e.g. tetrahydrofuran) by reaction with a suitable reducing agent (e.g. LiAlH)4) By reaction, may be converted into the corresponding reduced R9And (4) a substituent.
A compound of formula (I) wherein R3including-NHR10By reaction with the corresponding W- (C = O) -optionally substituted C in the presence of a suitable base (e.g. triethylamine) and a suitable solvent (e.g. acetonitrile)1-6Alkyl reactions (wherein W represents a suitable leaving group, e.g. halogen, e.g. chloro and the like) may be converted to compounds of formula (I) wherein R3comprising-NR10- (C = O) -optionally substituted C1-6An alkyl group.
A compound of formula (I) wherein R3Is represented by NR10(benzyl) substituted C1-6Alkyl groups may be converted to compounds of formula (I) wherein R is methyl chloroformate by reaction with 1-chloroethyl chloroformate in the presence of a suitable solvent such as methylene chloride3Is represented by NHR10Substituted C1-6An alkyl group.
A compound of formula (I) wherein R1Represents unsubstituted piperidine and is convertible by reaction with methyl iodide in the presence of a suitable base (e.g. potassium carbonate) and a suitable solvent (e.g. acetonitrile) to a compound of formula (I) wherein R is1Represents 1-methyl-piperidine.
A compound of formula (I) wherein R1Represents hydrogen by reaction with optionally substituted C in the presence of a suitable base (e.g. potassium carbonate) and a suitable solvent (e.g. acetonitrile)1-6alkyl-W reactions (wherein W represents a suitable leaving group, e.g. halogen, e.g. bromine etc.) may be converted to compounds of formula (I) wherein R1Represents optionally substituted C1-6An alkyl group.
A compound of formula (I) wherein R2Represents halogen, e.g. bromine, in a suitable catalyst (e.g. Pd)2(dba)3) And a suitable ligand (e.g., 1-bis (diphenylphosphino) ferrocene)) Can be converted into a compound of formula (I) wherein R is R by reaction with zinc cyanide in the presence of a suitable solvent, such as N, N-dimethylformamide2Represents cyano.
By reaction at NH3And nickel, said R2The substituent (cyano group) may be converted into-CH2-NH2。
A compound of formula (I) wherein R2represents-OCH3May be converted to compounds of formula (I) wherein R is2represents-OH.
A compound of formula (I) wherein R2represents-OH, which can be converted to compounds of formula (I) by reaction with methyl iodide in the presence of a base (e.g. potassium carbonate) and a suitable solvent (e.g. N, N-dimethylformamide), wherein R is2represents-OCH3。
A compound of formula (I) wherein R2Represents hydrogen, which can be converted into compounds of formula (I) by reaction with trifluoroacetaldehyde condensed half methanol (trifluoracetaldehydemethyl hemiacetal), wherein R is2represents-CHOH-CF3。
A further aspect of the invention is a process for the preparation of a compound of formula (I) as defined herein, which process comprises:
(i) deprotecting a compound of formula (XXX) in the presence of a suitable acid (e.g. HCl or trifluoroacetic acid), wherein P represents a suitable protecting group, e.g. butoxycarbonyl (-CO)2C(CH3)3)；
Or
(ii) A compound of formula (IX) or (IX
Or a protected form thereof, with a suitably substituted amine or reactive derivative thereof, e.g. NHR10R11(X)、NHR10P (X-a) or(XXI) for example, in a sealed vessel, in the presence of a suitable base (e.g. sodium hydride) and/or in the presence or absence of a solvent (e.g. acetonitrile, N-dimethylformamide or N, N-dimethylacetamide); or
(iii) A compound of formula (VI)
(VI)
Or a protected form thereof, with a compound of formula W in the presence of a suitable base (e.g., sodium hydride) and a suitable solvent (e.g., N-dimethylformamide or N, N-dimethylacetamide)6-C1-6alkyl-NR10Reaction of a compound of P, wherein P represents a suitable protecting group, W6Represents a suitable leaving group, for example halogen, such as bromine, etc., or-O-S (= O)2-CH3And then removing P, and optionally removing any further protecting groups present; or
(iv) A compound of formula (VI)
(VI)
Or a protected form thereof, with a compound of formula W in the presence of a suitable base (e.g., sodium hydride) and a suitable solvent (e.g., N-dimethylformamide or N, N-dimethylacetamide)6-C1-6alkyl-NHR10In which W is6Represents a suitable leaving group, for example halogen, such as bromine, etc., or-O-S (= O)2-CH3；
(v) A compound of formula (XXXVI)
With hydrazine in the presence of a suitable solvent (e.g., an alcohol, such as ethanol);
(vi) a compound of formula (IX-1), wherein Rurepresents-O-S (= O)2-CH3，
Reacting with an intermediate of formula (X) in the presence of a suitable solvent (e.g. acetonitrile);
(vii) a compound of formula (VI)
With formula W in the presence of a suitable base (e.g., NaH) and a suitable solvent (e.g., N-dimethylformamide)11-R3bWherein R is3bRepresents optionally substituted C2-6Alkynyl, W11Represents a suitable leaving group, for example halogen, such as chlorine, or-O-S (= O)2-CH3；
(viii) A compound of formula (VIII'), wherein RxAnd RyRepresents C1-4Alkyl radical, RzRepresents C1-4An alkyl group or a phenyl group, or a substituted or unsubstituted alkyl group,
with a suitable acid such as trifluoroacetic acid in the presence of a suitable solvent (e.g., tetrahydrofuran);
(viii) in the presence of a suitable base (e.g. K)2CO3) And a suitable solvent (e.g., an alcohol, such as methanol, and the like), deprotecting a compound of formula (xxxxxii);
(ix) a compound of formula (VI)
With di (C) in the presence of a suitable catalyst (e.g. tri-N-butylphosphine) and a suitable solvent (e.g. acetonitrile)1-6Alkyl) vinyl phosphonate reaction;
(x) In the presence of a suitable base (e.g. K)2CO3) And a suitable solvent (e.g., an alcohol, such as methanol, and the like), deprotecting the compound of formula (xxxxxxi);
(xi) In a suitable catalyst (e.g. palladium or Pd tetrakis (triphenyl) phosphine)2(dba)3(tris (dibenzylideneacetone) dipalladium (0))), a suitable ligand (e.g., 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl), a suitable base (e.g., Na)2CO3Or K3PO4) And a suitable solvent (e.g. ethylene glycol dimethyl ether or dioxane or water), reacting a compound of formula (XIX) with a compound of formula (III);
(xii) In a suitable placeCatalyst (e.g. palladium (II) acetate or Pd2(dba)3(tris (dibenzylideneacetone) dipalladium (0))), suitable ligands (e.g. 2-dicyclohexylphosphino-tri-isopropyl-biphenyl or 1,1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) A compound of formula (XX) wherein R is selected from the group consisting of sodium tert-butoxide, sodium tert-butoxide and a suitable solvent such as ethylene glycol dimethyl ether3aRepresents optionally substituted C1-6Alkyl, with a compound of formula (XIV);
(xiii) In a suitable base (e.g. NaHCO)3) And a suitable solvent (e.g. water or dioxane) with W8-CN reaction, wherein W8Represents a suitable leaving group, for example halogen, such as bromine;
(xiv) Reacting a compound of formula (XXXV) with a suitable base such as N, N-diisopropylethylamine and triethylamine in the presence of a suitable solvent (e.g. an alcohol such as methanol);
(xv) Deprotecting a compound of formula (XXVI) in the presence of a suitable acid (e.g. HCl or trifluoroacetic acid) or a suitable de-silylating agent (e.g. tetrabutylammonium fluoride) and a suitable solvent (e.g. an alcohol, such as methanol, or tetrahydrofuran), wherein P represents a suitable protecting group, for example-O-Si (CH)3)2(C(CH3)3) Or；
(xvi) Reacting a compound of formula (XXIX) with a compound of formula (XXI) in the presence of a suitable peptide coupling reagent (e.g. 1-hydroxy-benzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl);
(xvii) A compound of formula (XXIX) is reacted with NHR in the presence of a suitable peptide coupling reagent (e.g. 1-hydroxy-benzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide HCl) and a suitable base (e.g. triethylamine) and a suitable solvent (e.g. dichloromethane)4R5Carrying out reaction;
(xviii) In the presence of a suitable base (e.g. K)2CO3) And a suitable solvent (e.g., tetrahydrofuran), with NHR7R8Carrying out reaction;
(xviii) Deprotecting the following compound in the presence of hydrazine monohydrate and a suitable solvent (e.g., an alcohol, such as ethanol);
wherein R is1、R1a、R2、R10And n is as defined herein(ii) a And then optionally converting one compound of formula (I) to another compound of formula (I).
A further embodiment is a method of synthesizing a compound of formula (VI), wherein:
1) reacting a compound of formula (II) with an intermediate of formula (III) in the presence of a suitable catalyst (e.g. tetrakis (triphenylphosphine) palladium (0) or palladium (II) acetate), a suitable base (e.g. sodium carbonate), a suitable ligand (e.g. triphenylphosphine) and a suitable solvent or solvent mixture (e.g. ethylene glycol dimethyl ether and water); wherein W1And W2Each independently represents a suitable leaving group, for example halogen, such as chlorine or bromine;
then is covered with
2) In the presence of a suitable catalyst (e.g. palladium (II) acetate), a suitable base (e.g. sodium tert-butoxide or Cs)2CO3) Suitable ligands (e.g. 1,1'- [1, 1' -binaphthyl)]-2,2' -diylbis [1, 1-diphenylphosphine]) And a suitable solvent or solvent mixture (e.g. dioxane or ethylene glycol dimethyl ether and water) with an intermediate of formula (V);
wherein an intermediate of formula (II) (wherein W is prepared optionally as follows1Is chlorine, W2Is bromine): in a suitable solvent, such as toluene, 7-bromo-2 (1H) -quinoxalinone with phosphorus oxychloride or with thionyl chloride and N, N-dimethylformamide;
or vice versa, using the above method, the compound of formula (II) is first reacted with the intermediate of formula (V) and then with the intermediate of formula (III).
In a further embodiment, the present invention provides novel intermediates. In one embodiment, the present invention provides novel intermediates of formula (II) - (XXXI). In another embodiment, the present invention provides novel intermediates of formula (VI) or formula (IX). In another embodiment, the present invention provides compounds of formulae (I-a) - (I-I).
Pharmaceutically acceptable salts, solvates or derivatives thereof
In this section, as in all other sections of this application, formula (I) also includes all other sub-groups, preferences, embodiments and examples thereof as defined herein, unless the context indicates otherwise.
Unless otherwise specified, a particular compound also includes ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof, for example, as discussed below; preferably, an ionic form or salt or tautomer or isomer or N-oxide or solvate thereof; and more preferably, an ionic form or salt or tautomer or solvate or protected form thereof, more preferably a salt or tautomer or solvate thereof. Many of the compounds of formula (I) exist as salts, e.g., acid addition salts, or in some cases, as salts of organic and inorganic bases, e.g., carboxylates, sulfonates, and phosphates. All such salts are within the scope of the present invention and the compounds of formula (I) include salt forms of the compounds. It is understood that "derivatives" include ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters, prodrugs, isotopes and protected forms thereof.
According to one aspect of the present invention there is provided a compound as defined herein or a salt, tautomer, N-oxide or solvate thereof. According to a further aspect of the present invention there is provided a compound as defined herein or a salt or solvate thereof. The compounds of formula (I) and the groups below as defined herein include within their scope salts or solvates or tautomers or N-oxides of the compounds.
Salt forms of the compounds of the present invention are typically pharmaceutically acceptable salts, examples of which are discussed in the following: berge et al (1977) "pharmaceutical Acceptable Salts," J. pharm. Sci., Vol.66, pp. 1-19. However, non-pharmaceutically acceptable salts may also be prepared in intermediate form, which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, which may be used, for example, in the purification or isolation of the compounds of the invention, also form part of the invention.
Salts of the invention may be synthesized from the parent compound, which contains a basic or acidic moiety, using conventional chemical methods, for example, as described in: pharmaceutical Salts, Properties, Selection, and Use, P, Heinrich Stahl (Editor), Camile G, Wermuth (Editor), ISBN, 3-90639-. In general, such salts can be prepared as follows: reacting the free acid or base forms of these compounds with a suitable base or acid in water or an organic solvent, or a mixture of both; typically, a non-aqueous medium is used, for example, ether, ethyl acetate, ethanol, isopropanol or acetonitrile. The compounds of the present invention may exist in mono-or di-salt form, depending on the pKa of the acid used to form the salt.
Acid addition salts can be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with acids selected from the group consisting of: acetic acid, 2, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+) camphoric acid, camphorsulfonic acid, (+) - (1S) -camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, 2, 5-dihydroxybenzoic acid, glucoheptonic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), alpha-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+) -L-lactic acid, (+ -) -DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-) -L-malic acid, malonic acid, (+ -) -DL-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (e.g., naphthalene-2-sulfonic acid), naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, fatty acids, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, toluenesulfonic acid (e.g., p-toluenesulfonic acid), undecylenic and valeric acids, and acylated amino acids and cation exchange resins.
One particular group of salts includes salts formed from the following acids: acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, isethionic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid and lactobionic acid. Another group of acid addition salts includes the salts formed from the following acids: acetic acid, adipic acid, ascorbic acid, aspartic acid, citric acid, DL-lactic acid, fumaric acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloric acid, glutamic acid, DL-malic acid, methanesulfonic acid, fatty acid, stearic acid, succinic acid, and tartaric acid.
If the compound is anionic, or has a functional group which can form an anion (for example, -COOH may be-COO-) Salts may be formed with suitable cations. Examples of suitable inorganic cations include, but are not limited to: alkali metal ions, e.g. Na+And K+Alkaline earth metal cations, e.g. Ca2+And Mg2+And other cations, e.g. Al3+. Examples of suitable organic cations include, but are not limited to: ammonium ion (i.e., NH)4 +) And substituted ammonium ions (e.g., NH)3R+，NH2R2 +，NHR3 +，NR4 +)。
Some examples of suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, andand amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N (CH)3)4 +。
If the compounds of formula (I) contain amine functional groups, these compounds may form quaternary ammonium salts, for example, by reaction with alkylating agents according to methods well known to the skilled worker. Such quaternary amine compounds are within the scope of formula (I). The compounds of formula (I) comprising amine functions may also form N-oxides. The compounds of formula (I) mentioned herein comprising an amine function also include N-oxides. If the compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of the nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. The N-oxide may be formed as follows: the corresponding amines are treated with oxidizing agents such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids), see for example: advanced organic chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, the N-oxide may be prepared using the method of L.W. Deady (Syn. Comm. (1977), 7, 509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent, such as methylene chloride.
The compounds of the present invention may form solvates, for example with water (i.e. hydrates) or common organic solvents. The term "solvate" as used herein refers to a compound of the invention physically associated with one or more solvent molecules. Such physical binding includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. The term "solvate" includes both solution phase and isolatable solvates. Non-limiting examples of suitable solvates include solvates of the compounds of the present invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid or ethanolamine, and the like. The compounds of the invention may exert their biological effect when in solution.
Solvates are well known in pharmaceutical chemistry. They are important for the preparation of the substance (e.g., in terms of their purification), for the storage of the substance (e.g., its stability), and for the ease with which the substance can be handled, and generally form part of the isolation or purification stage of chemical synthesis. With the aid of standard and long-term techniques, one skilled in the art can determine whether a hydrate or other solvate has been formed by the isolation or purification conditions used to prepare a given compound. Examples of such techniques include: thermogravimetric analysis (TGA), Differential Scanning Calorimetry (DSC), X-ray crystal diffraction (e.g., single crystal X-ray crystal diffraction or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic angle rotating NMR or MAS-NMR). This technique, like NMR, IR, HPLC and MS, is part of the standard analytical kit of a skilled chemist. Alternatively, the skilled artisan may intentionally form solvates using crystallization conditions, including the amount of solvent required for a particular solvate. The standard method described above can then be used to determine whether a solvate has formed. Formula (I) also includes any complex of the compound (e.g., complexes or clathrates with compounds such as cyclodextrins, or complexes with metals).
Furthermore, the compounds of the present invention may have one or more polymorphic (crystalline) or amorphous forms and are included within the scope of the present invention.
The compounds of formula (I) may exist in many different geometric and tautomeric forms and the compounds of formula (I) include all such forms. For the avoidance of doubt, if a compound may exist in one of several geometric or tautomeric forms, and only one form is specifically described or shown, formula (I) still includes all other forms. Examples of other tautomeric forms include, for example, keto-, enol-and enolate-forms, for example, the following tautomeric pairs: keto/enol (exemplified below), imine/enamine, amide/imino alcohol, amidine/enediamine, nitroso/oxime, thione/enethiol, and nitro/isonitro.
If the compound of formula (I) contains one or more chiral cores, two or more optical isomer forms may be present, and the compound of formula (I) includes all optical isomer forms (e.g. enantiomers, epimers and diastereomers) thereof, and may be in the form of a single optical isomer or a mixture (e.g. racemic mixture) of two or more optical isomers, unless the context requires otherwise. They can be characterized and identified by the optical activity of the optical isomers (i.e., the + and-isomers, or the d and l isomers), or they can be characterized by their absolute stereochemistry using the "R and S" nomenclature disclosed by Cahn, Ingold, and Prelog, see Advanced Organic Chemistry by Jerry March, 4thEdition, JohnWiley&Sons, New York, 1992, pages 109-&Prelog (1966) angel w. chem. int. ed. engl., 5, 385-. Optical isomers can be separated by a number of techniques, including chiral chromatography (chromatography on a chiral support), which techniques are well known to those skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated as follows: forming diastereomeric salts with chiral acids (e.g., (+) -tartaric acid, (-) -pyroglutamic acid, (-) -di-toluoyl-L-tartaric acid, (+) -mandelic acid, (-) -malic acid and (-) -camphorsulfonic acid), separating the diastereomers by preferential crystallization, and dissociating the salt to obtain the single enantiomer of the free base.
If the compounds of formula (I) are present in two or more optically isomeric forms, one enantiomer of the pair may be more advantageous than the other, for example in terms of biological activity. Thus, in some instances, only one enantiomer of an enantiomer pair or only one of a plurality of diastereomers may be desirable therapeutic agents. Accordingly, the present invention provides compositions comprising a compound of formula (I) having one or more chiral cores, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of formula (I) is present as a single optical isomer (e.g., enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (I) may be present as a single optical isomer (e.g., enantiomer or diastereoisomer).
The compounds of the present invention include compounds having one or more isotopic substitutions, and a particular element includes within its scope all isotopes of that element. For example, included within the scope of hydrogen1H、2H, (D) and3h (T). Similarly, carbon and oxygen are included within their scope respectively12C、13C and14c and16o and18and O. The isotope may be a radioactive or non-radioactive isotope. In one embodiment of the invention, the compound does not comprise a radioisotope. Preferably, such compounds are for therapeutic use. However, in another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be used for diagnostics.
Formula (I) also includes esters (e.g., carboxylic acid esters and acyloxy esters) of compounds of formula (I) bearing a carboxyl or hydroxyl group. In one embodiment of the invention, formula (I) includes within its scope esters of compounds of formula (I) bearing a carboxyl or hydroxyl group. In another embodiment of the present invention, formula (I) excludes within its scope esters of compounds of formula (I) bearing a carboxyl or hydroxyl group. Examples of esters are compounds containing a group C (= O) OR, where R is an ester substituent, e.g. C1-6Alkyl, heterocyclyl or C5-20Aryl, preferably C1-6An alkyl group. Specific examples of ester groups include, but are not limited to: c (= O) OCH3，C(=O)OCH2CH3，C(=O)OC(CH3)3and-C (= O) OPh. Examples of acyloxy (reverse ester) groups are represented by OC (= O) R, where R is an acyloxy substituent, e.g., C1-7Alkyl radical, C3-20Heterocyclyl or C5-20Aryl, preferably C1-7An alkyl group. Specific examples of acyloxy groups include, but are not limited to: OC (= O) CH3(acetoxy)Base), OC (= O) CH2CH3，OC(=O)C(CH3)3OC (= O) Ph and OC (= O) CH2Ph。
For example, some prodrugs are esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. By "prodrug" is meant any compound that can be converted, for example, in vivo to a biologically active compound of formula (I). During metabolism, the ester group (-C (= O) OR) is cleaved, yielding the active drug. Such esters may be formed as follows: for example, esterification of any carboxyl group (-C (= O) OH) in the parent compound, if appropriate, pre-protecting any other reactive groups present in the parent compound, and then deprotecting if desired.
Examples of such metabolically labile esters include those of the formula-C (= O) OR, where R is: c1-6Alkyl (e.g., Me, Et, -nPr, -iPr, -nBu, -sBu, -iBu, tBu); c1-6Aminoalkyl groups [ e.g., aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); and acyloxy-C1-7Alkyl [ e.g., acyloxymethyl; an acyloxyethyl group; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl; 1- (benzoyloxy) ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1- (4-tetrahydropyranyloxy) carbonyloxyethyl; (4-tetrahydropyranyl) carbonyloxymethyl; and 1- (4-tetrahydropyranyl) carbonyloxyethyl]. In addition, some prodrugs are enzymatically activated to yield the active compound, or a compound that produces the active compound by a further chemical reaction (e.g., antigen-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), and ligand-directed enzyme prodrug therapy (LIDEPT), among others). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Protein Tyrosine Kinase (PTK)
The compounds of the invention described herein inhibit or modulate the activity of certain tyrosine kinases and are therefore useful in the treatment or prevention, especially treatment, of disease states or conditions mediated by those tyrosine kinases, especially FGFR.
FGFR
The Fibroblast Growth Factor (FGF) family of Protein Tyrosine Kinase (PTK) receptors regulates a diverse array of physiological functions, including mitogenesis, wound healing, cell differentiation, and angiogenesis and development. Normal and malignant cell growth and proliferation are affected by changes in local concentrations of FGF (extracellular signaling molecule that acts as an autocrine as well as paracrine factor). Autocrine FGF signaling is particularly important in the progression of steroid hormone-dependent cancers to a hormone-independent state. FGFs and their receptors are expressed at high levels in some tissues and cell lines, and overexpression is thought to contribute to the malignant phenotype. In addition, many oncogenes are homologs of the gene encoding growth factor receptors and may abnormally activate FGF-dependent signaling in human pancreatic Cancer (Knight et al, Pharmacology and Therapeutics 2010125: 1 (105-.
The two prototype members are acidic fibroblast growth factor (aFGF or FGF1) and basic fibroblast growth factor (bFGF or FGF2), and to date, at least 20 unique FGF family members have been identified. The response of cells to FGF is transmitted by four types of high affinity transmembrane protein tyrosine-kinase Fibroblast Growth Factor Receptors (FGFRs) (nos. 1 to 4) (FGFR1 to FGFR 4).
Disruption of the FGFR1 pathway should affect tumor cell proliferation since this kinase is activated in many tumor types in addition to proliferating endothelial cells. Over-expression and activation of FGFR1 in tumor-associated vasculature has suggested a role for these molecules in tumor angiogenesis.
Recent studies have shown that in traditional lobular carcinoma (CLC), there is a link between FGFR1 expression and tumorigenicity. Of all breast cancers, CLC accounts for 10-15% and typically lacks p53 and Her2 expression, while maintaining estrogen receptor expression. Gene amplification of 8p12-p11.2 was shown in-50% of CLC cases and was shown to be associated with increased expression of FGFR 1. Preliminary studies with small molecule inhibitors of FGFR1 or the receptor to which siRNA is directed have shown that cell lines presenting such expansion are particularly sensitive to inhibition of this signaling pathway. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, probably due to abnormal proliferation and differentiation during skeletal muscle formation. FGFR1 was overexpressed in primary rhabdomyosarcoma tumors and was associated with hypomethylation of the 5' CpG island and aberrant expression of the AKT1, NOG and BMP4 genes.
Fibroblast growth factor receptor 2 has a high affinity for acidic and/or basic fibroblast growth factors as well as for keratinocyte growth factor ligands. In addition, fibroblast growth factor receptor 2 increases the effective osteogenic effect of FGF during osteoblast growth and differentiation. Mutations in fibroblast growth factor receptor 2 that result in altered complex function can cause abnormal craniosynostosis (craniosynostosis), suggesting that FGFR signaling plays an important role in intramembranous bone formation. For example, in Apert (AP) syndrome (characterized by premature cranial suture ossification), most cases are associated with point mutations that cause acquired function of fibroblast growth factor receptor 2. In addition, mutations screened for in patients with craniosynostosis syndrome indicate that many recurrent FGFR2 mutations are responsible for the severe form of Pfeiffer syndrome. In FGFR2, specific mutations of FGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R.
Some severe human skeletal formation abnormalities, including Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin convolution syndrome (cutis gyrata), and Pfeiffer syndrome, are associated with mutations in the fibroblast growth factor receptor 2. Furthermore, most, if not all, cases of Pfeiffer Syndrome (PS) are caused by de novo mutations in the fibroblast growth factor receptor 2 gene, and recently it has been shown that mutations in fibroblast growth factor receptor 2 disrupt one of the fundamental principles governing ligand specificity. That is, two mutant spliced forms of the fibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired the ability to bind to and be activated by atypical FGF ligands. This loss of ligand specificity leads to aberrant signaling and suggests that the severe phenotype of these disease syndromes results from ectopic ligand-dependent activation of fibroblast growth factor receptor 2.
Genetic aberrations (e.g., chromosomal translocations or point mutations) in FGFR3 receptor tyrosine kinases produce FGFR3 receptors that ectopically express or deregulate structural activity. This abnormality is associated with subtypes of multiple myeloma and bladder, hepatocyte, oral squamous cell carcinoma and cervical cancer. Accordingly, FGFR3 inhibitors are useful for the treatment of multiple myeloma, bladder and cervical cancer. Furthermore, FGFR3 is overexpressed in bladder cancer, particularly in invasive bladder cancer. In Urothelial Cancer (UC), FGFR3 is frequently activated by mutation. Increased expression was associated with mutations (85% of mutant tumors showed high levels of expression), but 42% of tumors did not detect mutations that showed overexpression, including many muscle invasive tumors.
Overexpression of FGFR4 has been associated with poor prognosis in prostate and thyroid cancers. In addition, germline polymorphism (Gly388Arg) is associated with increased incidence of lung, breast, colon, liver (HCC) and prostate cancer. In addition, truncated forms of FGFR4 (including the kinase domain) were also found to be present in 40% of pituitary tumors, but not in normal tissues. FGFR4 overexpression has been observed in liver, colon and lung tumors. FGFR4 is associated with colorectal and liver cancer, in which expression of its ligand FGF19 is often elevated.
Fibrotic disorders are a major medical problem, resulting from abnormal or excessive deposition of fibrous tissue. This phenomenon occurs in a number of diseases, including cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and the natural process of wound healing. The mechanism of pathological fibrosis is not completely understood, but is thought to arise from the action of various cytokines involved in fibroblast proliferation, including Tumor Necrosis Factor (TNF), Fibroblast Growth Factor (FGF), platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF β), and the deposition of extracellular matrix proteins, including collagen and fibronectin. This results in changes in tissue structure and function and subsequent lesions.
A number of preclinical studies have shown that fibroblast growth factors are up-regulated in preclinical models of pulmonary fibrosis. TGF β 1 and PDGF are reported to be involved in the process of fibrogenesis, and further published work suggests that increased FGF and subsequent increased proliferation of fibroblasts may respond to increased TGF β 1. The reported clinical effects of the anti-fibrotic agent pirfenidone (pirfenidone) in, for example, Idiopathic Pulmonary Fibrosis (IPF) conditions, suggest a potential therapeutic benefit targeting the fibrotic mechanism. Idiopathic pulmonary fibrosis (also known as cryptogenic fibrositis) is a progressive disorder involving lung scarring. The alveoli of the lungs are gradually replaced by fibrotic tissue, becoming thicker, causing the tissue to irreversibly lose its ability to transport oxygen into the blood. Symptoms of this disorder include shortness of breath, chronic dry cough, fatigue, chest pain and loss of appetite (leading to rapid weight loss). The disorder is extremely severe and after 5 years, approximately 50% die.
Accordingly, compounds that inhibit FGFR may be used to provide a means of preventing tumor growth or causing apoptosis thereof, particularly inhibiting angiogenesis. It is therefore contemplated that the compounds may be useful in the treatment or prevention of proliferative disorders, such as cancer. In particular, tumors that have an activated mutant of a receptor tyrosine kinase or an upregulation of a receptor tyrosine kinase are particularly sensitive to the inhibitor. It has also been found that it is particularly advantageous to treat patients having activating mutants of any of the isoforms of the particular RTKs discussed herein with RTK inhibitors.
Vascular Endothelial Growth Factor (VEGFR)
Chronic proliferative diseases are often associated with extreme angiogenesis, which may contribute to or maintain an inflammatory and/or proliferative state, or result in tissue destruction through invasive proliferation of blood vessels.
Angiogenesis is commonly used to describe the formation of new or replacement blood vessels, or neovascularization. It is a normal process necessary and physiological for the formation of the vascular system in the embryo. Normally, angiogenesis does not occur in most normal adult tissues, except at the sites of ovulation, menses, and wound healing. However, many diseases are characterized by persistent and unrestricted angiogenesis. For example, in arthritis, new microvessels invade the joints and destroy cartilage. In diabetes (and in many different eye diseases), new blood vessels invade the macula or retina or other ocular structures, and can lead to blindness. The process of atherosclerosis is associated with angiogenesis. Tumor growth and metastatic lesions were found to be angiogenesis dependent.
The complexity of angiogenesis has been recognized through research in major diseases and inhibitors of angiogenesis have been identified and developed. These inhibitors are generally classified according to discrete targets in the angiogenic cascade, e.g., endothelial cells are activated by angiogenic signals; synthesis and release of degrading enzymes; endothelial cell migration; proliferation of endothelial cells; and formation of capillaries. Therefore, angiogenesis occurs in many stages, and attempts have been made to find and develop compounds that can act to block angiogenesis in these various stages.
Publications have taught that angiogenesis inhibitors that act by various mechanisms may be beneficial in diseases such as cancer and metastatic disease, eye disease, arthritis and hemangiomas.
Vascular Endothelial Growth Factor (VEGF), a polypeptide, causes mitosis of endothelial cells in vitro and stimulates the production of an angiogenic response in vivo. VEGF is also associated with inappropriate angiogenesis. VEGFR is a Protein Tyrosine Kinase (PTK) PTK catalyzes the phosphorylation of specific tyrosine residues in proteins involved in cellular function and thereby regulates cell growth, survival and differentiation.
Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1); VEGFR-2(Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction. Of particular interest is VEGFR-2, which is a transmembrane receptor PTK expressed primarily in endothelial cells. VEGFR-2 activation by VEGF is a key step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression can be structural expression for tumor cells and can be upregulated during response to certain stimuli. One such stimulus is hypoxia, where VEGF expression is upregulated in tumors and associated host tissues. The VEGF ligand activates VEGFR-2 by binding to its extracellular VEGF binding site. This results in receptor dimerization of VEGFR and autophosphorylation of tyrosine residues in the intracellular kinase domain of VEGFR-2. This kinase domain transports phosphate from ATP to tyrosine residues, thereby providing a binding site downstream of the signaling protein of VEGFR-2, ultimately leading to initiation of angiogenesis.
Inhibition of the kinase domain binding site of VEGFR-2 would block phosphorylation of tyrosine residues and serve to interfere with initiation of angiogenesis.
Angiogenesis is a physiological process of new blood vessel formation, mediated by various cytokines called angiogenic factors. Although its potential pathophysiological role in solid tumors has been extensively studied for over 30 years, increased angiogenesis has been recognized in Chronic Lymphocytic Leukemia (CLL) and other hematological malignancies in recent years. In bone marrow and lymph nodes of patients with CLL, increased levels of angiogenesis have been demonstrated using various assays. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that some angiogenic factors play a role in the development of the disease. Biomarkers of angiogenesis are also demonstrated to have prognostic relevance in CLL. This suggests that VEGFR inhibitors may also be beneficial in leukemia patients such as CLL.
In order for the tumor mass to exceed a critical size, an associated vascular system must be formed. It has been suggested that targeting tumor vasculature can limit tumor expansion and can be a useful cancer treatment. Observations of tumor growth have shown that small tumor masses can persist in tissues without the need for any tumor-specific vasculature. Growth inhibition of non-vascularized tumors is due to the hypoxic effect in the center of the tumor. In recent years, various pro-angiogenic and anti-angiogenic factors have been identified and the concept of "angiogenic switch" has been developed, a process that disrupts the normal proportion of angiogenic stimuli and inhibitors in the tumor mass that enables spontaneous angiogenesis. The generation of vascular switches appears to depend on the same genetic changes that lead to malignant transformation: activation of oncogenes and loss of tumor suppressor genes. Some growth factors act as positive regulators of angiogenesis. Among these, Vascular Endothelial Growth Factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin are predominant. Proteins such as thrombospondin (Tsp-1), angiostatin, and vascular endostatin act as negative regulators of angiogenesis.
In a mouse model, inhibition of VEGFR2 (rather than VEGFR1) significantly interfered with the generation of vascular switches, persistent angiogenesis, and initiation of tumor growth. In advanced tumors, phenotypic tolerance to VEGFR2 blockade appeared, and after the initial period of growth inhibition, tumors grew again during treatment. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, which is not associated with VEGF, but with hypoxia-mediated induction of other pro-angiogenic factors, including members of the FGF family. These other pro-angiogenic signals have been implicated in tumor revascularization and regrowth functions at an evasive stage, as FGF blockade impairs progression in the face of VEGF inhibition.
In a second phase of the study, there was evidence that treatment of patients with pan-VEGF receptor tyrosine kinase inhibitor (AZD2171) normalized the blood vessels of malignant gliomas. MRI assay data for vessel normalization (in combination with circulating biological indicators) provides an effective means of assessing the response to anti-angiogenic agents.
PDGFR
Malignant tumors are the product of uncontrolled cellular proliferation. Cell growth is controlled by a careful balance between growth promoting and growth inhibiting factors. In normal tissues, the production and activity of these factors results in the differentiation of cells that grow in a controlled and regulated manner that maintains the normal integrity and function of the organ. Malignant cells evade this control; the natural balance is disturbed (by various mechanisms) and unrestricted, abnormal cell growth occurs. An important growth factor in the process of tumor formation is platelet growth factor (PDGF), which comprises a family of peptide growth factors that signal through cell surface tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation and differentiation.
Advantages of Selective inhibitors
The development of FGFR kinase inhibitors with differentially selective properties provides new opportunities for using these targeted agents in patients with diseases resulting from FGFR dysregulation. Compounds with reduced inhibition of other kinases, particularly VEGFR2 and PDGFR- β, provide an opportunity to differentiate between side effects or toxicity profiles and therefore provide more effective treatment for these indications. Inhibitors of VEGFR2 and PDGFR- β are associated with toxicity, such as hypertension or edema, respectively. In the case of VEGFR2 inhibitors, this hypertensive effect is often dose-limiting, may be contraindicated in certain patient groups, and requires clinical control.
Biological activity and therapeutic use
The compounds of the invention and subgroups thereof have Fibroblast Growth Factor Receptor (FGFR) inhibitory or modulating activity and/or Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitory or modulating activity, and/or Platelet Derived Growth Factor Receptor (PDGFR) inhibitory or modulating activity and are useful in the prevention or treatment of a disease state or disorder described herein. In addition, the compounds of the present invention and sub-groups thereof are useful for the prevention or treatment of kinase mediated diseases or conditions. Preventing or treating a disease state or condition, such as cancer, includes within their scope alleviating cancer or reducing the incidence of cancer.
The term "modulate" as used herein as applied to kinase activity is used to define a change in the level of biological activity of a protein kinase. Thus, modulation includes physiological changes that affect an increase or decrease in the activity of the relevant protein kinase. In the latter case, modulation may be described as "suppression". Modulation may be initiated directly or indirectly, may be mediated by any mechanism, and may be mediated at any physiological level, including, for example, at the level of gene expression (including, for example, transcriptional, translational, and/or post-translational modifications), at the level of expression of a gene encoding a regulatory element that acts directly or indirectly on the level of kinase activity. Thus, modulation may mean increasing/inhibiting the expression of the kinase, or overexpression or underexpression of the kinase, including gene amplification (i.e. multigene replication) and/or increased or decreased expression due to transcriptional effects, as well as high (or low) activity and (de-) activation (including (de-) activation) of the protein kinase due to mutations. The terms "modulated", "modulating" and "modulating" may be construed accordingly.
The term "mediate" (e.g., as used in conjunction with a kinase described herein, as applied to, for example, various physiological processes, diseases, conditions, disorders, therapies, treatments, or interventions) as used herein means a restrictive procedure such that the various processes, diseases, conditions, disorders, treatments, and interventions to which the term is applied are those for which the kinase plays a biological role. If the term is applied to a disease, condition, or disorder, the biological effect exerted by the kinase may be direct or indirect and may be necessary and/or sufficient for the manifestation of the symptoms of the disease, condition, or disorder (or its etiology or progression). Thus, kinase activity (particularly abnormal levels of kinase activity, e.g., kinase overexpression) need not necessarily be the closest cause of the disease, state, or condition, but rather, the kinase-mediated disease, state, or condition includes those with multifactorial pathogens and complex progression in which the kinase is involved in part. If the term is applied to treatment, prevention or intervention, the effect exerted by the kinase may be direct or indirect and may be necessary and/or sufficient for the therapeutic, prophylactic or interventional result. Thus, a kinase-mediated disease state or condition includes development of resistance to any particular cancer drug or treatment.
Thus, for example, the compounds of the invention may be used to reduce cancer or reduce the incidence of cancer.
More particularly, the compounds of formula (I) and subgroups thereof are inhibitors of FGFR. For example, the compounds of the invention have activity against FGFR1, FGFR2, FGFR3 and/or FGFR4, in particular FGFR selected from FGFR1, FGFR2 and FGFR 3; or especially compounds of formula (I) and subgroups thereof are inhibitors of FGFR 4.
Preferred compounds are compounds that inhibit one or more FGFR selected from FGFR1, FGFR2, FGFR3 and FGFR 4. Preferred compounds of the invention are IC50Those compounds having a value of less than 0.1. mu.M.
The compounds of the present invention are also active against VEGFR.
Additionally, many of the compounds of the invention show selectivity for FGFR1, 2 and/or 3 and/or 4 as compared to VEGFR (especially VEGFR2) and/or PDGFR, and such compounds represent a preferred embodiment of the invention. In particular, the compounds show selectivity for VEGFR 2. For example, IC of many of the compounds of the invention for FGFR1, 2 and/or 3 and/or 450The values are in IC for VEGFR (especially VEGFR2) and/or PDGFR B50Between one tenth and one hundredth of the value. Especially preferably, the activity of a compound of the invention against FGFR or inhibiting FGFR is at least 10 times greater than the activity against or inhibiting VEGFR2, especially against FGFR1, FGFR2, FGFR3 and/or FGFR 4. More preferably, the activity of a compound of the invention against FGFR or inhibiting FGFR is at least 100 times greater than the activity against or inhibiting VEGFR2, in particular against FGFR1, FGFR2, FGFR3 and/or FGFR 4. This can be determined using the methods described herein.
Since the compounds have activity in modulating or inhibiting FGFR and/or VEGFR kinases, they are useful in providing a method of preventing tumor growth or causing apoptosis of tumors, particularly inhibiting angiogenesis. It is therefore expected that the compounds will prove useful in the treatment or prevention of proliferative disorders, such as cancer. In addition, the compounds of the present invention are useful in the treatment of diseases in which proliferative, apoptotic, or differentiative disorders are present.
In particular, patients with VEGFR-activating mutants or VEGFR-upregulating tumors and elevated serum lactate dehydrogenase levels are particularly sensitive to the compounds of the invention. It has also been found that it is particularly advantageous to treat patients having an activating mutant of any isoform of a particular RTK as discussed herein with a compound of the invention. For example, VEGFR is overexpressed in acute leukemia cells, where the clone female parent can express VEGFR. Furthermore, specific tumors having an activating mutant or up-regulated or overexpressed of any FGFR isoform (e.g. FGFR1, FGFR2 or FGFR3 or FGFR4) are especially sensitive to the compounds of the invention, whereby it was also found to be especially advantageous to treat the patients discussed herein with such specific tumors with the compounds of the invention. It may be preferred that the treatment is associated with, or directed against, a mutant form of a receptor tyrosine kinase (e.g. those discussed herein). Tumors having such mutations can be diagnosed using techniques known to those skilled in the art and described herein, e.g., RTPCR and FISH.
Examples of cancers that may be treated (or inhibited) include, but are not limited to: carcinomas, such as bladder cancer, breast cancer, colon cancer (e.g., colorectal cancer, such as colon adenocarcinoma and colon adenoma), kidney cancer, epidermal cancer, liver cancer, lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer, gallbladder cancer, ovarian cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, gastrointestinal (also known as stomach) cancer (e.g., gastrointestinal stromal tumor), cervical cancer, endometrial cancer, thyroid cancer, prostate cancer, or skin cancer (e.g., squamous cell carcinoma or dermatofibrosarcoma protruberans); hematopoietic tumors of the lymphatic system, such as leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (e.g., diffuse large B-cell lymphoma), T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy cell lymphoma, or burkitt's lymphoma; hematopoietic tumors of the myeloid system, such as leukemia, acute and chronic myelogenous leukemias, chronic myelomonocytic leukemia (CMML), myeloproliferative diseases, myeloproliferative syndromes, myelodysplastic syndromes, or promyelocytic leukemia; multiple myeloma; thyroid follicular cancer; tumors of mesenchymal origin (e.g. Ewing's sarcoma), such as fibrosarcoma or rhabdomyosarcoma; tumors of the central or peripheral nervous system, such as astrocytomas, neuroblastoma, glioma (e.g., glioblastoma multiforme) or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or kaposi's sarcoma of the skin.
Certain cancers are resistant to specific drug treatments. This may be due to the type of tumor, or may be induced by treatment with the compound. In this regard, multiple myeloma includes Bortezomib (Bortezomib) sensitive multiple myeloma or refractory multiple myeloma. Similarly, chronic myelogenous leukemia includes both imitanib-sensitive chronic myelogenous leukemia and refractory chronic myelogenous leukemia. Chronic myelogenous leukemia is also known as chronic myelogenous leukemia, chronic granulocytopenia, or CML. Also, acute myeloid leukemia is also called acute myeloblastic leukemia, acute myelocytic leukemia, acute non-lymphocytic leukemia or AML.
The compounds of the invention may also be used to treat hematopoietic disorders of abnormal cell proliferation, whether premalignant or stable, such as myeloproliferative and extramyeloproliferative disorders. Myeloproliferative and extramyeloproliferative disorders ("MPD") are a group of bone marrow disorders in which an excess of cells is produced. They are associated with and can progress through myelodysplastic syndrome. Myeloproliferative and extramyeloproliferative diseases include polycythemia vera, essential thrombocythemia and primary myelofibrosis. A further hematological disorder is hypereosinophilic syndrome. T cell lymphoproliferative disorders include those derived from natural killer cells.
In addition, the compounds of the present invention are useful in gastrointestinal (also known as gastric) cancers, such as gastrointestinal stromal tumors. Gastrointestinal cancer refers to a malignant condition of the gastrointestinal tract, including the esophagus, stomach, liver, biliary system, pancreas, intestine, and anus.
Thus, in one embodiment, in a pharmaceutical composition, use or method of the invention for treating a disease or disorder comprising abnormal cell growth, the disease or disorder comprising abnormal cell growth is cancer.
Specific sub-groups of cancers include multiple myeloma, bladder, cervical, prostate and thyroid cancer, lung, breast and colon cancer.
Further subordinate groups of cancers include multiple myeloma, bladder cancer, hepatocellular carcinoma, oral squamous cell carcinoma, and cervical cancer.
Compounds of the invention having FGFR such as FGFR1 inhibitory activity may be used, inter alia, for the treatment or prevention of breast cancer, in particular Conventional Lobular Cancer (CLC).
Since the compounds of the present invention have FGFR4 activity, they can be effectively used for the treatment of prostate or pituitary cancer, or they can be used for the treatment of breast, lung, prostate, liver (HCC) or lung cancer.
In particular, the compounds of the invention are useful as FGFR inhibitors for the treatment of multiple myeloma, myeloproliferative disease, endometrial, prostate, bladder, lung, ovarian, breast, gastric, colorectal and oral squamous cell carcinoma.
Further groups of cancers are multiple myeloma, endometrial, bladder, cervical, prostate, lung, breast, colorectal and thyroid cancers.
In particular, the compounds of the invention are useful for the treatment of multiple myeloma (especially multiple myeloma with t (4;14) migration or overexpression of FGFR3), prostate cancer (hormone refractory cancer), endometrial cancer (especially endometrial tumors with activating mutations in FGFR 2), and breast cancer (especially lobular breast cancer).
In particular, the compounds are useful for the treatment of lobular cancer, such as CLC (classical lobular cancer).
Because the compounds are active against FGFR3, they are useful for the treatment of multiple myeloma and bladder cancer.
In particular, the compounds are useful for treating t (4;14) migratory positive multiple myeloma.
In one embodiment, the compounds are useful for treating sarcoma. In one embodiment, the compounds are useful for treating lung cancer, such as squamous cell carcinoma.
As the compounds are active against FGFR2, they are useful for the treatment of endometrial, ovarian, gastric and colorectal cancers. FGFR2 is also overexpressed in epithelial ovarian cancer, and thus, the compounds of the invention may be specifically useful for treating ovarian cancer, e.g., epithelial ovarian cancer.
In one embodiment, the compounds are useful for the treatment of lung cancer, particularly NSCLC, squamous cell carcinoma, liver cancer, kidney cancer, breast cancer, colon cancer, colorectal cancer, prostate cancer.
The compounds of the present invention are also useful for treating tumors previously treated with VEGFR2 inhibitors or VEGFR2 antibodies, such as Avastin (Avastin).
In particular, the compounds of the present invention may be used to treat VEGFR2 resistant tumors. VEGFR2 inhibitors and antibodies are useful for treating thyroid and renal cell carcinoma, and therefore, the compounds of the present invention may be useful for treating VEGFR 2-resistant thyroid and renal cell carcinoma.
The cancer may be a cancer that is sensitive to inhibition of any one or more FGFR selected from FGFR1, FGFR2, FGFR3, FGFR4, e.g., one or more FGFR selected from FGFR1, FGFR2, or FGFR 3.
Whether a particular cancer is one that is sensitive to inhibition of FGFR or VEGFR, the signal can be determined by means of the cell growth assays listed below or the methods listed under the heading "diagnostic methods".
The compounds of the invention, especially those having FGFR or VEGFR inhibitory activity, may be used, inter alia, for the treatment or prevention of cancer types associated with or characterized by the presence of high levels of FGFR or VEGFR, e.g., the cancers mentioned in the introductory section of this application.
The compounds of the invention are useful for treating the adult population. The compounds of the invention are useful for treating pediatric populations.
It has been found that some FGFR inhibitors can be used in combination with other anticancer agents. For example, it is advantageous to combine an inhibitor that causes apoptosis with another agent that acts by modulating cell growth by a different mechanism, thereby addressing both characteristics of cancer evolution. Examples of such combinations are listed below.
The compounds of the invention may be used to treat other conditions resulting from proliferative disorders such as type II or non-insulin dependent diabetes mellitus, autoimmune diseases, head injury, stroke, epilepsy, neurodegenerative diseases such as alzheimer's disease, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease, such as autoimmune diseases and neurodegenerative diseases.
The following group of disease states and conditions that can be treated using the compounds of the present invention include: inflammatory diseases, cardiovascular diseases and wound healing.
FGFR and VEGFR are also known to play a role in apoptosis, angiogenesis, proliferation, differentiation and transcription, and therefore, the compounds of the present invention are also effective in the treatment of the following non-cancer diseases: chronic inflammatory diseases such as systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, autoimmune diabetes, eczema hypersensitivity, asthma, chronic obstructive pulmonary disease, rhinitis and upper respiratory diseases; cardiovascular diseases, such as cardiac hypertrophy, restenosis, atherosclerosis; neurodegenerative disorders such as alzheimer's disease, AIDS-related dementia, parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal myofibrillar atrophy and cerebellar degeneration; glomerulonephritis; myelodysplastic syndrome, ischemic injury associated with myocardial infarction, stroke and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, hematological diseases, e.g., chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, aspirin-sensitive sinusitis, cystic fibrosis, multiple sclerosis, kidney disease, and cancer pain.
In addition, mutations in FGFR2 are associated with some serious abnormalities in human skeletal formation, and thus, the compounds of the present invention are useful in the treatment of abnormalities in human skeletal formation, including abnormal cranial sutures ossification (craniosynostosis), apert (ap) syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin convolution syndrome, and Pfeiffer syndrome.
Compounds of the invention having FGFR (e.g. FGFR2 or FGFR3) inhibitory activity are particularly useful in the treatment or prevention of bone disease. A particular bone disease is achondroplasia or fatal dwarfism (also known as fatal dysplasia).
Compounds of the invention having FGFR (e.g. FGFR1, FGFR2 or FGFR3) inhibitory activity may be used, inter alia, for the treatment or prevention of progressive fibrosis as a symptomatic lesion. Fibrotic conditions for which the compounds of the invention may be useful include: fibrous tissues exhibit abnormal or excessive deposition of diseases such as cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, and the natural process of wound healing. In particular, the compounds of the present invention are also useful in the treatment of pulmonary fibrosis, in particular idiopathic pulmonary fibrosis.
Overexpression and activation of FGFR and VEGFR in tumor-associated vasculature also suggests that the compounds of the invention have the effect of preventing and interfering with tumor angiogenesis initiation. In particular, the compounds of the invention may be used for the treatment of cancer, metastatic disease, leukemia (e.g., CLL), eye diseases (e.g., age-related macular degeneration, especially wet age-related macular degeneration), ischemic retinal proliferative disorders (e.g., retinopathy of prematurity (ROP) and diabetic retinopathy), rheumatoid arthritis and hemangiomas.
The activity of the compounds of the invention as inhibitors of FGFR1-4, VEGFR and/or PDGFR A/B can be determined using the assays set forth in the examples below and can be determined according to IC50The values define the activity level exhibited by a given compound. Preferred compounds of the invention are IC50Compounds with a value of less than 1. mu.M, more preferably less than 0.1. mu.M.
The present invention provides compounds having FGFR inhibitory or modulating activity which may be used for the prevention or treatment of FGFR kinase mediated disease states or disorders.
In one embodiment, there is provided a compound as defined herein for use in therapy, for use as a medicament. In a further embodiment, there is provided a compound as defined herein for use in the prevention or treatment (especially for use in the treatment) of a FGFR kinase mediated disease state or disorder.
Thus, for example, the compounds of the invention may be used to reduce cancer or reduce the incidence of cancer. Thus, in a further embodiment, there is provided a compound as defined herein for use in the prevention or treatment (especially treatment) of cancer. In one embodiment, the compound as defined herein is for use in the prevention or treatment of an FGFR-dependent cancer. In one embodiment, the compounds as defined herein are for use in the prevention or treatment of a FGFR kinase mediated cancer.
Accordingly, the present invention provides, inter alia:
-a method of preventing or treating a FGFR kinase mediated disease state or disorder, the method comprising: administering to a patient in need thereof a compound of formula (I) as defined herein,
-a method of preventing or treating a disease state or condition described herein, the method comprising: administering to a patient in need thereof a compound of formula (I) as defined herein,
-a method of preventing or treating cancer, the method comprising: administering to a patient in need thereof a compound of formula (I) as defined herein,
a method of alleviating or reducing the incidence of a FGFR kinase-mediated disease state or disorder, the method comprising: administering to a patient in need thereof a compound of formula (I) as defined herein,
-a method of inhibiting a FGFR kinase, the method comprising: contacting the kinase with a kinase inhibiting compound of formula (I) as defined herein,
a method of modulating a cellular process (e.g. cell division) by inhibiting the activity of an FGFR kinase using a compound of formula (I) as defined herein,
the compounds of formula (I) as defined herein are useful as modulators of cellular processes (e.g. cell division) by inhibiting the activity of FGFR kinases,
a compound of formula (I) as defined herein for use in the prevention or treatment of cancer, in particular in the treatment of cancer,
a compound of formula (I) as defined herein for use as a modulator (e.g. inhibitor) of FGFR,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of a FGFR kinase mediated disease state or disorder, the compound having formula (I) as defined herein,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of a disease state or condition described herein,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of cancer, in particular for the treatment of cancer,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for modulating (e.g. inhibiting) the activity of FGFR,
the use of a compound of formula (I) as defined herein for the preparation of a medicament for modulating a cellular process (e.g. cell division) by inhibiting the activity of an FGFR kinase,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of a disease or condition characterised by upregulation of an FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4),
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of cancer characterized by upregulation of FGFR kinases such as FGFR1 or FGFR2 or FGFR3 or FGFR4,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of cancer in a patient selected from a subgroup with a genetic aberration of FGFR3 kinase,
-the use of a compound of formula (I) as defined herein for the preparation of a medicament for the prevention or treatment of cancer in a patient who has been diagnosed as part of a sub-population with genetic aberrations in FGFR3 kinase,
-a method of preventing or treating a disease or disorder characterised by upregulation of an FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising: administering a compound of formula (I) as defined herein,
a method of alleviating or reducing the incidence of a disease or condition characterised by upregulation of an FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4) which method comprises: administering a compound of formula (I) as defined herein,
-a method of preventing or treating (or reducing the incidence of) cancer in a patient having cancer or suspected of having cancer; the method comprises the following steps: (i) performing a diagnostic test on the patient to determine whether the patient has a genetic aberration of the FGFR3 gene; and (ii) if the patient does have said variant, administering to the patient a compound of formula (I) as defined herein having FGFR3 kinase inhibitory activity.
Methods of preventing or treating (or reducing the incidence of) a disease state or disorder characterized by upregulation of an FGFR kinase (e.g., FGFR1 or FGFR2 or FGFR3 or FGFR 4); the method comprises the following steps: (i) performing a diagnostic test on a patient, determining an index characteristic for FGFR kinase up-regulation (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), and (ii) administering to the patient a compound of formula (I) as defined herein having FGFR kinase inhibitory activity, if the diagnostic test shows FGFR kinase up-regulation.
In one embodiment, the FGFR kinase mediated disease is a tumor-associated disease (e.g., cancer). In one embodiment, the FGFR kinase-mediated disease is a non-tumor associated disease (e.g., any of the diseases disclosed herein, excluding cancer). In one embodiment, the FGFR kinase mediated disease is a disorder described herein. In one embodiment, the FGFR kinase mediated disease is a bone disorder described herein. In the process of human bone formation, specific abnormalities include: abnormal cranial suture ossification (craniosynostosis), apert (ap) syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin convolution syndrome, Pfeiffer syndrome, achondroplasia and lethal dwarfism (also known as lethal dysplasia).
Mutant kinase
Drug-resistant kinase mutations may occur in patient populations treated with kinase inhibitors. These occur in part in regions of the protein that bind to or interact with the particular inhibitor used in the treatment. Such mutations reduce or increase the ability of an inhibitor to bind to and inhibit the kinase. This may occur at any amino acid residue that interacts with the inhibitor or is important to support binding of the inhibitor to the target. Inhibitors that bind to the targeted kinase without the need to interact with the mutated amino acid residue may not be affected by the mutation and still be effective inhibitors of the enzyme.
Studies with gastric cancer patient samples indicated the presence of two mutations in FGFR 2: ser167Pro in exon IIIa and the splice site mutation 940-2A-G in exon IIIc. These mutations are consistent with germline activating mutations that cause craniosynostosis syndrome, and are observed in 13% of the primary gastric cancer tissues studied. In addition, an activating mutation in FGFR3 was observed in 5% of the patient samples tested, and overexpression of FGFR was correlated with poor prognosis in this patient group.
In addition, chromosomal translocations or point mutations have been observed in FGFR that result in gain-of-function, overexpression, or structurally active biological states.
Thus, the compounds of the invention have particular application for cancers that express a mutated molecular target (e.g., FGFR). Tumors having such mutations can be diagnosed using techniques known to those skilled in the art and described herein, e.g., RTPCR and FISH.
Mutations in conserved threonine residues at ATP binding sites of FGFR have been shown to lead to inhibitor tolerance. In FGFR1, amino acid valine 561 has been mutated to methionine, which corresponds to the previously reported mutations found in Abl (T315) and EGFR (T766), suggesting tolerance to selective inhibitors. Experimental data for FGFR 1V 561M indicate that this mutation is resistant to tyrosine kinase inhibitors compared to the wild type.
Diagnostic method
Prior to administration of a compound of formula (I), the patient may be screened to determine whether the disease or condition that the patient has or may have is one that is susceptible to treatment with a compound that is active against FGFR and/or VEGFR.
For example, a biological sample taken from a patient can be analyzed to determine whether a disorder or disease (e.g., cancer) that the patient has or is likely to have is a disorder or disease characterized by: genetic abnormalities or abnormal protein expression that result in up-regulation of the level of activity of FGFR and/or VEGFR, or in sensitization of pathways that result in normal FGFR and/or VEGFR activity, or in up-regulation of these growth factor signaling pathways (e.g., growth factor ligand level or growth factor ligand activity), or in down-regulation of biochemical pathways that result in FGFR and/or VEGFR activation.
Examples of such abnormalities that lead to activation or sensitization of FGFR and/or VEGFR signals include: loss or inhibition of apoptotic pathways, upregulation of receptors or ligands, or presence of mutants of receptors or ligands (e.g., PTK variants). Tumors with FGFR1, FGFR2 or FGFR3 or mutants of FGFR4 or FGFR1 upregulation (especially overexpression of FGFR 1) or gain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitive to FGFR inhibitors.
For example, point mutations that cause gain of function of FGFR2 have been identified in a number of disorders. In particular, activating mutations in FGFR2 have been identified in 10% of endometrial tumors.
In addition, genetic aberrations (e.g., chromosomal translocations or point mutations, production of constitutively active FGFR3 receptors that are ectopically expressed or deregulated) that result in FGFR3 receptor tyrosine kinases have been identified and are associated with multiple myeloma, bladder and cervical cancers. In imatinib-treated patients, a specific mutation T674I of the PDGF receptor has been identified. In addition, gene amplification of 8p12-p11.2 was demonstrated in-50% of lobular breast cancer (CLC) cases and was shown to be associated with increased expression of FGFR 1. Preliminary studies with small molecule inhibitors of FGFR1 or the receptor to which siRNA is directed have shown that cell lines presenting such expansion are particularly sensitive to inhibition of this signaling pathway.
Alternatively, biological samples taken from patients may be analyzed for loss of negative modulators or inhibitors of FGFR or VEGFR. In this context, the term "loss" includes deletion of a gene encoding a modulator or inhibitor, truncation of a gene (e.g., mutation), truncation of a transcription product of a gene or inactivation of a transcription product (e.g., point mutation), or sequestration by another gene product.
The term upward adjustment includes: increased expression or overexpression, including gene amplification (i.e., multiple gene replication), and increased expression due to transcriptional effects, and hyperactivity and activation, including activation due to mutations. Thus, a diagnostic test can be performed on a patient to determine an index characteristic of upregulation of FGFR and/or VEGFR. The term diagnosis includes screening. For indices, we include genetic indices, including, for example, assaying combinations of DNA to determine mutations in FGFR and/or VEGFR. The term index also includes: indices characteristic of FGFR and/or VEGFR up-regulation include enzyme activity, enzyme levels, enzyme status (e.g., phosphorylated or unphosphorylated), and mRNA levels of the above proteins.
Diagnostic tests and screens are typically performed on biological samples selected from the group consisting of: tumor biopsy samples, blood samples (isolation and enrichment of released tumor cells), stool biopsies, sputum, chromosome analysis, pleural fluid, peritoneal fluid, oral needle, biopsies or urine.
Methods for the identification and analysis of mutations and upregulation of proteins are known to those skilled in the art. Screening methods may include, but are not limited to: standard methods, such as reverse transcriptase polymerase chain reaction (RT-PCR), or in situ hybridization, such as Fluorescence In Situ Hybridization (FISH).
Identifying an individual carrying a mutation in FGFR and/or VEGFR means that the patient is particularly suitable for treatment with an FGFR and/or VEGFR inhibitor. Tumors in which FGFR and/or VEGFR variants are present can be preferentially screened prior to treatment. The screening process typically includes: direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies. In addition, tumors having such mutations can be diagnosed using techniques known to those skilled in the art and described herein, such as RT-PCR and FISH.
In addition, using PCR and the methods described above for direct sequencing of PCR products, mutant forms of, for example, FGFR or VEGFR2 can be determined by, for example, direct sequencing of tumor biopsies. The skilled person will recognise that all such accepted techniques for detecting overexpression, activation or mutation of the above proteins are applicable in the present context.
During screening by RT-PCR, mRNA levels in tumors were assessed as follows: a cDNA copy of the mRNA was formed and then the cDNA was amplified by PCR. The method of PCR amplification, the choice of primers and the amplification conditions are known to the skilled person. Nucleic acid manipulations and PCR were performed using standard methods described in the following: ausubel, F.M. et al, eds. (2004) Current Protocols in Molecular Biology, John Wiley&Sons Inc., or Innis, M.A. et al, eds. (1990) PCR Protocols a guide to methods and applications, academic Press, San Diego. Reactions and procedures involving nucleic acid technology are also described in the following: sambrook et al, (2001),3rdEd, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available RT-PCR kits (e.g., Roche Molecular Biochemicals) can be used, or the methods listed in U.S. Pat. Nos. 4,666,828, 4,683,202, 4,801,531, 5,192,659, 5,272,057, 5,882,864, and 6,218,529, which are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression is Fluorescence In Situ Hybridization (FISH) (see anger (1987) meth. enzymol., 152: 649).
In general, in situ hybridization comprises the following major steps: (1) fixing the analyzed tissue; (2) subjecting the sample to a prehybridization treatment to increase the accessibility of the target nucleic acids and reduce non-specific binding; (3) hybridizing a mixture of nucleic acids to nucleic acids in a biological structure or tissue; (4) washing after hybridization to remove unbound nucleic acid fragments during hybridization, and (5) detecting hybridized nucleic acid fragments. Probes used in such applications are typically labeled with, for example, a radioisotope or fluorescent indicator. Preferred probes are probes that are long enough, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to be capable of specific hybridization to a target nucleic acid under stringent conditions. Standard methods for achieving FISH are described in the following: autosubel, F.M. et al, eds. (2004) Current Protocols In Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization Technical overview John M.S. Bartlett In Molecular diagnostics of Cancer, Methods and Protocols, 2nd ed., ISBN: 1-59259-760-2, March 2004, pps. 077-088, and Series: Methods In Molecular Medicine.
Methods for gene expression profiling are described by DePrimo et al ((2003), BMC Cancer, 3: 3). Briefly, the scheme is as follows: double-stranded cDNA was synthesized from total RNA using a (dT)24 oligo to prime the first cDNA strand synthesis, followed by random hexamer primer synthesis of the second cDNA strand. Biotinylated nucleotides were used, and double-stranded cDNA was used as a template for in vitro transcription of cRNA. The cRNA was chemically fragmented and then hybridized overnight on human genomic arrays following the protocol described by Affymetrix (Santa Clara, Calif., USA).
Alternatively, tumor samples can be tested for protein production by immunohistochemistry, solid phase immunoassays (using microtiter plates), western blotting, two-dimensional SDS polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for the detection of specific proteins. Detection methods include the use of site-specific antibodies. The skilled artisan will recognize that all such accepted techniques for detecting upregulation of FGFR and/or VEGFR, or for detecting FGFR and/or VEGFR variants or mutants are applicable in the present context.
Abnormal levels of proteins such as FGFR or VEGFR can be determined using standard enzymatic assays, for example, those described herein. Activation or overexpression can also be measured in tissue samples, e.g., tumor tissue. Tyrosine kinase activity is determined using assays such as from Chemicon International. The tyrosine kinase of interest can be immunoprecipitated from the sample lysate and its activity determined.
An alternative method of determining overexpression or activation of FGFR or VEGFR (including isoforms thereof) comprises determining microvascular density. This can be determined, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). The assay methods also include the use of markers, for example, in the case of VEGFR, these markers include CD31, CD34, and CD 105.
Thus, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the compounds of the present invention.
The compounds of the invention are particularly useful for treating patients having a mutated FGFR. The G697C mutation of FGFR3 was observed in 62% of oral squamous cell carcinomas and resulted in structural activation of kinase activity. Activating mutations of FGFR3 were also identified in bladder cancer cases. These mutations were 6 with varying degrees of prevalence: R248C, S249C, G372C, S373C, Y375C, K652Q. In addition, the Gly388Arg polymorphism in FGFR4 has been found to be associated with increased incidence and invasiveness of prostate, colon, lung, liver (HCC), and breast cancer.
Thus, in a further aspect, the invention includes the use of a compound according to the invention for the preparation of a medicament for the treatment or prophylaxis of a disease state or condition in a patient screened for and determined to have or at risk of having a disease or condition susceptible to treatment with a compound active against FGFR.
Specific mutations for the patients screened included: the G697C, R248C, S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and the Gly388Arg polymorphism in FGFR 4.
In another aspect, the invention includes a compound of the invention for use in the prevention or treatment of cancer in a patient selected from a subgroup having a variant of the FGFR gene (the G697C mutation in FGFR3 and the Gly388Arg polymorphism in FGFR 4).
MRI assay data for vessel normalization in conjunction with circulating biomarkers (circulating progenitor cells (CPCs), CECs, SDF1, and FGF2) (e.g., using MRI gradient echoes, spin echoes, and contrast enhancement to determine blood volume, relative vessel specification, and vascular permeability) can also be used to identify VEGFR 2-resistant tumors treated with the compounds of the present invention.
Pharmaceutical composition and combination
The target compound may be formulated into various pharmaceutical forms for administration purposes, taking into account the useful pharmacological properties of the target compound.
In one embodiment, a pharmaceutical composition (e.g., formulation) comprises at least one active compound of the present invention in combination with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants or other substances well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
To prepare the pharmaceutical compositions of this invention, an effective amount of a compound of this invention, as the active ingredient, is intimately admixed with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, ocular, otic, rectal, intravaginal or transdermal administration. Preferably, the unit dosage forms of these pharmaceutical compositions are suitable for oral, rectal, transdermal or parenteral administration by injection. For example, in the preparation of compositions in oral dosage form, in the case of oral liquid preparations (e.g., suspensions, syrups, elixirs and solutions), any conventional pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed.
Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water (at least in large part), although other components, for example, to aid solubility, may be included. For example, injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally in combination with a small proportion of a suitable additive of any nature which does not have a significant deleterious effect on the skin. The additives may be easier to administer to the skin and/or may aid in the preparation of the subject compositions. These compositions may be administered in a variety of ways, for example, as transdermal patches, drops, ointments. It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein the specification and claims, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein the specification and claims, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient suitable for the purpose of bringing about the desired therapeutic effect, in association with a required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injections or suspensions, teaspoonfuls, tablespoonfuls and the like, and divided multiple doses thereof.
The compound of the invention should be administered in an amount sufficient to produce its anti-tumor activity.
The effective amount can be readily determined by one skilled in the art using the test results provided below. Generally, a therapeutically effective amount is from 0.005 mg/kg to 100 mg/kg body weight, especially from 0.005 mg/kg to 10 mg/kg body weight. Suitably, the required dose is administered in one, two, three, four or more sub-dose forms at suitable time intervals per day. The sub-doses may be formulated in unit dosage forms, for example, each unit dosage form containing from 0.5 to 500mg of the active ingredient, especially from 1mg to 500mg, more especially from 10mg to 500 mg.
Depending on the mode of administration, preferably, the pharmaceutical composition comprises from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of a compound of the invention and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
As a further aspect of the invention, the compounds of the invention are designed for use in combination with another anti-cancer agent, particularly for use as a medicament, more particularly for the treatment of cancer or related diseases.
For the treatment of the above-mentioned conditions, it may be preferred that the compounds of the invention be used in combination with one or more other agents, more particularly, with other anti-cancer agents or adjuvants, in the treatment of cancer. Examples of anti-cancer agents or adjuvants (carriers in therapy) include, but are not limited to:
platinum complexes, such as cisplatin (optionally combined with amifostine), carboplatin or oxaliplatin;
taxane (taxane) compounds, e.g. paclitaxel, paclitaxel protein-binding particles (Abraxane)TM) Or docetaxel;
topoisomerase I inhibitors, for example camptothecin compounds, for example irinotecan, SN-38, topotecan HCl;
topoisomerase II inhibitors, such as anti-tumour epipodophyllotoxins or podophyllotoxin derivatives, for example etoposide, etoposide phosphate or epipodophyllotoxin thiophene glycosides;
anti-tumour vinca alkaloids, such as vinblastine, vincristine or vinorelbine;
antineoplastic nucleoside derivatives, such as 5-fluorouracil, folinic acid, gemcitabine HCl, capecitabine, cladribine, fludarabine, nelarabine (nelarabine);
alkylating agents, such as nitrogen mustards or nitrosoureas, such as cyclophosphamide, chlorambucil, carmustine, thiotepa, melphalan (melphalan), lomustine, altretamine, busulfan, dacarbazine, estramustine, ifosfamide (optionally in combination with mercaptoethanesulfonic acid sodium salt), dibromopropylpiperazine, procarbazine, streptozotocin, temozolomide (telozolomide), uracil;
anti-tumour anthracycline derivatives, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), doxil, idarubicin, mitoxantrone, epirubicin HCl, valrubicin;
molecules targeting the IGF-1 receptor, such as picropodophilin;
-tetracaine derivatives, such as tetrarcin a;
-glucoortico, such as dehydrocortisone;
antibodies, such as trastuzumab (HER2 antibody), rituximab (CD20 antibody), gemtuzumab ozogamicin (gemtuzumab ozogamicin), cetuximab, pertuzumab (pertuzumab), bevacizumab, alemtuzumab (alemtuzumab), eculizumab (eculizumab), ibritumomab (ritumomab tiuxetan), norflumumab (nofebumomab), panitumumab (panitumumab), tositumomab (tositumomab), CNTO 328;
-an estrogen receptor antagonist, or a selective estrogen receptor modulator, or an inhibitor of estrogen synthesis, such as tamoxifen, fulvestrant, toremifene citrate, droloxifene, faslodex, raloxifene or letrozole;
aromatase inhibitors, such as exemestane, anastrozole, letrozole, testolactone and vorozole;
differentiation agents, such as retinoids, vitamin D or retinoic acid and Retinoic Acid Metabolism Blockers (RAMBA), such as isotretinoin (accutane);
-DNA transmethylase inhibitors, such as azacytidine or decitabine;
antifolates, such as pemetrexed disodium;
antibiotics, such as antimycin (antinomycin) D, bleomycin, mitomycin C, actinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin;
metabolic antagonists, such as clofarabine (clofarabine), aminopterin, cytarabine or methotrexate, azacitidine, cytarabine, azauridine, pentostatin, thioguanine;
apoptosis-inducing agents and anti-angiogenic agents, e.g., Bcl-2 inhibitors, e.g., YC 137, BH312, ABT 737, gossypol, HA 14-1, TW 37 or decanoic acid;
-tubulin binding agents, such as combestin, colchicine or thiabendazole;
kinase inhibitors (e.g. EGFR (epithelial growth factor receptor) inhibitors, MTKI (multi-targeted kinase inhibitors), mTOR inhibitors), such as flavoperidol, imatinib mesylate, erlotinib, gefitinib, dasatinib, lapatinib (lapatinib), lapatinib ditosylate (lapatinib), sorafenib (sorafenib), Sunitinib (Sunitinib), Sunitinib maleate (Sunitinib), sirolimus (temsirolimus);
farnesyl transferase inhibitors, such as tipifarnib (tipifarnib);
-Histone Deacetylase (HDAC) inhibitors, such as sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin (trichostatin) a, vorinostat;
-inhibitors of the ubiquitin-proteasome pathway, such as PS-341, mln.41 or Bortezomib (Bortezomib);
-taybelis specific (Yondelis);
telomerase inhibitors, such as telomestatin;
matrix metalloproteinase inhibitors, such as batimastat, marimastat (marimastat), prinostat or metastat;
recombinant interleukins, such as aldesleukin, interleukin fusion toxin (denileukin bifittox), interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2 b;
-a MAPK inhibitor;
retinoids, such as alitretinoin (alitretinoid), bexarotene (bexarotene), tretinoin;
-arsenic trioxide;
-asparaginase;
steroids, such as drotasandrosterone propionate, megestrol acetate, nandrolone (caprate, phenylpropionate), dexamethasone;
-gonadotropin releasing hormone agonists or antagonists such as aberrax (Abarelix), capromorelin acetate, histrelin acetate, leuprolide acetate;
-discontinuation of reaction, lenalidomide (lenalidomide);
mercaptopurine, mitotane, pamidronate, pegase (pegademase), pegafese, labyrinase (rasburicase);
-BH3 mimetics, such as ABT-737;
MEK inhibitors, such as PD98059, AZD6244, CI-1040;
colony-stimulating factor analogs, such as filgrastim, pegfilgrastim, sargrastim; erythropoietin or an analog thereof (e.g., alfa bepotin (darbepoetin alfa)); interleukin 11; oprelvekin; zoledronic acid salt, zoledronic acid; fentanyl; a bisphosphonate; palifermin (palifermin).
Steroidal cytochrome P45017 alpha-hydroxylase-17, 20-lyase inhibitors (CYP17), such as abiraterone, abiraterone acetate.
The compounds of the invention also have therapeutic applications that sensitize tumor cells to radiation and chemotherapy.
Thus, the compounds of the invention may be used as "radiosensitizers" and/or "chemosensitizers", or may be used in combination with another "radiosensitizer" and/or "chemosensitizer".
The term "radiosensitizer," as used herein, is defined as a molecule, preferably a low molecular weight molecule, administered to an animal in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and/or to facilitate the treatment of diseases treatable with ionizing radiation.
The term "chemosensitizer" as used herein is defined as a molecule, preferably a low molecular weight molecule, administered to an animal in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and/or to facilitate the treatment of a disease for which a chemotherapeutic drug can be used.
Some mechanisms of the mode of action of radiosensitizers have been described in the literature, including: hypoxic cell radiosensitizers that mimic oxygen or behave like a biological deoxidizer under hypoxic conditions (e.g., 2-nitroimidazole compounds and benzotriazine compounds); non-hypoxic cell radiosensitizers (e.g., halogenated pyrimidines) can be analogs of DNA bases and preferentially bind into the DNA of cancer cells, thereby promoting radiation-induced fragmentation of DNA molecules, and/or preventing normal DNA repair mechanisms; various other potential mechanisms of action of radiosensitizers have been postulated during the treatment of disease.
Many cancer treatment protocols currently use radiosensitizers in combination with X-ray radiation. Examples of X-ray activated radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmisodazole, pimonidazole (pimonidazole), etanidazole, nimorazole (nimorazole), mitomycin C, RSU 1069, SR 4233, EO9, RB6145, niacinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorouracil deoxynucleoside (FudR), hydroxyurea, cisplatin and therapeutically effective analogs and derivatives thereof.
Photodynamic therapy (PDT) of cancer uses visible light as a radiation activator of sensitizers. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, the present tin porphyrins, phenobiode-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanines and therapeutically effective analogs and derivatives thereof.
The radiosensitizer can be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: a compound that promotes binding of the radiosensitizer to the target cell; compounds that control the flow of therapeutic agents, nutrients and/or oxygen to target cells; chemotherapeutic agents that act on tumors (with or without additional radiation); or other therapeutically effective compounds for the treatment of cancer or other diseases.
The chemosensitizer may be administered in combination with a therapeutically effective amount of one or more other compounds, including but not limited to: a compound that promotes binding of the chemotherapeutic sensitizer to the target cell; compounds that control the flow of therapeutic agents, nutrients and/or oxygen to target cells; chemotherapeutic agents acting on tumors; or other therapeutically effective compounds for the treatment of cancer or other diseases. Calcium antagonists, such as verapamil, may be used in combination with anti-tumor agents to establish chemosensitivity in tumor cells that are resistant to receiving chemotherapeutic agents and to enhance the effectiveness of such compounds in drug-sensitive malignancies.
In view of the useful pharmacological properties of the combination according to the invention, the components of the combination according to the invention, i.e. the one or more further pharmaceutical agents and the compound according to the invention, may be formulated in various pharmaceutical forms for administration purposes. The components may be formulated individually in a single pharmaceutical composition or in a unit pharmaceutical composition containing all of the components.
Thus, the invention also relates to pharmaceutical compositions comprising one or more other pharmaceutical agents and a compound according to the invention together with a pharmaceutical carrier.
The invention further relates to the use of a combination according to the invention for the preparation of a pharmaceutical composition for inhibiting tumor cell growth.
The invention further relates to products containing a compound according to the invention (as the first active ingredient) and one or more anticancer agents (as further active ingredients), as a combined preparation for simultaneous, separate or sequential use in the treatment of a patient suffering from cancer.
One or more other agents and a compound according to the invention may be administered simultaneously (e.g., in separate compositions or unit compositions) or sequentially in any order. In the latter case, the two or more compounds are administered over a period of time, and the amounts and manner of administration should be sufficient to ensure that a beneficial or synergistic effect is achieved. It will be appreciated that the preferred method and sequence of administration and the corresponding dosage and schedule of administration for each of the components of the combination will depend upon the particular other agents and compounds of the invention being administered, their route of administration, the particular tumor being treated and the particular host being treated. Optimal methods and sequences of administration and dosages and schedules can be readily determined by those skilled in the art using conventional methods and in view of the information set forth herein.
When administered as a combination, the weight ratio of the compound according to the invention and one or more other anti-cancer agents can be determined by one skilled in the art. The ratio and exact dose and frequency of administration will depend on the particular compound according to the invention and other anti-cancer agent used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, diet, time and general physical conditions of the particular patient, mode of administration and other drugs that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is clear that the effective daily amount can be reduced or increased depending on the response of the patient to be treated and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The specific weight ratio of the compound of formula (I) of the present invention and the other anticancer agent may be in the range of 1/10 to 10/1, more particularly 1/5 to 5/1, still more particularly 1/3 to 3/1.
Preferably, the dosage per treatment course is 1 to 500mg per square meter of body surface area (mg/m)2) Administration of platinum complexes, e.g. 50 to 400 mg/m2Especially for cisplatin, the dose is about 75 mg/m2For carboplatin, the dose is about 300mg/m2。
Preferably, the dosage per treatment course is 50 to 400 mg per square meter of body surface area (mg/m)2) Administration of taxane (taxane) compounds, e.g. 75 to 250 mg/m2Especially for paclitaxel, the dosage is about 175 to 250 mg/m2For docetaxel, the dose is about 75 to 150 mg/m2。
Preferably, the dosage is 0.1 to 400 mg per square meter of body surface area per treatment course (mg/m)2) Administration of camptothecin compounds, e.g. 1 to 300mg/m2Especially for irinotecan, the dosage is about 100 to 350 mg/m2For topotecan, the dosage is about 1 to 2mg/m2。
Preference is given toWith a dosage of 30 to 300mg per square meter of body surface area (mg/m) per treatment course2) Administration of an antitumor Podophyllotoxin derivative, e.g. 50 to 250 mg/m2Especially for etoposide, the dosage is about 35 to 100 mg/m2For epipodophyllotoxin thiophenoglycosides, the dosage is about 50 to 250 mg/m2。
Preferably, the dosage is 2 to 30mg per square meter of body surface area (mg/m) per treatment course2) Administering an antitumor alkaloid of Elsholtzia camara, especially vinblastine, in a dose of about 3 to 12 mg/m2For vincristine, the dosage is about 1 to 2mg/m2For vinorelbine, the dose is about 10 to 30 mg/m2。
Preferably, the dosage per treatment course is 200 to 2500 mg per square meter of body surface area (mg/m)2) Administration of antitumor nucleoside derivatives, e.g. 700 to 1500 mg/m2Especially for 5-FU, at a dose of 200 to 500 mg/m2For gemcitabine, the dose is about 800 to 1200 mg/m2For capecitabine, the dosage is about 1000 to 2500 mg/m2。
Preferably, the dosage per treatment course is 100 to 500mg per square meter of body surface area (mg/m)2) Administration of alkylating agents, e.g. nitrogen mustards or nitrosoureas, e.g. 120 to 200 mg/m2Especially for cyclophosphamide, the dose is about 100 to 500 mg/m2For chlorambucil, the dosage is about 0.1 to 0.2 mg/m2For carmustine, the dosage is about 150 to 200 mg/m2For lomustine, the dosage is about 100 to 150 mg/m2。
Preferably, each course of treatment is at a dose of 10 to 75 mg per square meter of body surface area (mg/m)2) Administration of antitumor anthracycline derivatives, e.g. 15 to 60 mg/m2Especially for doxorubicin, the dose is about 40 to 75 mg/m2For daunorubicin, the dosage is about 25 to 45 mg/m2For idarubicin, the dosage is about 10 to 15 mg/m2。
Preferably, the antiestrogen is administered at a dosage of about 1 to 100 mg per day, depending on the particular agent and condition being treated. Preferably, tamoxifen is administered orally at a dose of 5 to 50mg, preferably 10 to 20mg, twice daily for a sufficient time for treatment to be achieved and maintained. Preferably, toremifene citrate is administered orally at a dose of about 60mg once a day for a sufficient time to achieve and maintain the therapeutic effect. Preferably, anastrozole is administered orally at a dose of about 1mg once a day. Preferably, droloxifene is administered orally at a dose of about 20-100 mg once a day. Preferably, the raloxitol is administered orally at a dose of about 60mg once a day. Preferably, exemestane is administered orally, once a day, in a dose of about 25 mg.
Preferably, the dosage is about 1 to 5mg per square meter of body surface area (mg/m)2) The antibody is administered, or if different, in a dose known in the art. Preferably, each treatment course is at a dose of about 1 to 5mg per square meter of body surface area (mg/m)2) Trastuzumab administration, in particular 2 to 4 mg/m2。
Each course of treatment may be given, for example, one, two or more such doses, which may be repeated, for example, every 7, 14, 21 or 28 days.
The compounds of formula (I), their pharmaceutically acceptable addition salts (especially the pharmaceutically acceptable acid addition salts) and stereoisomeric forms have valuable diagnostic properties because they can be used to determine or identify the formation of complexes between a marker compound and other molecules, peptides, proteins, enzymes or receptors.
The measuring or identifying method may use a compound labeled with a labeling agent (e.g., radioisotope, enzyme, fluorescent substance, luminescent substance, etc.). Examples of radioactive isotopes include125I、131I、3H and14C. the enzyme is typically detectable by conjugation to a suitable substrate (which also catalyzes the detection reaction). examples include, for example, β -galactosidase, β -glucosidase, alkaline phosphatase, peroxidase, andmalate dehydrogenase, preferably horseradish peroxidase. Luminescent substances include, for example, luminol derivatives, luciferin, aequorin and luciferase.
A biological sample may be defined as a body tissue or fluid. Examples of body fluids are cerebrospinal fluid, blood, plasma, serum, urine, sputum, saliva, etc.
General synthetic route
The following examples illustrate the invention, but they are only examples and do not limit the scope of the claims in any way.
Experimental part
Hereinafter, the term' CH3CN 'means acetonitrile,' DCM 'means dichloromethane,' TBAF 'means tetrabutylammonium fluoride,' K2CO3'means Potassium carbonate,' MgSO4'means magnesium sulfate,' MeOH 'means methanol,' EtOH 'means ethanol,' EtOAc 'means ethyl acetate,' Et3N ' means triethylamine, ' HOBt ' means 1-hydroxy-1H-benzotriazole, ' DPPP ' means 1, 3-propanediylbis [ diphenylphosphine ]]' DIPE ' means diisopropyl ether, ' THF ' means tetrahydrofuran, ' NH4Cl 'refers to ammonium chloride,' Pd (PPh)3)4'means tetrakis (triphenylphosphine) palladium,' DIPEA 'means N-ethyl-N- (1-methylethyl) -2-propylamine,' DMF 'means N, N-dimethylformamide,' NaH 'means sodium hydride,' Pd2(dba)3'means tris (dibenzylideneacetone) dipalladium (0),' HOAc 'means acetic acid,' PPh3'means triphenylphosphine and' NH4OH 'means ammonium hydroxide,' TBDMSCl 'means t-butyldimethylsilyl chloride,' S-Phos 'means dicyclohexyl (2', 6 '-dimethoxy [1, 1' -biphenyl)]-2-yl) -phosphine, 'X-Phos' means dicyclohexyl [ 2',4',6 '-tris (1-methylethyl) [1, 1' -biphenyl]-2-yl]-phosphine,' Na2SO4'means sodium sulfate,' i-PrOH 'means 2-propanol,'t-BuOH 'means 2-methyl-2-propanol,' K3PO4' refers to potassium phosphate, MP isRefers to the melting point.
A. Preparation of intermediates
Example A1
a-1) preparation of intermediate 1
7-bromo-2 (1H) -quinoxalinone (47.2 g; 210mmol) was added to phosphorus oxychloride (470 ml). The reaction mixture was stirred at 100 ℃ for 2 hours, cooled to room temperature and evaporated to dryness. The crude product was taken up in DCM and poured onto ice, water and K2CO3In the powder. The mixture was filtered through celite. Celite was washed twice with DCM. Decanting the organic layer over MgSO4Drying, filtration and evaporation to dryness gave 49g (96%) of intermediate 1 (grey solid). MP =146 ℃.
Intermediate 1 may also be prepared using the following method:
thionyl chloride (407.5 mL; 5.59 mol) and then N, N-dimethylformamide (34.6 mL; 0.45mol) were added dropwise to a mixture of 7-bromo-2 (1H) -quinoxalinone (500 g; 2.24mol) in toluene (7.61L). The reaction mixture was stirred at 80 ℃ for 17 hours, then cooled to 35 ℃ and carefully poured into water. The biphasic mixture was stirred for 30 minutes and then decanted. The organic layer was evaporated to dryness and the residue was crystallized from methyl-tert-butyl ether, filtered and the precipitate was washed with methyl-tert-butyl ether and dried to give 407g (74.7%) of intermediate 1. The filtrate was evaporated and recrystallized from methyl-tert-butyl ether to give a second portion of 72g (13.2%) of intermediate 1.
b-1) preparation of intermediate 2
Intermediate 1(20 g; 82.1mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane under nitrogen-2-yl) -1H-pyrazole (17.1 g; 82.1mmol), 2M aqueous sodium carbonate solution (41.1 ml; 82.1mmol) in ethylene glycol dimethyl ether (200ml) was degassed by bubbling nitrogen for 15 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.95 g; 0.82mmol) was added and heated at reflux for 15 h. The reaction mixture was poured into water and extracted with EtOAc. With MgSO4The organic layer was dried, filtered and evaporated to dryness to give 29.9 g. Purification of the crude compound by silica gel chromatography (random SiOH, 20-45 μm, 1000g MATREX; mobile phase 0.1% NH)4OH，98% DCM，2% CH3OH). The pure fractions were collected and concentrated to dryness to give 19.5g (82%) of intermediate 2. MP =172 ℃.
Intermediate 2 may also be prepared using the following method:
intermediate 1(502 g; 2.06mol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (450.42 g; 2.16mol), triphenylphosphine (10.82 g; 0.041mol) and palladium (II) acetate were added to a mixture of sodium carbonate (240.37 g; 2.267mol), 1, 2-dimethoxyethane (5.48L) and water (1.13L). The reaction mixture was stirred at reflux for 20H, then 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (42.9 g; 0.206 mol) was added and the reaction mixture was refluxed until complete conversion (4H). The reaction mixture was poured into water, stirred at room temperature for 2 hours, filtered, and the precipitate was washed with water. The precipitate was then triturated in methanol and filtered. The precipitate was washed with methanol and dried to give 532.2g (89%) of intermediate 2 (off-white powder).
c-1) preparation of intermediate 3
Intermediate 2(20 g; 69.2mmol), 3, 5-dimethoxyaniline (10.6 g; 69.2mmol), sodium tert-butoxide (20 g; 0.21mol) and 1,1'- [1, 1' -binaphthyl]-2,2' -diylA mixture of bis [1, 1-diphenylphosphine (2.2 g; 3.5mmol) was degassed in dioxane (500ml) at room temperature under a stream of nitrogen. After 10 minutes, palladium (II) acetate (0.78 g; 3.5mmol) was added portionwise at room temperature under nitrogen. The reaction mixture was heated at 90 ℃ overnight. The reaction mixture was cooled to rt and partitioned between water and EtOAc. The organic layers were combined and MgSO4Drying, filtration and concentration gave 40g of crude compound. The residue was taken up in DCM/Et2O (3/7), and the mixture was stirred for 30 minutes. The precipitate was filtered off and dried to yield 20g of intermediate 3 (brown solid). The filtrate was evaporated to dryness to give 40g of crude compound, which was purified by silica gel chromatography (random SiOH, 20-45 μm, 450g MATREX; mobile phase 0.1% NH)4OH，98% DCM，2% CH3OH). The pure fractions were concentrated to yield 4.2g of intermediate 3 (brown solid). MP =199 ℃ (DSC).
Overall yield = 96.8%.
Intermediate 3 may also be prepared using the following method.
A mixture of intermediate 2(80 g; 277mmol), 3, 5-dimethoxyaniline (47.6 g; 304mmol) and cesium carbonate (108.2 g; 332mmol) was stirred in 1, 2-dimethoxyethane (1.1L) at 80 ℃ under a stream of nitrogen and then cooled to room temperature (solution A). In another flask, a mixture of palladium (II) acetate (0.62 g; 2.8mmol) and rac-2, 2 '-bis (diphenylphosphino) -1,1' -binaphthyl (1.76 g; 2.8mmol) was stirred at 40 ℃ for 15 minutes under a nitrogen atmosphere and then added to solution A at 35 ℃. The new reaction mixture was stirred at 80 ℃ for 20 h, cooled to 50 ℃ and water (1.11L) was added. The reaction mixture was seeded with crystals of intermediate 3, additional water (0.55L) was added, and then cooled to room temperature. The precipitate is filtered off, washed with water and then recrystallized in isopropanol (seeding). The precipitate was filtered off, washed with diisopropyl ether and dried to give 79.2g (79.2%) of intermediate 3.
Intermediate 3 may also be prepared using the following method.
a-2) preparation of intermediate 4
2-chloro-7-nitroquinoxaline (27.8g, 133mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (30.4g, 146mmol), 2M Na2CO3The aqueous solution (66.3ml, 133mmol) was degassed with nitrogen in ethylene glycol dimethyl ether (330ml) for 15 minutes. Tetrakis (triphenylphosphine) palladium (0) (1.5g, 1.33mmol) was added and the reaction mixture was heated at 100 ℃ for 7 h. The reaction was poured into water. The precipitate was filtered off, taken up in EtOAc, then filtered and dried in vacuo to yield 31.4g (93%) of intermediate 4 (yellow solid). MP =231 ℃ (DSC).
b-2) preparation of intermediate 5
A mixture of intermediate 4(15.7g, 61.5mmol) and Raney nickel (16g) was placed in CH at a pressure of 3 bar3OH (380ml) and THF (60ml) were hydrogenated overnight. The reaction mixture was filtered over a pad of celite, and the pad of celite was washed with CH3OH/DCM (50/50) was washed 3 times and then several times with a mixture of MeOH/acetone. The combined filtrates were evaporated to dryness to give 13.1g (95%) of intermediate 5 (brown solid). MP =240 ℃ (DSC).
Intermediate 5 may also be prepared using the following method.
To a 200ml stainless steel autoclave, under nitrogen atmosphere, was added intermediate 2(5g, 17.3mmol), NH4OH (100ml) and Cu2O (0.1 g). The autoclave was closed and the reaction was allowed to proceed at a temperature of 150 ℃ for 16 hours. The reaction mixture was extracted with DCM, the organic layer was washed with water and dried (MgSO)4) And (4) filtering. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel (kromasil C18100A 5 μm, Eka nobel; mobile phase: 90% 0.25% aqueous ammonium bicarbonate, 10% MeOH to 100% MeOH). The pure fractions were collected to yield 2.4g (61.6%) of intermediate 5.
c-2) preparation of intermediate 3
The experiment was performed 3 times with the following numbers.
Intermediate 5(2.12g, 9.4mmol), 1-bromo-3, 5-dimethoxybenzene (2.25g, 10.4mmol), sodium tert-butoxide (2.71g, 28.3mmol) and 1,1'- [1, 1' -binaphthyl]-2,2' -diylbis [1, 1-diphenylphosphine]The mixture (0.29g, 0.47mmol) was degassed with nitrogen in ethylene glycol dimethyl ether (40ml) for 10 minutes. Palladium (II) acetate (0.21g, 0.94mmol) was added and the mixture was heated at 135 ℃ for 60 minutes under microwave irradiation. The mixture was cooled to room temperature, poured into water and EtOAc. The 3 experiments were pooled and worked up. The mixture was filtered through celite. The filtrate was extracted with EtOAc. With MgSO4The combined organic layers were dried, filtered and evaporated to dryness to give 11.3g of crude compound. The residue (random SiOH, 20-45 μm, (450g) MATREX; mobile phase 0.1% NH) was purified by silica gel chromatography4OH, 95% DCM, 5% iPrOH). The pure fractions were collected and the solvent was evaporated, yielding 7.6g (74%) of intermediate 3 (brown solid).
a-4) preparation of intermediate 6
Tert-butyldimethylsilyl chloride (2.096g, 13.9mmol) was added to 3-chloro-5-anisole methanol (2g, 11.6mmol) in DCM (40ml) at 0 deg.C, followed by imidazole (2.5g, 36.85 mmol). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was partitioned between EtOAc and water. Separate 2 phases and dry (MgSO)4) The organic phase was filtered and concentrated to give an oil which solidified on standing. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 90 g; mobile phase: 30% EtOAc, 70% pentane). The fractions were collected and the solvent was evaporated, yielding 2.56g (77%) of intermediate 6.
b-4) preparation of intermediate 7
Intermediate 6(1.39g, 3.9mmol), intermediate 5(0.7g, 3.1mmol), Cs2CO3(3g, 0.3mmol), tris (dibenzylideneacetone) dipalladium (0.28g, 0.3mmol) and X-Phos (0.33g, 0.68mmol) were stirred in t-BuOH (20ml) at 100 ℃ for 3 h under microwave irradiation. The reaction mixture was filtered through celite and the filtrate was concentrated to about 1/3 of the initial volume. Water and EtOAc were added and the organic phase was separated and dried (MgSO4) Filtering, and concentrating. The residue was purified by chromatography on silica gel (Hyperprep C18 HS BDS 100A 8mu (Shandon); mobile phase gradient: 70% 0.25% aqueous ammonium bicarbonate/30% CH3CN to 10% of 0.25% aqueous ammonium bicarbonate/90% CH3CN). The pure fractions were collected and the solvent was evaporated, yielding 418mg of intermediate 7.
a-5) preparation of intermediate 8
Intermediate 13 (see below) (9.45g, 29.9mmol), 1- (1-methylethyl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (8.48g, 35.9mmol), potassium phosphate(15.88g, 74.8mmol) and dicyclohexyl (2 ',6' -dimethoxy [1, 1' -biphenyl)]A mixture of-2-yl) phosphine (1.23g, 3.0mmol) was degassed in dioxane (125ml) and water (25ml) at room temperature in a stream of nitrogen. After 10 minutes, Pd (PPh) was added in portions3)4(1.73g, 1.5 mmol). The reaction mixture was then heated at 80 ℃ overnight, then cooled to room temperature and poured into ice water. EtOAc was added and the organic layer was washed with water, then brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (20.2g) was chromatographed on silica gel (random SiOH, 20-45 μm, 1000g MATREX; mobile phase: 95% DCM, 5% MeOH, 0.1% NH)4OH). The product fractions were collected and the solvent was evaporated, yielding 10g (85%) of intermediate 8.
Example A2
Preparation of intermediate 9
NaH (1.77 g; 44.27mmol) was added portionwise to a solution of intermediate 3(8 g; 22.13mmol) in N, N-dimethylformamide (160ml) at 5 ℃ in a stream of nitrogen. The reaction mixture was stirred at 5 ℃ for 1 hour. Then, (2-bromoethoxy) -tert-butyldimethylsilane (9.5 ml; 44.27mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature and stirred overnight. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and solvent evaporation to dryness to give 17g of residue which was purified by silica gel chromatography (random SiOH, 15-40 μm, 200 g; mobile phase gradient: 100% DCM to 96% DCM, 4% MeOH).
The pure fractions were collected and concentrated to yield 11g (95%) of intermediate 9.
Intermediate 9 may also be prepared using the following method.
a) Preparation of intermediate 40
A mixture of 3, 5-dimethoxyaniline (250 g; 1.63mol), cesium carbonate (319 g; 0.98mol) and water (0.33L) was heated to 60 ℃ in 1, 2-dimethoxyethane (2L). 2-chloroethyl chloroformate (carbochloroxidic acid, 2-chloroethyl ester, 250 g; 1.75mol) was then added dropwise at this temperature over 1 hour. A portion of aqueous potassium hydroxide (458 g; 8.2mol) solution (1.3L) was added. The reaction mixture was stirred at 60 ℃ for 30 minutes and then heated at 100 ℃ and 1, 2-dimethoxyethane was distilled off using a Dean-Starck trap. The residue was cooled to 50 ℃ and extracted with methyl-tert-butyl ether (1.14L). The organic layer was washed with water and dried (MgSO)4) Filtered and the filtrate evaporated to dryness. The residue was crystallized from a mixture of methyl-tert-butyl ether and heptane. The precipitate was filtered off and dried to provide 241.8g (75%) of intermediate 40.
b) Preparation of intermediate 41
TBDMSCl (262.7 g; 1.74mol) was added portionwise to a solution of intermediate 40(327.4 g; 1.66mol) and 1H-imidazole (124.3 g; 1.825mol) in DCM (3.3l) at room temperature over 10 minutes under a nitrogen atmosphere. After the reaction was complete, water (3.3L) was added, the organic layer was decanted, washed with water (3.3L), and dried (MgSO)4) Filtration, filtration of the filtrate over silica gel and concentration gave 496g (95.9%) of intermediate 41, which was the crude product used in the next step.
c) Preparation of intermediate 9
Palladium (II) acetate (1.16 g; 5.2mmol), racemic 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (4.4 g; 6.9mmol) in 1, 2-dimethoxyethane (52ml) was added to a solution of intermediate 2(100 g; 346mmol), intermediate 41(118.5 g; 380.5mmol) and cesium carbonate (135 g; 415mmol) in 1, 2-dimethoxyethane (1.4L) at room temperature under an inert atmosphere. The reaction mixture was heated at 80 ℃ for 1 hour, stirred at this temperature for 2 hours, and refluxed overnight. Then, water (0.5L) and DCM (1.5L) were added at room temperature and the organic layer was separated, washed with water and evaporated to dryness to give crude intermediate 9(211g) which was used directly in the next step.
Example A3
Preparation of intermediate 10
Methanesulfonyl chloride (3.8 ml; 49.33mmol) was added dropwise to compound 1(10 g; 24.66mmol) and Et at 5 ℃ under a nitrogen atmosphere3N (8.58 ml; 61.67mmol) in DCM (250 ml). The reaction mixture was stirred at 5 ℃ for 1 hour, then at room temperature for 1 hour. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness (30 ℃). The residue was precipitated by adding DIPE. The solid was filtered and, after drying, 10.09g (94%) of intermediate 10 (red solid) was obtained. MP =161 ℃ (kofler).
Example A4
a-1) preparation of intermediate 11
NaH (1.1 g; 27.67mmol) was added portionwise to a solution of intermediate 3(5 g; 13.83mmol) in N, N-dimethylformamide (80mL) at 5 ℃ in a stream of nitrogen. The reaction mixture was brought to 5 deg.CAfter stirring for 1 hour, (3-bromopropoxy) (1, 1-dimethylethyl) dimethylsilane (6.41ml, 27.67mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature and stirred overnight. The reaction was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtration and evaporation of the solvent to dryness gave a crude residue (9.1 g). Purification by silica gel chromatography (random SiOH, 15-40 μm; mobile phase gradient: 100% DCM to 98% DCM, 2% MeOH) gave, after concentration, 7g (94%) of the pure fraction of intermediate 11.
Intermediate 11 may also be prepared using the following method.
NaH (31.65g, 60% w/w in oil; 0.79 mol) was added portionwise over 15 minutes to a cooled (-2 ℃) solution of intermediate 3(130 g; 0.36 mol) in N, N-dimethylacetamide. The reaction mixture was stirred at-2 ℃ for 30 minutes, then (3-bromopropoxy) (1, 1-dimethylethyl) dimethylsilane (100.2 g; 0.4 mol) was added. The reaction mixture was further stirred at-2 ℃ for 1.5 hours, and after removing the cooling system, it was stirred at room temperature overnight. The reaction mixture was then poured into water (2.5L), DCM (1L) was added and the pH was adjusted to 6 with acetic acid. The layers were separated, the organic layer was washed with water and dried (MgSO)4) Filtration and concentration to dryness afforded 167.2g (87%) of intermediate 11.
Intermediate 11 may also be prepared using the following method.
a-2) preparation of intermediate 12
7-bromo-2 (1H) -quinoxalinone (25 g; 0.11mol), 3, 5-dimethoxyaniline (20.42 g; 0.133mol), sodium tert-butoxide (32 g; 0.333mol), 1'- [1, 1' -binaphthyl]-2,2' -diyl bis[1, 1-Diphenylphosphine](6.9 g; 0.011mol) in ethylene glycol dimethyl ether (400ml) was degassed with nitrogen for 10 minutes. Palladium (II) acetate (2.5 g; 0.011mol) was added and the mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and the solvent was concentrated to 150mL under vacuum. The residue was poured into ice water (1.5L) with stirring and EtOAc (100mL) was added. The suspension was stirred at room temperature overnight, and the precipitate was filtered off, washed with water and then with CH3CN was washed and dried to yield 33g of intermediate 12.
b-2-a) preparation of intermediate 13
Intermediate 12(30 g; 0.1mol) was added portionwise to phosphorus oxychloride (415ml) at room temperature. The reaction mixture was then heated at 80 ℃ and stirred at this temperature for 40 minutes. The mixture was cooled to room temperature and the phosphorus oxychloride was removed in vacuo. Carefully pour the residue at K2CO3In an aqueous solution of (a). The aqueous layer was extracted with DCM. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 450 g; mobile phase: gradient from 100% DCM to 98% DCM, 2% MeOH). The product fractions were collected and the solvent was evaporated, yielding 22.6g (70%) of intermediate 13. MP =137 ℃ (Kofler).
Intermediate 13 may also be prepared using the following method.
b-2-b) N-chlorosuccinimide (11.23 g; 84.08mmol) was added portionwise to PPh3(22.05g, 84.08mmol) in dioxane (500 ml). The reaction mixture was stirred for 30 minutes. Intermediate 12(5 g; 16.8mmol) was added and the reaction mixture was refluxed for 5 hours, then cooled to room temperature and stirred with Et3Basified with N (10 ml). The suspension was stirred overnight and the insoluble material was removed by filtration. The filtrate was concentrated and the residue (35g) was chromatographed on silica gel (random SiOH, 15-40 μm, 400 g; mobile phase 100% DCM). The pure fractions were collected and evaporated to dryness to yield 2g (37%) of intermediate 13.
c-2) preparation of intermediate 14
NaH (1.48 g; 37.1mmol) was added portionwise to a solution of intermediate 13(9 g; 28.50mmol) in DMF (100mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, and then (3-bromopropoxy) (1, 1-dimethylethyl) dimethylsilane (8.58 ml; 37.1mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature and stirred for 4 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (17.5g) was purified by chromatography on silica gel (random SiOH, 20-45 μm, 1000g, MATREX; mobile phase: 98% DCM, 2% cyclohexane). The pure fractions were collected and the solvent was evaporated, yielding 13.3g (95%) of intermediate 14.
d-2) preparation of intermediate 11
Intermediate 14(15.5 g; 31.8mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (9.9 g; 47.6mmol), potassium phosphate (13.5 g; 63.5mmol) and dicyclohexyl (2 ',6' -dimethoxy [1, 1' -biphenyl)]-2-yl) phosphine (1.3 g; 3.2mmol) was stirred in dioxane (380ml) and water (150ml) at room temperature under nitrogen atmosphere. After 10 minutes, Pd acetate was added in portions at room temperature under a nitrogen atmosphere2(dba)3(1.45 g; 1.6 mmol). The reaction mixture was heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was filtered through celite. Celite was washed with DCM. With saline waterThe organic layer was washed and dried (MgSO)4) Filtration and evaporation of the solvent gave 21g (99%) of intermediate 11.
Example A5
a) Preparation of intermediate 15
Methanesulfonyl chloride (3.53ml, 45.77mmol) was added dropwise to a solution of compound 3(9.6g, 22.88mmol) and triethylamine (7.96ml, 57.21mmol) in DCM (250ml) at 5 deg.C under nitrogen. The reaction mixture was stirred for 1 hour and the temperature was raised to room temperature. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The crude residue was taken up in DIPE. The precipitate was filtered off and, after drying, 10.5g (92%) of intermediate 15 were obtained.
b) Preparation of intermediate 16
Methanesulfonyl chloride (0.97ml, 12.52mmol) was added dropwise to compound 2(0.98g, 2.50mmol) and Et at 5 ℃ under nitrogen atmosphere3N (2.09ml, 15.02mmol) in DCM (50 ml). The mixture was stirred at room temperature for 3 hours. The solution was evaporated at room temperature to give 1.38g of intermediate 16. The residue was used in the next step without purification.
c) Preparation of intermediate 143
Methanesulfonyl chloride (519 μ L, 6.7 mmol) was added dropwise to a solution of compound 389(1.5g, 3.35 mmol), triethylamine (1.2 mL, 8.4mmol), 4-dimethylaminopyridine (40.95 mg, 0.335 mmol) in DCM (50mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and then at room temperature for 36 hours. Water and DCM were added, the organic layer was washed with water and dried (MgSO4) Filtered and the solvent evaporated. The residue was taken up in acetonitrile and Et2And (4) crystallizing the O. The resulting solid was filtered and dried to yield 622 mg (35%) of intermediate 143 as a yellow solid.
Example A6
a-1) preparation of intermediate 17
NaH (16.88 g; 0.42mol) suspended in heptane was slowly added at 0 ℃ to a solution of intermediate 17a (100 g; 0.201mol) and N- (2,2, 2-trifluoroethyl) -carbamic acid 1, 1-dimethylethyl ester (48.03 g; 0.241mol) in N, N-dimethylacetamide (1L). The reaction mixture was stirred at 0 ℃ for 1 hour, warmed to room temperature over 1 hour, and stirred at room temperature for 5 hours. The reaction mixture was carefully quenched with water (1L) and the solution was extracted twice with DCM. The combined organic layers were washed with water, decanted, and evaporated to dryness. The residue was dissolved in toluene, the organic layer was washed with water and evaporated to dryness to afford 147g of intermediate 17, which was used in the next step without further purification.
Intermediate 17 may also be prepared using the following method.
a-2) NaH (1 g; 24.94mmol) was added portionwise to intermediate 3(4.5 g; 12.47mmol) and intermediate 69(5.02 g; 14.96mmol) in DMF (47 ml). The reaction mixture was heated at 60 ℃ for 1 hour, thenAfter cooling to room temperature, poured into ice water and extracted with EtOAc. The organic layer was decanted, washed with water, then brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue was combined with a similarly prepared product fraction (using 1.4g of intermediate 3) and then chromatographed on silica gel (random SiOH, 15/40 μm), mobile phase gradient: 99% DCM/1% CH3OH to 97% DCM/3% MeOH). The pure fractions were collected and evaporated to dryness to yield 5.8g (77%) of intermediate 17. MP =113 ℃.
Example A7
a) Preparation of intermediate 18
NaH (830 mg; 20.75mmol) was added portionwise to a solution of intermediate 3(5 g; 13.84mmol) in N, N-dimethylformamide (150mL) at 5 ℃ in a stream of nitrogen. The reaction mixture was stirred at 5 ℃ for 1 hour, then 2- (3-bromopropoxy) tetrahydro-2H-pyran (3.5 ml; 20.75mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature. The reaction was stirred at room temperature for 4 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 8.46 g of intermediate 18.
Example A8
a) Preparation of intermediate 19
NaH (882 mg; 22.04mmol) was added portionwise to a solution of intermediate 13(5.8 g; 18.4mmol) in DMF (100mL) at 5 ℃ under nitrogen. The reaction mixture was stirred for 20 minutes and (bromomethyl) cyclopropane (2.2 ml; 22.04mmol) was added dropwise. The mixture was stirred at 5 ℃ for another 20 minutes and then at room temperature for 1.5 hours. The reaction mixture was poured into water and extracted with EtOAc. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to yield 6.7g (98%) of intermediate 19.
b) Preparation of intermediate 20
A mixture of intermediate 19(3 g; 8.1mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (2.86 g; 9.7mmol), potassium phosphate (3.44 g; 16.2mmol), 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (0.33 g; 0.811mmol) was stirred in dioxane (60ml) and water (6ml) at room temperature under a nitrogen atmosphere. After 10 minutes, tris (dibenzylideneacetone) dipalladium (0.3 g; 0.41mmol) was added portionwise at room temperature and the mixture was heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc was added and the mixture was filtered through a layer of celite. The celite was washed with EtOAc, then the filtrate was extracted with EtOAc, washed with brine, and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 0.05% NH)4OH, 99% DCM, 1% iPrOH). The pure fractions were collected and evaporated to dryness to yield 1.48g (36%) of intermediate 20。
Example A9
a-1) preparation of intermediate 21
7-bromo-2-chloroquinoxaline (10g, 41.1mmol), 1- (tetrahydro-2H-pyran-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (11.42g, 41.1mmol), 2M sodium carbonate (20.5ml, 41.1mmol) in ethylene glycol dimethyl ether (100ml) were degassed with nitrogen for 15 minutes and Pd (PPh) was added3)4(1.4g, 1.2mmol) and heated at reflux for 20 h. The reaction mixture was cooled to room temperature and poured into water and EtOAc. The precipitate was filtered and dried in vacuo to yield 12g (84%) of intermediate 21.
Intermediate 21 may also be prepared using the following method.
a-2) trifluoroacetic acid (5.55 μ l; 0.075mmol) was added dropwise to 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (410 mg; 1.5mmol) and 3, 4-dihydro-2H-pyran (0.16 ml; 1.8mmol) in toluene (4ml) and the reaction mixture was heated to 60 ℃ for 2 days, then cooled to room temperature and evaporated to dryness to give 550mg of intermediate 21.
b) Preparation of intermediate 22
Intermediate 21(1.5 g; 4.2mmol), aniline (0.58 ml; 6.23mmol), sodium tert-butoxide (1.2 g; 12.5mmol) and 1,1'- [1, 1' -binaphthyl]-2,2' -diylbis [1, 1-diphenylphosphine](260 mg; 0.42mmol) of the mixture in ethylene glycol dimethyl ether (45ml) was degassed with nitrogen for 30 minutes and then palladium (II) acetate (93.7 mg; 0.42 m) was addedmol). The reaction mixture was refluxed for 4 hours. Water/ice was added and the product was extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl solution and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The crude product was purified by silica gel chromatography (random SiOH, 15-40 μm, 90 g; mobile phase gradient: 99% DCM/1% MeOH to 97% DCM/3% MeOH/0.1% NH)4OH). The pure fractions were collected and the solvent was evaporated to dryness to yield 1.1g (70%) of intermediate 22. A portion (0.7g) was repurified by silica gel chromatography (Sunfire silica 5 μm150x30.0 mm; mobile phase gradient: 100% DCM to 0.4% NH)4OH，96% DCM，4% CH3OH). The pure fractions were collected and the solvent was evaporated to dryness to yield 0.071g (4.5%) of intermediate 22.
c) Preparation of Compound 123
NaH (116.3 mg; 2.9mmol) was added portionwise to a solution of intermediate 22(0.9 g; 2.4mmol) in DMF (14mL) at 5 ℃. The reaction mixture was stirred for 30 minutes. (bromomethyl) cyclopropane (0.28 mL; 2.9mmol) was added dropwise and the reaction mixture was stirred at 5 ℃ for 1 hour and then at room temperature overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with saturated aqueous NaCl solution and dried (MgSO)4) Filtered and the solvent evaporated to dryness. Purification of the crude product by silica gel chromatography (random SiOH, 30g, 15-40 μm; mobile phase: 98% DCM/2% CH)3OH). The pure fractions were collected and the solvent was evaporated to dryness to yield 0.5g (48%) of the compound. A portion (0.4g) was repurified by silica gel chromatography (spherical SiOH, 10 μm, 60g, PharmPrep MERCK; mobile phase: 99% DCM, 1% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 85mg (8%) of compound 123.
d) Preparation of Compound 54
HCl/i-PrOH (80 μ l 5/6N; 0.4mmol) was added to CH of compound 123(85 mg; 0.2mmol) at 5 deg.C3OH (5mL) solution. The reaction mixture was stirred at 5 ℃ for 4 hours. Diethyl ether (8mL) was added and the mixture was stirred for 30 min, then the precipitate was filtered and dried in vacuo to give 58mg (71%) of compound 54. MP =138 ℃ (Kofler).
e) Preparation of intermediate 23
The reaction was carried out under nitrogen atmosphere. NaH (0.058 g; 1.46mmol) was added portionwise to a solution of compound 54(0.25 g; 0.73mmol) in DMF (5mL) at 5 ℃. The reaction mixture was stirred for 30 minutes, then 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.23 ml; 1.46mmol) was added dropwise and the reaction mixture was further stirred at room temperature overnight. The reaction mixture was poured into aqueous potassium carbonate and extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. Purification of the crude product by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.1% NH)4OH，99% DCM，1% CH3OH). The pure fractions were collected and the solvent was evaporated to dryness to yield 250mg (72%) of intermediate 23.
Preparation of intermediate 691 according to an analogous procedureFor the preparation of compound 691 according to B14A:
the experiment was performed 4 times with the following numbers.
Compound 137(HCl salt) (2 g; 4.6mmol), 2-bromoethoxy-tert-butyldimethylsilane (1.3 mL; 7.4 mmol) and K2CO3(1.3 g; 9.3 mmol) in CH3CN (80mL) at 80 ℃ for 24 hours. The reaction was poured into ice water and EtOAc was added. The organic layers were combined, separated, washed with brine,drying (MgSO)4) Filtered and the solvent evaporated. The residue (12.3g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 450; mobile phase gradient: 0.5% NH)4OH, 97% DCM, 3% MeOH to 0.5% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated to yield 6g of intermediate 691.
Example A10
Preparation of intermediate 24
To a solution of intermediate 65(1.1 g; 2.25mmol) in THF (15ml) and water (15ml) was added lithium hydroxide monohydrate (0.34 g; 4.5 mmol). The reaction mixture was stirred at room temperature overnight. THF was evaporated, water and HCl were added. The precipitate was filtered off and dried to yield 976mg (94%) of intermediate 24.
Example A11
Preparation of intermediate 25
Intermediate 2(1 g; 0.35mmol), cyclopropylmethylamine (0.51g, 6.9mmol), 1'- [1, 1' -binaphthyl]-2,2' -diylbis [1, 1-diphenylphosphine]A solution of (0.215g, 0.35mmol) and sodium tert-butoxide (1.0g, 10.4mmol) in ethylene glycol-dimethyl ether (15ml) was degassed with nitrogen for 10 minutes. Palladium (II) acetate (47% Pd) (77.6mg, 0.35mmol) was then added and the reaction heated to 135 ℃ under microwave irradiation for 30 minutes. The reaction mixture was cooled to room temperature and then poured into K2CO3In aqueous solution and extracted with EtOAc. The organic layers were combined and dried (MgSO)4) Filtration ofAnd (5) drying by distillation. The residue was chromatographed on silica gel (random SiOH, 15-40 μm; mobile phase: gradient from 10% DCM to 95% DCM/5% MeOH/0.1% NH)4OH). The pure fractions were collected and evaporated, yielding 710mg (74%) of intermediate 25. MP =149 ℃ (kofler).
Example A12
a) Preparation of intermediate 26
Methanesulfonyl chloride (61 μ L, 0.78mmol) was added dropwise to compound 24(0.13g, 0.26mmol), Et at 5 ℃ under nitrogen atmosphere3N (0.18mL, 1.3mmol) in DCM (10 mL). The solution was stirred at 10 ℃ for 1.5 hours. The solution was poured into ice water, the organic layer was extracted and dried (MgSO)4) Evaporated to dryness at room temperature to give 137 mg of intermediate 26.
b) Preparation of intermediate 27
Mixing the intermediate 26(0.31 g; 0.0006mol), phthalimide (0.17 g; 0.0012mol) and K2CO3A solution of (0.21 g; 0.0015mol) 1-methyl-2-pyrrolidone (10ml) was heated at 150 ℃ for 15 hours. The mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in DCM and then K was added2CO3Aqueous solution (10%). The organic layer was separated and dried (MgSO)4) Filtering and evaporating to dryness. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 0.1% NH)4OH/99% DCM/1% MeOH). The product fractions were collected and the solvent was evaporated, yielding 212mg (63%) of intermediate 27.
Example A13
a) Preparation of intermediate 28
Hydrazine monohydrate (2.57ml, 0.083mol) was added to a solution of compound 65(3.71g, 8.29mmol) in EtOH (35 ml). The mixture was stirred at reflux overnight. Hydrazine monohydrate (2.57ml, 0.083mol) was added again and the mixture was refluxed for 15 hours. After cooling to room temperature, the precipitate was filtered off, washed with EtOH and dried to yield 2.6g (72%) of intermediate 28.
Example A14
a) Preparation of intermediate 29
NaH (0.077 g; 2mmol) was added portionwise to a solution of compound 107(0.63 g; 1.2mmol) in DMF (10 ml). The mixture was stirred at 10 ℃ for 60 minutes, then ethyl bromoacetate (0.16ml, 1.45mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with water, brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue (1g) was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.55g (75%) of intermediate 29.
Example A15
a) Preparation of intermediate 30
Mixing intermediate 2(700 mg; 2.4mmol), intermediate 39(781 mg; 2.66mmol), sodium tert-butoxide (698 mg; 7.3mmol), 1'- [1, 1' -binaphthyl]-2,2' -diylbis [1, 1-diphenylphosphine](151 mg; 0.24mmol) of the mixture was degassed in dioxane (12ml) at room temperature under nitrogen. After 10 minutes, at room temperature under nitrogen atmosphereTo this was added palladium (II) acetate (109 mg; 0.48 mmol). The reaction was allowed to proceed under microwave irradiation at 130 ℃ for 1 hour. The reaction mixture was poured into ice water and filtered through celite. Celite was washed with DCM. The organic layer was decanted and dried (MgSO)4) Filtering and evaporating. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 0.1% NH)4OH, 97% DCM, 3% iPrOH). The product fractions were collected and the solvent was evaporated, yielding 320mg (26%) of intermediate 30.
b) Preparation of intermediate 31
Intermediate 30(300mg, 0.598mmol) was stirred in HCl (3N) (10.96ml, 33mmol) and THF (10ml) at 65 ℃ for 2h then at 70 ℃ for 6 h and poured onto ice. By K2CO3The solution was made basic by powdering and extracted with DCM. Drying (MgSO)4) The organic layer was filtered and evaporated to yield 270mg (98%) of intermediate 31.
Example A16
a) Preparation of intermediate 32
Acetic anhydride (3.24ml) was added portionwise over ten minutes to a stirred suspension of 3, 5-dimethoxyaniline (5g, 32.64mmol) in toluene (25 ml). After stirring at room temperature for 17 hours, petroleum ether was added and the precipitate was collected by suction filtration and dried in vacuo. The crude product (6.1g, 96%) was used in the next step without further purification.
b) Preparation of intermediate 33
N- (3, 5-dimethoxy-phenyl) -acetamide (intermediate 32) (15g, 76.8mmol)Dissolved in acetic acid (50 ml). The solution was cooled to 0 ℃ and 32% aqueous hydrochloric acid (41ml, 461mmol) was added. Aqueous sodium chlorate (3.5g, 33mmol) solution (4ml) was added. The mixture was stirred at 0 ℃ for 30 minutes. The reaction mixture was poured into ice and water and washed with K2CO3The powder makes it alkaline. The precipitate was filtered off and washed with water.
The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 80% DCM, 20% EtOAc) to give 8.8g (50%) of intermediate 33.
c) Preparation of intermediate 34
Potassium hydroxide (10.7g, 192mmol) was added to a solution of N- (2-chloro-3, 5-dimethoxy-phenyl) -acetamide (intermediate 33) (8.8g, 38.3mmol) in EtOH (500ml) and water (50ml) and the reaction mixture was heated to reflux for 18 h. Once cooled, water (approximately 30ml) was added and EtOH was removed in vacuo. The residue was then partitioned between water and diethyl ether. The organic layer was separated and dried (MgSO)4) Filtration and concentration gave 7g (97%) of intermediate 34 (white solid).
Example A17
Preparation of intermediate 35
A mixture of 2, 4-dimethoxy-6-nitrotoluene (2g, 10.1mmol) and nickel (2g) was hydrogenated in MeOH (30ml) under a pressure of 3 bar for 6 hours. The product was filtered through a pad of celite, which was washed 3 times with a solution of MeOH/DCM (50/50). The combined filtrates were evaporated to dryness to yield 1.68g (99%) of intermediate 35.
Example A18
a) Preparation of intermediate 36
A mixture of 3-amino-5-methoxy-benzoic acid (300mg, 1.8mmol), 1-hydroxybenzotriazole (292mg, 2.1mmol), N-ethyl-N' - β -dimethylaminocarbodiimide hydrochloride (413mg, 2.1mmol) and ethylamine (2.7ml, 5.4mmol, 2M in MeOH) was stirred in dimethylformamide (6ml) at room temperature overnight2SO4) And (4) concentrating. The residue was purified by column chromatography on silica gel eluting with 2% MeOH/DCM. The desired product fractions were collected and the solvent was evaporated, yielding 150mg (43%) of intermediate 36 (colorless oil).
b) Preparation of intermediate 135
A mixture of 3-amino-5-fluorobenzoic acid (10 g; 64.5 mmol), methylamine/THF (96.7 mL; 193.4 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (14.8 g; 77.4 mmol), 1-hydroxybenzotriazole (10.5 g; 77.4 mmol) was stirred in N, N-dimethylformamide (150mL) at room temperature for 18 h. The reaction mixture was poured into 1N sodium hydroxide solution and DCM was added. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated.
The aqueous layer was neutralized with concentrated HCl and extracted with EtOAc. The organic layer was separated and dried (MgSO)4) Filtered and evaporated to dryness to give 5g of 3-amino-5-methoxy-N-methyl-benzamide (intermediate 135).
Example A19
Preparation of intermediate 37
A solution of deoxyfluor in toluene (0.478 mmol; 0.176ml) was added dropwise to a solution of compound 124(0.159 mmol; 90mg) in DCM (8ml) at 5 ℃ under a nitrogen atmosphere. After 5 minutes, EtOH (one drop) was added. The mixture was stirred at 5 ℃ for 1 hour and then at room temperature overnight. The reaction mixture was poured into ice water and DCM was added. With 10% K2CO3The mixture was basified and the organic layer was separated, washed with brine and dried (MgSO4) Filtered and the solvent evaporated. The residue obtained (0.090g) was purified by silica gel column chromatography (random SiOH, 15/40 μm, 30 g; mobile phase gradient: 100% DCM to 97% DCM/3% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.070g, 77%) was treated with diethyl ether/CH3CN crystallization, filtration and vacuum drying gave 0.055g (60%) of intermediate 37.
Example A20
Preparation of intermediate 38
In a round bottom flask, 3, 5-dimethoxyaniline (500mg, 3.26mmol), 3-oxetanone (588mg, 8.16mmol) and acetic acid (374 μ l, 6.53mmol) were diluted in MeOH (21 ml). The reaction mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (410mg, 6.53mmol) in MeOH (5mL) was added, and the reaction mixture was stirred at room temperature overnight. Then, 3N NaOH (15ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between water and DCM. The organic layer was dried (MgSO4) Filtering, and concentrating. The residue (1g) was purified by chromatography on silica gel (random SiOH, 15-40 μm; mobile phase: 100% DCM). The target fraction was collected and the solvent was evaporated, yielding 377mg (55%) of intermediate 38 (colorless oil).
Example A21
Preparation of intermediate 39
Sodium cyanoborohydride (4.55g, 72.5mmol) was added to CH 3, 5-dimethoxyaniline (3.7g, 24.15mmol), 1, 4-cyclohexanedione monoethylene glycol ketal (15g, 96.6mmol) and acetic acid (5.5ml, 96mmol) at room temperature3CN (50ml) solution (exotherm observed). The reaction mixture was stirred overnight. Adding NaHCO3Aqueous solution, and the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine and dried (MgSO)4) Filtering and drying. The residue (21g) (random SiO) was purified by silica gel column chromatography215-40 μm, 90 g; mobile phase gradient: 100% DCM to 7% CH3OH/93% DCM). The pure fractions were collected and evaporated to dryness to give 4.2g (59%) of intermediate 39.
Example A22
Preparation of intermediate 42
3-bromo-5-methoxyphenol (3.12 g; 15.4 mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (2.66 mL; 16.9 mmol) and K2CO3(1.63 g; 11.8 mmol) of CH3The CN (40mL) solution was heated at 80 ℃ overnight. The solution was cooled and the mixture poured into cooled water, the product extracted with EtOAc, the organic layer washed with water, dried (MgSO)4) Filtered and evaporated to dryness (5.5 g). The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 200 g; mobile phase: 80% cyclohexane, 20 EtOAc). The product fractions were collected and the solvent was evaporated, yielding 3.7g (73%) of intermediate 42.
Example A23
Preparation of intermediate 43
Sodium hydride (1.03g, 25.86 mmol) was added portionwise to a solution of 3-bromo-5-methoxyphenol (3.5g, 17.24 mmol) in DMF (20mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 0.5 h, then deuterated iodomethane (1.29mL, 20.69 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature and stirred for 2 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 4g of intermediate 43 which was used in the next step without further purification.
Example A24
Preparation of intermediate 44
3-bromo-5-methoxyphenol (2g, 9.85 mmol), 1-bromo-2-fluoroethane (1.56g, 0.012mol) and K2CO3(1.4g, 10mmol) of CH3The CN (30mL) solution was heated at 80 ℃ overnight. The solution was cooled and the mixture poured into chilled water and treated with Et2And O, extracting a product. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to give 2.27 g of intermediate 44, which was used in the next step without further purification.
Example A25
Preparation of intermediate 45
Hunig's base (9.64 ml; 55.16 mmol) was added to a solution of 3-bromo-5-methoxyphenol (5.6g, 27.58 mmol) in THF (100ml) at 10 ℃ under a nitrogen atmosphere. 2-Methoxyethoxymethyl chloride (CAS 3970-21-6) (6.3 mL, 55.16 mmol) was added and the solution was stirred at room temperature overnight. The solution was poured into cooled water and the product was extracted with EtOAc. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to give 8g (99.6%) of intermediate 45 which was used in the next step without further purification.
Example A26
Preparation of intermediate 46
3-bromo-5-methoxyphenol (0.3g, 1.5mmol), isopropyl iodide (0.21 mL, 1.6mmol) and K2CO3(1.63g, 12 mmol) of CH3The CN (20ml) solution was heated at 80 ℃ for 24 hours. The solution was cooled and the mixture poured into cooled water and the product extracted with EtOAc. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness to give 350mg (97%) of intermediate 46, which was used in the next step without further purification.
Example A26A
Preparation of intermediate 136
NaH (0.74 g; 18.4mmol) was added portionwise to a solution of (3-chloro-5-methoxyphenyl) methanol (2.9 g; 16.7 mmol) in N, N-dimethylformamide (30mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour. Then, ethyl iodide (0.96 mL; 12.0 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture is warmedBrought to room temperature and stirred for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 0.8g (25%) of intermediate 136.
Example A27
a) Synthesis of intermediate 66
A mixture of (3-bromopropoxy) -tert-butyldimethylsilane (20 g; 79mmol) and 2,2, 2-trifluoroethylamine (31 ml; 395mmol) was heated in DMSO (140ml) at 80 ℃ for 18 hours. The reaction mixture was cooled to room temperature, water was added and the mixture was taken up in Et2And (4) extracting. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to give 19.5g (91%) of intermediate 66.
b) Synthesis of intermediate 67
Di-tert-butyl dicarbonate (7.96; 36.5mmol), triethylamine (6 ml; 43.11mmol) and N, N-dimethyl-4-aminopyridine (202 mg; 1.7mmol) were added to a solution of intermediate 66(9 g; 33.16mmol) in DCM (90 ml). The reaction mixture was stirred at room temperature for 2 hours and diluted with DCM and water. The organic layer was decanted, followed by water, HCl solution (0.5N) and K2CO3Aqueous (10%) wash. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to give 11.3g (92%) of intermediate 67.
c) Synthesis of intermediate 68
A mixture of intermediate 67(10.8 g; 29.1mmol) and tetrabutylammonium fluoride (34.9 mL, 1M solution in THF; 34.9mmol) in THF (80mL) was placed in a chamberStir at room temperature overnight. Water was added and the reaction mixture was extracted with DCM. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 80 g; mobile phase: gradient from 99% DCM, 1% MeOH to 96% DCM, 4% MeOH). The pure fractions were collected and evaporated to dryness to give 3.65g (49%) of intermediate 68.
d) Synthesis of intermediate 69
Methanesulfonyl chloride (431 μ L; 5.8mmol) was added dropwise to a solution of intermediate 68(1 g; 3.9mmol) and triethylamine (811 μ L; 5.8mmol) in DCM (15ml) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness and the resulting intermediate 69 was used in the next step without further purification.
Example A28
a) Preparation of intermediate 70
The experiment was performed 5 times with the following numbers.
NaH (0.25 g; 5.4 mmol) was added portionwise to a solution of 2-amino-isobutanol (1.54 mL; 16.1 mmol) in N, N-dimethylformamide (12mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 15 minutes. Then, compound 76(1.4 g; 3.35 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and solvent evaporation to dryness to give 10.5g of residue which was purified by silica gel chromatography (random SiOH, 15-40 μm, 300 g; mobile phase: 1% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated to give 3.6g of (C42%) intermediate 70.
b) Preparation of intermediate 71
Di-tert-butyl dicarbonate (0.24 g; 1.1mmol) is added to intermediate 70(0.62 g; 1.1mmol) and NaHCO3(0.19 g; 2.3 mmol) in dioxane (15mL) and water (15 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The residue (0.8g) (SiOH, 5 μm, 150x30 mm; mobile phase: 0.2% NH) was purified by silica gel chromatography4OH, 98% DCM, 2% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 0.59g (85%) of intermediate 71.
c) Preparation of intermediate 72
Methanesulfonyl chloride (0.96 mL; 12.4mmol) was added dropwise to a solution of intermediate 71(2.7 g; 4.45mmol) and triethylamine (1.86 mL; 13.35 mmol) in DCM (25mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred for 18 hours and the temperature was raised to room temperature. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The residue (4.1g) was purified by silica gel chromatography (random SiOH, 20-45 μm, 450 g; mobile phase: 0.2% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 3g (100%) of intermediate 72.
d) Preparation of intermediate 73
Trifluoroacetic acid (0.97 mL; 13.1 mmol) was added to a solution of intermediate 72(0.6 g; 0.87 mmol) in DCM (12.5 mL) at 0 deg.C. The reaction was stirred at room temperature for 1 hour. Will be provided withThe mixture was poured into ice water and DCM was added. With NaHCO3Basifying the mixture with a solution and separating the organic layer with MgSO4Drying, filtration and evaporation of the solvent gave 597 mg of intermediate 73, which was used in the next step without further purification.
Example A29
Preparation of intermediate 74
Methanesulfonyl chloride (3.32 mL; 42.9 mmol) was added dropwise to a solution of compound 606(6 g; 14.3 mmol) and triethylamine (10 mL; 71.5 mmol) in DCM (240 mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and warmed to room temperature for 1 hour. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 9.6g of intermediate 74 which was used in the next step without further purification.
Example A30
a) Preparation of intermediate 75
NaH (11.4 g; 82.5 mmol) was added portionwise to a solution of 4,4,5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1,3, 2-dioxaborolane (4 g; 20.6 mmol) in acetone (60mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 15 minutes. Then, 2-bromo-N-methylacetamide (6.3 g; 41.3 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 65 ℃ for 24 hours. The reaction mixture was cooled to room temperature. The precipitate was filtered off and washed with DCM. The filtrate was evaporated to dryness, taken up in DIPE/diethyl ether and stirred at room temperature for 15 min. The precipitate was filtered off and washed with DCM. The filtrate was evaporated to dryness to give 9g of intermediate 75, which was used in the next step without further purification.
b) Preparation of intermediate 76
Intermediate 14(5.7 g; 11.7 mmol), intermediate 75 (N-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-acetamide) (6.2 g; 23.5 mmol), potassium phosphate (7.5 g; 35.2mmol) and dicyclohexyl (2 ',6' -dimethoxy [1, 1' -biphenyl)]-2-yl) phosphine (0.482 g; 1.2mmol) was stirred in dioxane (140mL) and water (60mL) at room temperature under nitrogen atmosphere. After 10 minutes, Pd was added in portions at room temperature under a nitrogen atmosphere2(dba)3(1 g; 1.2 mmol). The reaction mixture was heated at 80 ℃ for 4 hours. The reaction mixture was cooled to room temperature and poured into ice water. The mixture was filtered through a pad of celite and washed with DCM. The organic layer was washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (8.3g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and concentrated to yield 3.5g (51%) of intermediate 76.
Example A31
Preparation of intermediate 77
Methanesulfonyl chloride (0.73 mL; 9.4mmol) was added dropwise to a solution of compound 614(1.5 g; 3.15 mmol) and triethylamine (2.2 mL; 15.7 mmol) in DCM (40mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and warmed to room temperature for 1 hour. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and evaporated to drynessSolvent, 2.5g of intermediate 77 was obtained, which was used in the next step without further purification.
Example A32
a) Preparation of intermediate 78
NaH (0.44 g; 10.9 mmol) was added portionwise to a solution of 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (1.5 g; 5.45 mmol) in N, N-dimethylformamide (40mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 15 minutes. N- (3-bromopropyl) -1, 1-dimethylethyl carbamate (2.6 g; 10.9 mmol) was then added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with water, diethyl ether and dried (MgSO)4) Filtration and evaporation gave 1.3g of intermediate 78 which was used in the next step without further purification.
b) Preparation of intermediate 79
Palladium acetate (0.11 g; 0.48mmol), racemic 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (0.3 g; 0.48mmol) were added to intermediate 41(3.3 g; 10.6 mmol), intermediate 78(4.2 g; 9.63 mmol) and cesium carbonate (3.8 g; 11.6mmol) of dimethoxyethane (50 mL). The reaction mixture was stirred at 85 ℃ for 3 days. The reaction mixture was cooled to room temperature, poured into ice water and 10% K was added2CO3And EtOAc. The mixture was filtered through a pad of celite. The organic layer was washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (8.5g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). Collecting pure fraction, concentratingThis gave 3.3g (52%) of intermediate 79.
c) Preparation of intermediate 80
A solution of 1M tetrabutylammonium fluoride in THF (5.5 mL; 5.5 mmol) was added dropwise to a solution of intermediate 79(3.3 g; 5mmol) in THF (60mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and EtOAc was added. With 10% K2CO3The mixture was basified and the organic layer was separated, washed with brine and dried (MgSO4) Filtering and evaporating the solvent. The residue was taken up in diethyl ether/CH3And (4) crystallizing CN. The precipitate was filtered off and dried in vacuo to afford 2g (73%) of intermediate 80.
d) Preparation of intermediate 81
Methanesulfonyl chloride (0.85 mL; 10.9 mmol) was added dropwise to a solution of intermediate 80(2 g; 3.65 mmol) and triethylamine (2.54 mL; 18.2 mmol) in DCM (50mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and warmed to room temperature for 2 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 2.5g of intermediate 81 which was used in the next step without further purification.
e) Preparation of intermediate 82
A mixture of intermediate 81(2.5 g; 4mmol) and isopropylamine (5.2 mL; 59.9 mmol) was heated in acetonitrile (25mL) at 100 ℃ for 18 hours in a sealed vessel. The reaction mixture was cooled to room temperature. The reaction was poured into ice water and EtOAc was added. Separating the organic layer with NaHCO3Washing with the solution, and dryingDried (MgSO)4) Filtered and evaporated to dryness. The residue (3g) was chromatographed on silica gel (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated to yield 1.1g (47%) of intermediate 82.
Example A33
a) Preparation of intermediate 83
A mixture of 5-bromo-benzene-1, 3-diol (7.3 g; 38.6 mmol), cesium carbonate (37.75 g; 115.9 mmol) and iodomethane-D3 (4.8 mL; 77.25 mmol) was placed in CH3CN (150mL) at 80 ℃ for 18 hours. The reaction mixture was cooled to room temperature, poured into ice water and EtOAc was added. The organic layer was washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 5.3 g of intermediate 83, which was used in the next step without further purification.
b) Preparation of intermediate 84
A solution of palladium acetate (0.21 g; 0.9 mmol), racemic 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (0.57 g; 0.9 mmol) was added to a solution of intermediate 5(2 g; 10.6 mmol), intermediate 83(2.45 g; 11mmol) and sodium tert-butoxide (2.64 g; 27.4 mmol) in dioxane (150mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 100 ℃ for 4 days. The reaction mixture was cooled to room temperature, poured into ice water and EtOAc was added. The mixture was filtered through a pad of celite. The organic layer was washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (6g) was chromatographed on silica gel (random SiOH, 15-40 μm, 300 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated.
The residue (4g) was crystallized from diethyl ether. The precipitate was filtered off and dried in vacuo to afford 3.6g (90%) of intermediate 84. MP: 198 Deg.C (DSC).
c) Preparation of intermediate 85
NaH (0.107 g; 2.69 mmol) was added portionwise to intermediate 84(0.49 g; 1.35 mmol) in N, N-dimethylformamide (10 mL). The reaction mixture was stirred at 5 ℃ for 1 hour. Then, a solution of deuterated (2-bromoethoxy) (1, 1-dimethylethyl) dimethyl-silane (deuterated form of CAS 86864-60-0; prepared using deuteration methods known in the art) (0.65 g; 2.7 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 0.88 g of intermediate 85, which was used in the next step without further purification.
Example A34
Preparation of intermediate 86
Methanesulfonyl chloride (0.17mL, 2.1mmol) was added dropwise to a solution of compound 617(0.294g, 0.7mmol) and triethylamine (0.49 mL, 3.5mmol) in DCM (5mL) at 5 ℃ under nitrogen. The reaction mixture was stirred at 5 ℃ for 1 hour and warmed to room temperature for 1 hour. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 0.45 g of intermediate 86 which was used in the next step without further purification.
Example A35
Preparation of intermediate 87
Compound 4(1.3 g; 2.9mmol), N- (3-bromopropyl) phthalimide (phtalimide) (1.56 g; 5.8mmol) and K2CO3(0.805 g; 5.8mmol) in CH3CN (100mL) was stirred at 80 ℃ for 48 hours. The reaction mixture was cooled to room temperature, poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (0.566g) was purified by silica gel chromatography (SiOH, 15-40 μm, 50 g; mobile phase: 0.1% NH)4OH, 96% DCM, 4% MeOH). The product fractions were collected and the solvent was evaporated, yielding 1.26g (34%) of intermediate 87.
Example A36A
Preparation of intermediate 88
Intermediate 88b(see A4c-2) (0.53 g; 1.1mmol), 1,3, 5-trimethyl-4- (tributylstannyl) -1H-pyrazole (Synthesis, (13), 1949-1958; 2001) (1.33 g; 3.33 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.064 g; 0.055 mmol) were stirred in toluene (3 mL) at 160 ℃ for 40 minutes (using a single mode microwave (Biotage)). The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by chromatography on silica gel (random SiOH, 40 μm; mobile phase gradient: 90% DCM, 10% heptane to 100% DCM, then 99% DCM, 1% MeOH). The pure fractions were collected and concentrated to yield 0.41 g (68%) of intermediate 88.
Intermediate 88bTo a solution of intermediate 88b (2.742mmol;1.30g) in THF (25ml) was added dropwise a solution of tetrabutylammonium fluoride (3.016 mmol; 3.016 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, EtOAc was added, and the organic layer was separated, washed with brine, and dried (MgSO)4) Filtered and the solvent evaporated. Purification of the residue by column chromatography on silica gel (SiO)2=30g-15/40 μm), eluent: CH (CH)2Cl2100 to CH2Cl298/MeOH 2 to afford intermediate 88 a.
Other pyrazole derivatives that may be used in the above scheme may be prepared as follows:
A)
a) preparation of intermediate 125
N-butyllithium (1.6M in hexane, 33.5 mL; 53.6 mmol) was added dropwise to a solution of 1-methylpyrazole (4 g; 48.8 mmol) in THF (66 mL) at-78 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 0 deg.C, then (2-bromoethoxy) -tert-butyldimethylsilane (12.5 mL; 58.5 mmol) was added to the solution at-78 deg.C and stirred for 1 hour. The temperature of the reaction mixture was raised to room temperature and stirred for 18 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (16g) was purified by chromatography on silica gel (random SiOH, 20-45 μm, 1000 g; mobile phase: 65% heptane, 35% EtOAc). The pure fractions were collected and concentrated to yield 3g (25%) of intermediate 125.
b) Preparation of intermediate 126
Pyridine hydrobromide perbromide (95% (3.5 g; 10.8mmol) was added to intermediate 125(2.6 g; 10.8mmol)In MeOH (130 mL). The reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature for 18 hours. The solvent was evaporated and the residue poured into water and 10% K2CO3In (1). DCM was added and the organic layer was separated and dried (MgSO4) Filtering and evaporating the solvent. The residue (2.5g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 300 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated to yield 2g (92%) of intermediate 126.
c) Preparation of intermediate 127
Tert-butyldimethylsilyl chloride (1.9 g; 12.7 mmol) and imidazole (1.6 g; 23.4 mmol) were added successively to a solution of intermediate 126(2 g; 9.75 mmol) in N, N-dimethylformamide (7 ml). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and Et2And (4) extracting. The organic layer was decanted, washed with water, then brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (SiOH, 10-40 μm, 90 g; mobile phase: 100% DCM to 97% DCM, 3% MeOH). The pure fractions were collected and concentrated to yield 2.8g (90%) of intermediate 127.
d) Preparation of intermediate 128
N-butyllithium (1.6M in hexane, 0.22 mL; 0.35mmol) was added dropwise to intermediate 127(0.102 g; 0.32 mmol) in Et at-78 deg.C under a nitrogen atmosphere2O (1.5 mL) solution. The reaction mixture was stirred for 30 minutes, then tributyltin chloride (0.095 mL; 0.35mmol) was added to the solution and stirred at room temperature for 18 hours. The reaction mixture was poured into ice water and Et was added2And O. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The residue (0.160g) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60 g; Amersham pharmacia Biotech; AmerMoving phase: 80% heptane, 20% EtOAc). The pure fractions were collected and concentrated to yield 0.055g (32%) of intermediate 128.
B)
a) Preparation of intermediate 129
N-butyllithium (1.6M in hexane, 25 mL; 40.2 mmol) was added dropwise to a solution of 1-methylpyrazole (3 mL; 35.5 mmol) in THF (50mL) at-78 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 0 ℃ and Eschenmoser's salt (8.1 g; 43.85 mmol) was then added to the solution at-78 ℃ and stirred for 1 hour. The temperature of the reaction mixture was raised to room temperature and stirred for 18 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtration and evaporation of the solvent gave 3.1g of intermediate 129.
b) Preparation of intermediate 130
Pyridine hydrobromide homobromide 95% (6.9 g; 21.6mmol) was added to a solution of intermediate 130(3 g; 21.6mmol) in MeOH (200 mL). The reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature for 18 hours. The solvent was evaporated and the residue poured into water and 10% K2CO3In (1). DCM was added and the organic layer was separated and dried (MgSO4) Filtering and evaporating the solvent. The residue (3.1g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated to yield 1.35 g (29%) of intermediate 130.
c) Preparation of intermediate 131
N-butyllithium (1) was added at-78 ℃ under a nitrogen atmosphere6M in hexanes, 0.8 mL; 1.26 mmol) was added dropwise to intermediate 130(0.25 g; 1.15 mmol) of Et2O/THF (1/2) (3 mL). The reaction mixture was stirred for 30 minutes. Tributyltin chloride (1.58 mL; 5.8mmol) was then added to the solution and stirred at room temperature for 18 hours. The reaction mixture was poured into ice water and Et was added2And O. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 0.52 g of intermediate 131, which was used in the next step without further purification.
Example A36B
Preparation of intermediate 89
Methanesulfonyl chloride (0.066 mL; 0.85 mmol) was added dropwise to a solution of compound 622(0.185 g; 0.43 mmol), triethylamine (0.14 mL; 0.98 mmol) and 4-dimethylaminopyridine (0.005 g; 0.043mmol) in THF (5mL) at 5 deg.C under a nitrogen atmosphere. The temperature of the reaction mixture was raised to room temperature and maintained for 2 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 0.26 g (yellow oil) of intermediate 89, which was used in the next step without further purification.
Example A37
Preparation of intermediate 91
Methanesulfonyl chloride (1 mL; 12.8 mmol) was added dropwise to 1-piperidinecarboxylic acid, 4- (3-hydroxy-1-propyn-1-yl) -, 1, 1-dimethylethyl ester (2 g; 8.5 mmol), triethylamine (1.8 mL; 12.8 mmol) and 4-dimethylaminopyridine (10.4 g; 85mmol) in DCM (20 mmol) at 5 ℃ under a nitrogen atmospheremL) in solution. The temperature of the reaction mixture was raised to room temperature and maintained for 18 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 1.41g of intermediate 91 which was used in the next step without further purification.
Example A38
Preparation of intermediate 92
NaH (0.24 g; 6.0mmol) was added portionwise to intermediate 3(1 g; 3.0mmol) in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at 10 ℃ for 1 hour. Then, under nitrogen atmosphere, 2-butyn-1-ol, 4- [ [ (1, 1-dimethylethyl) dimethylsilyl group, were added dropwise]Oxy radical]-, 1-Methanesulfonate (4.2 g; 15.0 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (4.2g) was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300 g; mobile phase: 60% heptane, 4% MeOH, 36% EtOAc). The pure fractions were collected and concentrated to yield 0.185 g (11%) of intermediate 92.
Example A39
Preparation of intermediate 93
Methanesulfonyl chloride (9.9 mL; 127.7 mmol) was added dropwise to a solution of compound 2(10 g; 25.55 mmol), triethylamine (24.9 mL; 178.8 mmol) in DCM (400mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and DCM was added. Is divided intoThe organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 17.6 g of intermediate 93, which was used in the next step without further purification.
Example A40
Preparation of intermediate 94
Will be provided with(see A4c-2) (9.5 g; 20 mmol), 4,5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1,3, 2-dioxaborolane (4.3 g; 22 mmol), potassium phosphate (8.5 g; 40mmol) in dioxane (1L) and water (120 mL) were degassed with nitrogen for 15 minutes, then S-Phos (0.83 g; 2mmol) and Pd were added2(dba)3(7.6 g; 6.6 mmol). The reaction mixture was heated at 80 ℃ for 15 hours. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice water, EtOAc was added and filtered over a pad of celite. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue (18.5g) was purified by chromatography on silica gel (random SiOH, 20-45 μm, 1000 g; mobile phase: 96% DCM, 4% MeOH). The pure fractions were collected and concentrated to yield 5.1g (51%) of intermediate 94.
Example A41
a) Preparation of intermediate 95
NaH (0.2 g; 4.75 mmol) was added portionwise to intermediate 94(2 g; 4mmol) in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at 10 ℃ for 1 hour. Then, 1-bromo-3-chloropropane (0.5 mL; 4.75 mmol) was added dropwise under a nitrogen atmosphere. Reacting the mixtureThe mixture was stirred at room temperature for 1 hour. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 2.5g of intermediate 95, which was used in the next step without further purification.
b) Preparation of intermediate 96
Intermediate 95(1.1 g; 1.48 mmol), 1- (2-hydroxyethyl) piperazine (0.407 g; 2.95 mmol) and K2CO3(1.92 g; 14.74 mmol) in CH3CN (10mL) at 90 ℃ for 12 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 0.9g of intermediate 96, which was used in the next step without further purification.
c) Preparation of intermediate 97
A mixture of intermediate 96(0.56 g; 0.83 mmol), acetyl chloride (0.12 mL; 1.66mmol), triethylamine (0.27 mL; 1.9 mmol) and 4-dimethylaminopyridine (0.01 g; 0.083 mmol) was stirred in DCM (10mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred to room temperature and held for 18 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 0.85g of intermediate 97 which was used in the next step without further purification.
d) Preparation of intermediate 98
A solution of 1M tetrabutylammonium fluoride in THF (2.5 mL, 2.5mmol) was added dropwise to a solution of intermediate 97(0.75 g, 0.84 mmol) in THF (5mL) at room temperature. Reacting the mixtureThe mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and washed with 10% K2CO3Basified and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. DCM and a little MeOH were added, then the insoluble fraction was filtered and the filtrate was evaporated. The residue and precipitate were combined and dissolved in DCM. The organic layer was washed with water and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (0.5g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 90 g; mobile phase: 0.3% NH)4OH, 97% DCM, 3% MeOH to 1% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated to yield 0.238 g (47%) of intermediate 98.
e) Preparation of intermediate 99
Methanesulfonyl chloride (0.1 mL; 1.3mmol) was added dropwise to a solution of intermediate 98(0.19 g; 0.26mmol) and triethylamine (0.11 mL; 0.78mmol) in DCM (5mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 10 ℃ for 2 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 0.51g of intermediate 99-AAA, which was used in the next step without further purification.
f) Preparation of intermediate 100
A mixture of intermediate 99(0.51 g; 0.26mmol) and isopropylamine (5.9 mL; 68.9 mmol) was heated in acetonitrile (1 mL) at 100 deg.C for 12 hours in a sealed vessel. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated, washed and dried (MgSO)4) Filtered and evaporated to dryness. The residue (0.59g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.7% NH)4OH, 93% DCM, 7% MeOH). The pure fractions were collected and,concentration gave 0.09g (54%) of intermediate 100.
Example A42
a) Preparation of intermediate 101
Intermediate 5(3 g; 13.3 mmol), intermediate 45(3.9 g; 13.3 mmol), sodium tert-butoxide (3.9 g; 40mmol) and 1,1'- [1, 1' -binaphthyl]A mixture of (E) -2,2' -diylbis [1, 1-diphenylphosphine (0.83 g; 1.33mmol) was degassed with nitrogen in ethylene glycol dimethyl ether (100ml) for 10 minutes. Palladium (II) acetate (0.3 g; 1.33mmol) was added and the mixture was stirred at 90 ℃ for 2 hours. The mixture was cooled to room temperature and poured into water and DCM. The mixture was filtered through a pad of celite. The filtrate was extracted with DCM. Drying (MgSO)4) The combined organic layers were filtered and evaporated to dryness to give 5g of crude compound. The residue was purified by chromatography on silica gel (SiOH, 20-45 μm, 40 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 3.6g (62%) of intermediate 101.
b) Preparation of intermediate 102
NaH (0.37 g; 9.2mmol) was added portionwise to a solution of intermediate 101(2 g; 4.6mmol) in N, N-dimethylformamide (20mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 30 minutes. Then, (2-bromoethoxy) -tert-butyldimethylsilane (1.3 ml; 6.0mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 3g of intermediate 102.
c) Preparation of intermediate 103
A solution of 1M tetrabutylammonium fluoride in THF (5 mL; 5mmol) was added dropwise to a solution of intermediate 102(3 g; 5mmol) in THF (50mL) at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The mixture was poured into ice water and washed with 10% K2CO3Basified and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) And the solvent was evaporated to dryness. The residue (3g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 40 g; mobile phase: 0.1% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated to yield 2.2g (61%) of intermediate 103.
d) Preparation of intermediate 104
Methanesulfonyl chloride (0.7 mL; 9.2mmol) was added dropwise to a solution of intermediate 103(2.2 g; 4.6mmol), triethylamine (1.6 mL; 11.5 mmol) in DCM (30mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 10 ℃ for 2 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 2.8g of intermediate 104, which was used in the next step without further purification.
e) Preparation of intermediate 105
A mixture of intermediate 104(2 g; 3.6 mmol) and 2-propylamine (1.6 mL; 17.9 mmol) was heated in acetonitrile (15mL) at 100 ℃ for 18 hours in a sealed vessel. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue (2.2g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 40 g; mobile phase: 0.1% NH)4OH，95% DCM, 5% MeOH). The pure fractions were collected and concentrated to yield 0.8g (43%) of intermediate 105.
Example A43
Preparation of intermediate 107
Methanesulfonyl chloride (0.19 mL; 2.4mmol) was added dropwise to compound 625(0.69 g; 1.2mmol) (prepared as described in B39, starting from intermediate 41 and intermediate 106) prepared as described in A2c, at 5 deg.C under a nitrogen atmosphereStarting), triethylamine (0.4 mL; 3mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness to give 0.8g of intermediate 107 as an orange oil, which was used in the next step without further purification.
Intermediate 107 was converted to compound 650 following the procedure described for B3 (first alternative).
Example A43A
Preparation of intermediate 106
NaH (0.3 g; 7.2 mmol) was added portionwise to a solution of 7-bromo-2- (1H-pyrazol-4-yl) quinoxaline (1.6 g; 6mmol) in N, N-dimethylformamide (100mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour. Then, 4-methanesulfonyloxy-1-piperidinecarboxylic ester CAS [141699-59-4 ] was added dropwise at 5 ℃ under a nitrogen atmosphere](3.5 g; 12.6 mmol). Will be provided withThe reaction mixture was stirred at 100 ℃ for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (8.4g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and concentrated to yield 3.7g (67%) of intermediate 106 (yellow oil).
Example A44
Preparation of intermediate 109
NaH (0.29 g; 7.4 mmol) was added portionwise to intermediate 108(1.5 g; 3.7 mmol) (prepared as described under A33 b) in N, N-dimethylformamide (25 mL). The reaction mixture was stirred at 0 ℃ for 30 minutes. Then, 3-bromo- (1-trimethylsilyl) -1-propyne (1.6 mL; 10.2 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (2g) was chromatographed on silica gel (SiOH, 15-40 μm, 80 g; mobile phase: 98% DCM, 2% MeOH) to give 1.4g of intermediate 109.
Example A45
Preparation of intermediate 110
Compound 4(0.5 g; 1.2mmol), 4-nitrobenzyl bromide (0.29 g; 1.35 mmol) and K2CO3(0.24g of the total weight of the mixture; 51.8 mmol) in CH3CN (20mL) was stirred at room temperature for 48 hours. The reaction mixture was cooled to room temperature, poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (0.8g) was purified by chromatography on silica gel (stable SiOH, 5 μm, 150x30 mm; mobile phase gradient: 71% heptane, 1% MeOH, 28% EtOAc to 20% MeOH, 80% EtOAc). The product fractions were collected and the solvent was evaporated, yielding 0.34g (52%) of intermediate 110.
Example A46
a) Preparation of intermediate 113
NaH (0.52 g; 13mmol) is added portionwise to 7-bromo-2- (1H-pyrazolyl-4-yl) quinoxaline (3 g; 11mmol) in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at 5 ℃ for 1 hour. Then, 4-bromomethyl tetrahydropyran (2.4 mL; 13mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature and stirred for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was washed with DIPE and CH3And (4) crystallizing CN. The precipitate was filtered and dried to yield 2.6g (64%) of intermediate 113.
b) Preparation of intermediate 112
A solution of palladium acetate (0.08 g; 0.35mmol), racemic 2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl (0.22 g; 0.35mmol) was added to a solution of intermediate 113(2.6 g; 7.0 mmol), 3, 5-dimethoxyaniline (1 g; 7.0 mmol) and sodium tert-butoxide (2 g; 21mmol) in dioxane (40mL) at room temperature under an inert atmosphere. At 90 deg.CThe reaction mixture was stirred for 18 hours. The reaction mixture was cooled to room temperature, poured into ice water and DCM was added. The mixture was filtered through a pad of celite. The organic layer was washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (3.5g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 40 g; mobile phase: 98% DCM, 2% MeOH). The pure fractions were collected and concentrated to yield 1.6 g (63%) of intermediate 112.
Example A47
a) Preparation of intermediate 114
Intermediate 13(9 g; 28.5 mmol), intermediate 132(20.9 g; 57mmol), potassium phosphate (12.1 g; 57mmol) in dioxane (200mL) and water (80mL) were degassed with nitrogen for 15 minutes, then S-Phos (1.2 g; 2.9mmol) and Pd were added2(dba)3(1.3g, 1.4 mmol). The reaction mixture was heated at 80 ℃ for 6 hours. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice water, EtOAc was added and filtered over a pad of celite. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue (28g) was purified by chromatography on silica gel (random SiOH, 20-45 μm, 1000 g; mobile phase: 99% DCM, 1% MeOH). The pure fractions were collected and concentrated to yield 13.6 g (92%) of intermediate 114.
Intermediate 132The preparation method comprises the following steps:
NaH (77.3 mmol; 3g) was added to a solution of 4,4,5, 5-tetramethyl-2- (1H-pyrazol-4-yl) -1,3, 2-dioxaborolane (10 g; 51.5 mmol) in N, N-dimethylformamide (150mL) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 hour. Then, (3-bromopropoxy) -tert-butyldimethylsilyl was added dropwise at room temperature under a nitrogen atmosphereAlkane (18.5 mL; 77.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration and evaporation of the solvent gave 23.8 g (70%) of intermediate 132, which was used without further purification.
Preparation of intermediates following the scheme for intermediate 114 above。
b) Preparation of intermediate 115
A solution of 1M tetrabutylammonium fluoride in THF (24 mL; 24mmol) was added dropwise to a solution of intermediate 114(12.5 g; 24mmol) in THF (250mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into ice water and washed with 10% K2CO3Basified and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 8.8g (90%) of intermediate 115. MP: 118 deg.C (Kofler).
c) Preparation of intermediate 116
Methanesulfonyl chloride (1.9 mL; 24.7 mmol) was added dropwise to a solution of intermediate 115(2 g; 5.0mmol), triethylamine (4.9 mL; 34.5 mmol) in DCM (80mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give 3.4g of intermediate 116 which was used in the next step without further purification.
d) Preparation of intermediate 117
NaH (0.42 g; 10.4mmol) was added portionwise to di-tert-butyl iminoformate (2.3 g; 10.4mmol) in N, N-dimethylformamide (40 mL). The reaction mixture was stirred at 10 ℃ for 30 minutes. Then, intermediate 116(2.5 g; 5.2mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours and then at 50 ℃ for 4 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (4g) was chromatographed on silica gel (15-40 μm, 80 g; mobile phase: 98% DCM, 20% MeOH). The pure fractions were collected and concentrated to yield 1.7 g (54%) of intermediate 117.
e) Preparation of intermediate 118
Trifluoroacetic acid (3 mL; 39.7 mmol) was added to a solution of intermediate 117(1.5 g; 2.5mmol) in DCM (20 mL). The reaction was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water and washed with 10% K2CO3Basified and EtOAc was added. The layers were separated and the aqueous layer was evaporated to dryness. The residue was dissolved in MeOH. The precipitate was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in DCM. The precipitate was filtered off and the filtrate was evaporated to dryness to yield 0.45 g (45%) of intermediate 118. MP: 96 deg.C (Kofler).
Example A48
a) Preparation of intermediate 119
Thionyl chloride (26 mL; 359 mmol) was added dropwise to a solution of 3-amino-5-methoxybenzoic acid (10 g; 59.82 mmol) in MeOH (150mL) at 0 deg.C. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was filtered off, washed with DIPE and dried in vacuo at 50 ℃ to yield 8.6 g (79%) of intermediate 119 (white solid).
b) Preparation of intermediate 120
A2.4M solution of lithium in THF (35.8 mL; 85.9 mmol) was added dropwise to a solution of intermediate 119(8.62 g; 39.6 mmol) in dry THF (150mL) at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. Reacting the reaction mixture with NH4Treated with Cl and stirred at 0 ℃ for 10 min. The precipitate was filtered off and washed with EtOAc. The filtrate was separated, the organic layer was washed with brine and dried (MgSO)4) Filtering and evaporating the solvent. The residue (6g) was purified by chromatography on silica gel (200 g; mobile phase gradient: 100% DCM to 7% MeOH/DCM). The pure fractions were collected and concentrated to yield 3.26 g of intermediate 120.
c) Preparation of intermediate 121
A solution of tris (dibenzylacetone) palladium (0) (1.12 g; 1.2mmol), 2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl (1.28 g; 2.7 mmol) was added to a solution of intermediate 2(3.52 g; 12.2 mmol), intermediate 120(3.3 g; 17.45 mmol) and cesium carbonate (11.9 g; 36.49 mmol) in t-BuOH (80mL) at room temperature under an inert atmosphere. The reaction mixture was stirred at 105 ℃ for 1 hour using a single mode microwave. The reaction mixture was cooled to room temperature, poured into ice water (400mL), and stirred for 15 minutes. The precipitate was filtered off and washed with water. The precipitate was dissolved in DCM/MeOH (95/5) and the insoluble product was filtered off and dried to give 4.7 g of intermediate 121, which was used in the next step without further purification.
d) Preparation of intermediate 122
MnO of2(5.65 g; 65mmol) was added to a solution of intermediate 121(4.7 g; 13mmol) in THF (270 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated to give 1.5g (32%) of intermediate 122, which was used in the next step without further purification.
e) Preparation of intermediate 123
Intermediate 122(0.3 g; 0.64 mmol) and diethylamine (0.14 g; 1.9 mmol) were added to a solution of 10% Pd/C (0.05g) and 0.2mL 4% thiophene in DIPE-MeOH/THF (100mL) under a nitrogen atmosphere. The reaction mixture was incubated at 50 ℃ under 75 atm H2The atmosphere was stirred until 1 eq of hydrogen was absorbed. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated to give 0.354 g of intermediate 123.
Example A49
Preparation of intermediate 124
A mixture of 3-bromo-5-methoxyphenol (2 g; 9.8mmol), cesium carbonate (6.4 g; 19.7mmol) was degassed in N, N-dimethylformamide (20mL) and water (4mL) for 1 hour under a nitrogen atmosphere, and then acetic acid-2-chloro-2, 2-difluoro-sodium salt (5.3 g; 34.5 mmol) was added. The reaction mixture was stirred at 120 ℃ for 2 days. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (2.5g) was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300 g; mobile phase gradient: 95% heptane, 5% EtOAc to 90% heptane, 10% EtOAc). The pure fractions were collected and concentrated to yield 0.56g (23%) of intermediate 124.
Example A50
a) Preparation of intermediate 133
2-chloro-4-methoxypyrimidine (1.24 g; 8.5mmol), 4-piperidinemethanol (1.2 g; 10.25 mmol) and K2CO3(2.4 g; 17.0 mmol) in CH3CN (15mL) at 80 ℃ for 18 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The residue (1.8g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 40 g; mobile phase: 0.1% NH)4OH, 99% DCM, 1% MeOH). The pure fractions were collected and concentrated to yield 1.6g (83%) of intermediate 133.
b) Preparation of intermediate 134
Methanesulfonyl chloride (0.94 mL; 12.1 mmol) was added dropwise to a solution of intermediate 133(0.54 g; 2.42 mmol), triethylamine (2.4 mL; 16.9 mmol) in DCM (15mL) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 10 ℃ for 1 hour. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The residue (1.1g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 40 g; mobile phase: 99% DCM, 1% MeOH). The pure fractions were collected and concentrated to yield 0.5g (69%) of intermediate 134.
This intermediate was used in the preparation of compound 839.
Example A51
a) Preparation of intermediate 137
4-methyl-1-dimethylsulfamoylimidazole (2.9 g, 15.6 mmol) was diluted in THF (105 mL). The resulting solution was cooled to-78 deg.C and 2M N-butyllithium/cyclohexane (11.7 mL, 18.7 mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 30 minutes, N-dimethylformamide (7.6 mL, 98.0 mmol) was added, and the mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature over 1 hour. Reacting the reaction mixture with NH4Aqueous Cl was neutralized and then poured into water and EtOAc. Drying (MgSO)4) The organic layer was filtered and concentrated to give 3.7g of intermediate 137.
b) Preparation of intermediate 138
A mixture of intermediate 137(3.7 g; 17mmol) was dissolved in MeOH (32 mL). The reaction mixture was then cooled to 0 ℃ and sodium borohydride (0.6 g; 17mmol) was added. The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture was then concentrated and poured into water and EtOAc. Drying (MgSO)4) The organic layer was filtered and concentrated to give 2.9 g (78%) of intermediate 138. It was used directly in the next step without further purification.
c) Preparation of intermediate 139
Intermediate 138(3.2 g; 14.3mmol) was dissolved in THF (26 mL) and N, N-dimethylformamide (13 mL). The solution was then cooled to 0 deg.C and triethylamine (4.1 mL; 28.6 mmol) was added followed by methanesulfonyl chloride (1.3 mL; 17.2 mmol) and lithium chloride (1.8 g; 43 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into EtOAc and water. The organic layer was washed once with brine and dried (MgSO)4) Filtering, and concentrating. The residue was purified by chromatography on silica gel (3.5g) (mobile phase gradient: 100% DCM to 0.1% NH)4OH, 99% DCM, 1% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 2.2g (70%) of intermediate 139, which was used to prepare compound 695.
Example A52
Preparation of
A mixture of 3, 5-dimethoxyboronic acid (18.5 g; 101.5mmol), 1- (2,2, 2-trifluoroethyl) -4-piperidinemethylamine (16.6 g; 61.7 mmol), copper (II) acetate (18.5 g; 101.5mmol) and triethylamine (59.8 mL;425 mmol) was stirred in DCM (350mL) at room temperature for 18 h. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel (mobile phase gradient: 89% petroleum ether/11% ethyl acetate to 45% petroleum ether/55% ethyl acetate). The pure fractions were collected and the solvent was evaporated, yielding 3.8 g (19%) of the compound.
Example A53
Preparation of intermediate 142
A mixture of intermediate 15(1.8 g; 3.6 mmol) and tert-butyl glycinate (2.5 g; 18mmol) was stirred in N, N-dimethylformamide (25mL) at 80 ℃ for 6 h in a sealed tube. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (2.52g) was purified by silica gel chromatography (SiOH, 20-45 μm, 450 g; mobile phase: 0.1% NH)4OH, 96% DCM, 4% MeOH). The pure fractions were collected and concentrated to yield 0.96 g (50%) of intermediate 142, which was used in the next step without further purification.
B. Preparation of the Compounds
Example B1
Preparation of Compound 1
Tetrabutylammonium fluoride (38.5ml, 38.5mmol) was added dropwise to a solution of intermediate 9(20g, 38.5mmol) in THF (350ml) at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The mixture was poured into ice water and EtOAc was added. With 10% K2CO3The mixture was basified and the organic layer was separated, washed with brine and dried (MgSO4) Filtered and the solvent evaporated. The residue was triturated with diethyl ether, filtered and dried in vacuo to give 11.7g (75%) of compound 1. MP =153 ℃ (DSC).
Compound 1 can also be prepared using the following method.
525g (1.01mol) of intermediate 9 were dissolved in a mixture of THF (0.89L), acetic acid (2.68L) and water (0.89L) and the reaction mixture was stirred at 50 ℃ until complete conversion to the alcohol. The reaction mixture was evaporated to dryness. The residue was taken up in DCM (3.68L) and water (3.68L) and the pH of the mixture was adjusted to 7 using ammonia. The layers were separated. The aqueous layer was extracted with DCM (0.5L) and the organic layers were combined and dried (MgSO 5)4) Filtered and evaporated to dryness. The residue was crystallized from toluene. The precipitate was filtered off, washed with toluene and dried to provide 204g (49.8% yield) of compound 1.
a) Preparation of Compound 2
A mixture of intermediate 47(1.50 g; 2.476mmol), 3N HCl (2ml) was heated overnight at 70 ℃ in dioxane (25 ml). The reaction mixture was cooled to room temperature and poured into ice water. EtOAc is added and the mixture is taken over with K2CO3The aqueous solution (10%) was basified. Separating the organic layerWashed with brine and dried (MgSO)4) Filtered and the solvent evaporated. This compound was triturated with diethyl ether, filtered and dried in vacuo to give 0.790g (81%) of compound 2. MP =169 ℃ (DSC).
Example B2
a) Preparation of Compound 3
Tetrabutylammonium fluoride (14.6 mL, 14.6 mmol) was added dropwise to a solution of intermediate 11(6.5g, 12.2mmol) in THF (100mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was poured into ice water and EtOAc was added. By K2CO3The mixture was basified with aqueous solution (10%), the organic layer was separated, washed with brine and dried (MgSO)4) Filtering, and evaporating the solvent to dryness to obtain 7.8g of a crude compound, and purifying the crude compound by silica gel chromatography (random SiOH, 20-45 μm, 450g MATREX; mobile phase: 0.1% NH4OH, 97% DCM, 3% MeOH). The pure fractions were collected and evaporated to dryness to yield 4.9g (96%) of compound l 3. The compound was extracted with Et2O/CH3CN crystallized, the precipitate was filtered and dried to yield 4.37g (85%) of Compound 3. MP =168 ℃ (Kofler).
Compound 3 can also be prepared using the following method.
Intermediate 11(167.2 g; 313mmol) was added to a mixture of acetic acid (846ml), THF (282ml) and water (282ml) and the mixture was stirred at 50 ℃ for 18 h and evaporated to dryness. The crude compound 3 was used without further purification to prepare intermediate 17 a.
Compound 3 can also be prepared using the following procedure B2B.
HCl/i-PrOH (11.3 ml; 56.5mmol) was added dropwise to intermediate 18(8.5 g; 16.87mmol) in CH at 10 deg.C3OH (100ml) solution and the mixture was stirred at room temperature for 1 hour. Adding ice waterInto NH4OH basified in this solution. The product was extracted with DCM. The organic layer was dried (MgSO4) And (5) drying by distillation. The residue was purified by silica gel chromatography (random SiOH, 15-40 μm, 200 g; mobile phase: 97% DCM, 3% CH)3OH，0.1%NH4OH). The pure fractions were collected and evaporated to dryness to yield 3.7g (52%) of compound 3 and 1.2g of an impure fraction. The impure fraction was purified by silica gel chromatography (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 0.5% NH)4OH，97% DCM，3% CH3OH). The pure fractions were collected and the solvent was evaporated, yielding 700mg (10%) of compound 3.
Example B3
Preparation of Compound 4
A mixture of intermediate 10(8.7 g; 17.99mmol) and isopropylamine (61.3ml, 719.68mmol) was heated at 90 ℃ for 3 hours in a sealed vessel. The reaction mixture was cooled to room temperature and the mixture was evaporated to dryness. DCM and water were added and the organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (8g) was taken up in Et2O/CH3CN crystallized, filtered and dried under vacuum at 60 deg.C to give 6.68g (83%) of Compound 4. MP =142 ℃ (DSC).
Compound 4 can also be prepared using the following method.
A mixture of intermediate 10(322 g; 666mmol) and 2-propylamine (196.8 g; 3.3mol) was heated in acetonitrile (2.66L) at 100 ℃ for 18 hours in a sealed vessel. The reaction mixture was cooled to room temperature and concentrated to about 30% of the initial volume. Water (1.5L), 2-methyltetrahydrofuran (2.5L) and NaHCO were added3(50g) In that respect The layers were separated and washed with NaHCO3(50g) The organic layer was washed with aqueous solution (1L) and dried (MgSO)4) It was filtered through silica gel and evaporated to dryness. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried in vacuo to give 257.2g (86.5%) Compound 4.
Compound 4 can also be prepared using the following method.
Intermediate 3(20.0 g; 55.3mmol) and then tetra-N-butylammonium bromide (9.06 g; 27.7mmol) are added to a solution of potassium hydroxide (46.6 g; 830mmol) in THF (387ml) and water (6ml) at 2 ℃ under an inert atmosphere. The reaction was stirred at room temperature for 2 hours, after which N- (2-chloroethyl) -2-propylamine HCl (CAS [6306-61-2] was added portionwise]) And then complete conversion at 50 ℃. Water was added, the layers were separated, and the organic layer was concentrated, taken up in DCM/water and neutralized to neutral pH with HCl. The organic layer was washed with water and dried (MgSO)4) Filtration and evaporation to dryness gave 26.6g of Compound 4.
The HCl salt of compound 4 (.1HCl) was prepared using the following method.
To a stirred mixture of 2-methyltetrahydrofuran (1.5L) and KOH (140g, 250mmol) was added water (30 ml). Intermediate 3(60g, 166mmol)) and tetrabutylammonium bromide (13.4g, 41mmol) were then added and the mixture was heated at 50 ℃ for 1 hour with stirring. Then, 1 part of N- (2-chloroethyl) -2-propylamine HCl (CAS [6306-61-2]) (48g, 299mmol) was added. The mixture was stirred at 50 ℃ for 18 hours. When conversion was complete, water (600mL) was added to the reaction mixture. The layers were separated and the organic layer was concentrated. The residue was dissolved in 2-propanol (120ml) and HCl/2-propanol was added at 60 ℃. After cooling, the HCl salt was separated by filtration. After drying in a vacuum oven at 50 ℃, the HCl salt was obtained in 83% yield (compound 4 a).
To 51.69g (107mmol) of the HCl salt of the previous step were added water (258ml) and DCM (258 ml). The pH of the reaction mixture was adjusted using ammonium hydroxide (17.25mL) until pH = 9.5. The layers were separated and the organic layer was concentrated. The residue was crystallized from 2-propanol (258 mL). After vacuum drying at 50 ℃, compound 4 was obtained in 91% yield (43.4 g).
Example B3A
Preparation of Compound 6
Intermediate 48(7.2 g; 12.7mmol), 3-difluoropyrrolidine hydrochloride (7.3 g; 50.7mmol), sodium carbonate (6.72 g; 63.42mmol) and potassium iodide (2.1 g; 12.7mmol) were heated in 1-butanol (220ml) to 90 ℃ for 15 hours. The mixture was cooled to room temperature and poured into water/K2CO3And extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 35-40 μm, Grace Resolv; mobile phase gradient: 100% DCM to 95% DCM, 5% MeOH, 0.1% NH)4OH). The fractions of the desired product were collected and the solvent was evaporated, yielding 3.2g (44%) of compound 6.
Example B3B
Preparation of Compound 580
Intermediate 10(2.8 g; 5.8mmol) and 1, 4-dioxa-8-azaspiro [4-5 ] was reacted in a sealed tube using a monomode microwave (Biotage Initiator EXP 60)]A mixture of decane (1.5 g; 18mmol) was heated in 1-methyl-2-pyrrolidone (10mL) at 140 ℃ for 1 hour. The reaction mixture was evaporated to dryness. Purification of the crude product (6 g) (15-40 μm, 300 g; mobile phase: 0.2% NH) by silica gel chromatography4OH, 95% DCM, 5% MeOH). The pure fractions were collected and the solvent was evaporated to dryness to yield 1.9g (61%) of compound 580.
Example B3C
Preparation of Compounds 666 and 665
A mixture of intermediate 10(0.3 g; 0.6mmol), 2-piperidine-2-carboxamide (0.32 g; 2.5mmol), potassium iodide (0.1 g; 0.6mmol) and sodium carbonate (0.41 g; 4.4 mmol) was stirred in 1-butanol (12mL) at 85 ℃ for 4 days. The reaction was poured into ice water and EtOAc was added. The organic layer was washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. Purification of the residue (0.33 g) with preparative LC (random SiOH, 15-40 μm, 30 g; mobile phase gradient: 0.1% NH)4OH, 98% DCM, 2% MeOH to 0.1% NH4OH, 96% DCM, 4% MeOH). The pure fractions were collected and the solvent was evaporated. The first product (0.1g) was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.081g (25%) of compound 665. MP: 206 ℃ (Kofler). The second product (0.1g) was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.082g (25%) of compound 666. MP: 163 ℃ (Kofler).
Example B3D
Preparation of Compound 677
Intermediate 10(1.3 g; 2.7mmol), methoxyamine hydrochloride (2.3 g; 26.9 mmol) were heated in triethylamine (15 mL; 107.5 mmol) in a sealed tube at 90 ℃ for 5 h. The reaction was poured into ice water. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (2g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 300 g; mobile phase: 96% DCM, 4% i-PrOH). The pure fractions were collected and concentrated. The residue (0.38g) was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.32g (27%) of compound 677. MP: 177 ℃ (DSC).
Example B3E
Preparation of compound 923 (free base) and compound 886(HCl salt)
AndHCl salt
A mixture of intermediate 10(1.0 g; 2.07 mmol) and 3-pyrroline (628. mu.l, 8.3mmol) was heated in acetonitrile (4mL) at 90 ℃ for 90 minutes in a microwave biotage apparatus. The reaction mixture was cooled to room temperature and the mixture was evaporated until dryness. DCM and water were added and the organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. Purification of the residue by chromatography on silica gel (5 μm, mobile phase: gradient from NH)4OH 0.2%, DCM 98%, MeOH 2% to NH4OH 0.8%, DCM 92%, MeOH 8%). The eluted fractions were evaporated and the residue was dissolved in DCM and stirred at room temperature under bubbling air for 24 hours. The solvent was evaporated to give a yellow foam which was chromatographed on silica gel (SiOH, 10 μm, 60g, mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The desired product fraction was evaporated to afford 100mg (11%) of compound 923. In MeOH, the compound was converted to the HCl salt. The precipitate was filtered off, washed with MeOH, and dried to provide 41mg (4%) of compound 886.
Example B3F
Preparation of Compounds 891 and 894
And preparation of Compounds 924 and 925
A mixture of intermediate 143(622 mg, 1.2mmol) and isopropylamine (8.06 mL, 94.6 mmol) was heated at 120 ℃ for 48 hours in a sealed vessel. The reaction mixture was cooled to room temperature and DCM was added. The organic layer was washed with water and dried (MgSO)4) Filtered and the solvent evaporated to dryness to give a yellow oil. The residue was purified by chromatography on silica gel (5 μm, mobile phase: gradient from 100% DCM to 0.7% NH)4OH, 93% DCM, 7% MeOH). The desired product fractions were collected and evaporated to yield 33 mg (6%) of compound 924 and 40mg (7%) of compound 925. Compound 924 was converted to the HCl salt in MeOH. The precipitate is filtered off and Et2O wash and dry to give 25mg (4%) of compound 891. Compound 925 was converted to the HCl salt in MeOH. Evaporation of the solvent in Et2The residue is triturated in O, filtered off and Et2O wash and dry to yield 51mg (7%) of a residue. The fractions were taken up in MeOH and stirred at room temperature for 10 min. The solvent was evaporated to dryness. The product was triturated and dried to yield 24mg (3%) of compound 894.
Example B4
a) Preparation of Compound 5
A solution of intermediate 17a (0.2 g; 0.402mmol) in 2,2, 2-trifluoroethylamine (2 ml; 25mmol) was heated at 90 ℃ for 12 hours in a sealed tube. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc was added and the organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was chromatographed on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 98% DCM, 2% CH)3OH). The pure fractions were collected and the solvent was evaporated. The residue (0.14g, 69%) was crystallized from DIPE/diethyl ether/pentane (1/1/1). The precipitate was filtered and dried in vacuo to yield 0.134g (67%) of compound 5. MP =126 ℃ (DSC).
Compound 5 can also be prepared using method B4B below.
b) 3M HCl (60ml) was added to intermediate 17(9.49 mmol; 5.7g) of CH3OH (120ml) solution. The reaction mixture was heated at 60 ℃ overnight. The reaction mixture was cooled to room temperature, diluted with DCM and poured onto ice-cold K2CO3Solution (10%). The mixture was stirred for 30 minutes, the organic layer was decanted, washed with water and dried (MgSO)4) Filtering and evaporating to dryness. The residue was purified by HPLC. The residue (5.3g) was chromatographed on silica gel (random SiOH, 15-40 μm, 300 gMERCK; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and evaporated to dryness. The oily residue (3.93g, 83%) was treated with DiPE/diethyl ether/CH3And (4) crystallizing CN. The precipitate was filtered off and dried to yield 3.7g (78%) of compound 5.
Compound 5 can also be prepared using the following method.
A mixture of intermediate 17(268.5 g; 447mol) and trifluoroacetic acid (0.5L) was stirred in DCM (2.24L) at room temperature for 18 h and then at 50 ℃ for 1 h. The reaction mixture was evaporated to dryness, taken up in toluene (0.3L) and evaporated again. The residue was dissolved in DCM (3L) and water (2L) and the pH was adjusted to neutral with ammonia. The layers were separated, the aqueous layer was extracted with DCM (0.3L) and the organic layers were combined and evaporated to dryness. The residue was dissolved in EtOAc (1.5L) and stirred with a mixture of silica gel (275g) for 1 hour. The silica gel was filtered off, washed with EtOAc and the filtrate was evaporated to dryness to give 226g of compound 5. It was crystallized from 2-propanol, filtered and dried to give 180.8g (80%) of compound 5.
Example B4A
Preparation of Compound 7
And compound 8
A solution of methylamine in anhydrous ethanol (5.15 mL, 33% w/w, 41.4mmol) was added dropwise to intermediate 10(2g, 4.1mmol), K at room temperature2CO3(2.86g, 20.7mmol) of anhydrous CH3CN (40ml) suspension. In a sealed container, the mixture was heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc was added and the organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (1.85g) was chromatographed on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase gradient: from 0.1% NH)4OH, 95% DCM, 5% MeOH to 0.1% NH4OH, 90% DCM, 10% MeOH). The desired fraction was collected and the solvent was evaporated, yielding 0.30g of fraction I (15%) and 1.25g of fraction II (72%). Fraction I was crystallized from diethyl ether, filtered and dried in vacuo to yield 0.240g (12%) of Compound 7. MP = 160-. Fraction II was taken up in DCM and K2CO3In aqueous solution (10%). The mixture was stirred for 1 hour, then the organic layer was separated and dried (MgSO4) Filtered and the solvent evaporated. The product was reacted with diethyl ether/CH3CN crystallized, filtered and dried under vacuum at 60 deg.C to give 1.05g (59%) of Compound 8. MP = 180-.
Example B4B
Preparation of Compound 679
Intermediate 3- { (3-fluoro-5-methoxyphenyl) [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] prepared according to A3 was placed in a sealed tube]A mixture of amino } propyl methanesulfonate (0.35 g; 0.72 mmol), (S) - (+) -2-pyrrolidinemethanol (0.1 mL; 1mmol) and triethylamine (0.4 mL; 2.9 mmol) was heated in 1-methyl-2-pyrrolidone (1 mL) at 140 ℃ for several days. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4)，Filtered and the solvent was evaporated. The residue (0.12g) was purified by chromatography on silica gel (SiOH, 5 μm; mobile phase: gradient from 0.52% NH)4OH, 98% DCM, 2% MeOH to 0.8% NH4OH, 92% DCM, 8% MeOH). The pure fractions were collected and concentrated to yield 0.031g (9%) of compound 679.
Example B4C
Preparation of Compound 694Of HCl salt of
NaH (0.24 g; 5.9 mmol) was added portionwise to 2-pyrrolidone (0.46 mL; 5.9 mmol) in N, N-dimethylformamide (30mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then, at 5 ℃ under a nitrogen atmosphere, the intermediate (1 g; 2mmol) prepared according to A5 was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was poured into ice water. The precipitate was filtered off and washed with water. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.8g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 300 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated. The residue was dissolved in isopropanol, stirred at 0 ℃ and then 0.5mL of 5N HCl/i-PrOH was added dropwise. Diethyl ether was added and the solution was stirred at 0 ℃ for 1 hour, the precipitate was filtered and dried to yield 0.33 g (26%) of compound 694. MP: 197 Deg.C (DSC).
Example B5
Preparation of Compound 9
NaH (0.556 g; 13.9mmol) was added portionwise to a solution of intermediate 49(3 g; 6.95mmol) in DMF (85ml) at 5 ℃ under nitrogen. The reaction mixture was stirred for 30 minutes. 1-bromo-3-chloropropane (2 ml; 20.9mmol) is added dropwise and the mixture is stirred at room temperature for 15 hours and then poured into water/K2CO3In (1), extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue obtained was chromatographed on silica gel (random SiOH, 15-40 μm, 90g MERCK; mobile phase gradient from 100% DCM to 97% DCM, 3% MeOH, 0.1% NH)4OH). The fractions of the desired product were collected and the solvent was evaporated, yielding 2.94g (86%) of compound 9.
a) Preparation of Compound 10
NaH (925mg, 23.1mmol) was added portionwise to a solution of intermediate 3(4.18g, 11.6mmol) in DMF (52ml) at 5 ℃. The mixture was stirred at 5 ℃ for 30 minutes, then a solution of 4- (phenylmethyl) -2-morpholinomethanol 2-methanesulfonate (4.95g, 17.3mmol) in DMF (13.5ml) was added. The reaction mixture was heated at 60 ℃ for 18 hours. The mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO)4) Filtering and evaporating. The residue obtained was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The desired product fractions were collected and the solvent was evaporated, yielding 2.74g (43%, purity 90%) of a yellow foam. Purification of samples (440mg) by achiral supercritical fluid chromatography (AMINO 6. mu.m 150 X21.2mm; mobile phase, 0.3% 2-propylamine, 20% MeOH, 80% CO2). The desired product fraction was collected and the solvent was evaporated to yield 356mg of residue which was crystallized from DCM/acetone/diethyl ether. The precipitate was filtered off and dried to yield 188mg of compound 10. MP =134 ℃ (Kofler).
b-1) preparation of Compound 11
To a solution of intermediate 3(67mg, 0.18mmol) in tetrahydrofuran (4ml) was added NaH (12mg, 0.28 mmol). The suspension was stirred at room temperature until no bubbling was observed, cooled to 0 ℃, and methyl iodide (0.08ml, 1.3mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc, and washed with brine. The organic layer was separated and dried (Na)2SO4) And (4) concentrating. The crude residue was purified by chromatography on silica gel to give 38mg (54%) of compound 11 as a yellow powder.
b-2) preparation of Compound 12
To a solution of intermediate 3(100mg, 0.277mmol) in tetrahydrofuran (3ml) was added potassium hexamethyldisilazide (0.5M in toluene, 12mg, 0.831 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and propyl bromide (0.30ml) was added dropwise. The reaction mixture was stirred at room temperature for a further 3 hours and diluted with DCM and water. The solid residue was filtered off, dissolved in MeOH and combined with other organic extracts and dried (MgSO)4) And then concentrated. The crude residue was purified by chromatography on silica gel to give 10mg (9%) of compound 12 as a yellow powder.
b-3) preparation of Compound 13
A mixture of intermediate 3(50mg, 0.139mmol), cesium carbonate (226mg, 0.693mmol) and 1-bromo-2-methylpropane (95mg, 0.693mmol) was placed in CH3CN (1 mL). The reaction mixture was heated in a CEM Discovery microwave at 100 ℃ for 1 hour. Once cooled, the reaction mixture was partitioned between DCM and water. The organic layer was separated and the aqueous layer was further extracted with DCM. The combined organic layers were dried (MgSO)4) And (4) concentrating. The crude residue was purified by chromatography on silica gel to give 5mg (9%) of the compound13 (yellow powder).
Example B6
Preparation of Compound 14And
compound 14aOf HCl salt of
NaH (513.5mg, 12.8mmol) was added portionwise to a solution of intermediate 8(2.5g, 6.4mmol) in DMF (25ml) at 5 ℃ under nitrogen. The reaction mixture was stirred at 5 ℃ for 1 hour, and then glycidyl methyl ether (1.1mL, 12.8mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and then warmed to room temperature. The reaction was stirred at 80 ℃ for 5 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 0.1% NH)4OH, 97.5% DCM, 2.5% MeOH). The fractions of the desired product were collected and the solvent was evaporated, yielding 0.66g (21.5%) of compound 14, which was converted to its HCl salt with HCl/2-propanol (5-6N) in MeOH. The mixture was evaporated and the resulting solid was triturated in diethyl ether, filtered and dried to give 0.488g (15%) of compound 14a (0.95eq HCl) (MP =110 ℃, kofler).
Example B7
Preparation of Compound 15
3N HCl (13.5ml) was added to intermediate 50(2g, 2.98mmol) in CH at 5 deg.C3OH(65ml) of the solution. The reaction mixture was stirred at room temperature for 2.5 hours and then heated at 60 ℃ overnight. The solution was poured into ice water and used with K2CO3The aqueous solution (10%) was basified. The product was extracted with DCM. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (random SiOH, 20-45 μm, 450g MATREX; mobile phase: 0.1% NH)4OH, 96% DCM, 4% MeOH). The target fraction was collected and the solvent was evaporated. The residue was purified by achiral supercritical fluid chromatography (DIETHYLAMINOPROPYL 5 μm150 X21.2mm; mobile phase: 0.3% 2-propylamine, 80% CO220% MeOH). The target fraction was collected and the solvent was evaporated. The residue is treated with CH3CN/DIPE crystals, the precipitate filtered off and dried, giving 760mg (53%) of Compound 15. MP =121 ℃ (DSC).
Example B8
Preparation of Compound 16
HCl/i-PrOH (0.33ml, 0.0017mol) was added dropwise to intermediate 51(0.25g, 0.0004mol) in CH at 10 deg.C3OH (6ml) solution. Then, the mixture was stirred for 3 hours. The solution was concentrated, taken up in ice water and washed with NH4The OH was basified and the product was extracted with DCM. The organic layer was dried (MgSO4) And (4) evaporating. The residue was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 1% NH)4OH, 92% DCM, 8% MeOH). The desired product fractions were collected and the solvent was evaporated, yielding 138mg (78%) of compound 16. MP =80 ℃ (Kofler).
Example B9
a) Preparation of Compound 17
At room temperature, 3N HCl (4ml) was added dropwise to a solution of intermediate 20(1.5g, 3.0mmol) in dioxane (20 ml). The reaction mixture was heated at 70 ℃ overnight. The reaction was cooled to room temperature and poured into ice water. EtOAc is added and the mixture is taken over with K2CO3The aqueous solution (10%) was basified. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The compound was crystallized from diethyl ether, filtered and dried under vacuum at 60 ℃ to yield 1g (83%) of compound 17. MP =158 and 160 ℃ (Kofler).
Compound 17 can also be prepared using method B9B below.
b) Under a nitrogen atmosphere, intermediate 19(3.0 g; 8.1mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.9 g; 9.7mmol), 2M sodium carbonate (6.1 ml; 12.2mmol) in ethylene glycol dimethyl ether (30ml) was degassed by bubbling nitrogen for 10 minutes. Adding Pd (PPh)3)4(0.75 g; 0.65mmol) and the mixture is heated at reflux for 15 hours. The residue was poured into ice water and extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 90 g; mobile phase: gradient from 100% DCM to 95% DCM, 5% MeOH, 0.1% NH)4OH)15-40 mu m, 90 g). The pure fractions were collected and evaporated to dryness. The obtained residue was crystallized from DIPE, filtered and dried to yield 1.66g (51%) of compound 17.
Compound 17 can also be prepared using method B9c below.
c) Intermediate 19(3.3g, 8.9mmol), 1-dimethylethyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (3.15g, 10.7mmol), potassium phosphate (3.79g, 17.8mmol), dicyclohexyl (2 ', 6 ' -dimethoxy [1, 1' -biphenyl) were reacted at room temperature under a nitrogen atmosphere]A mixture of-2-yl) phosphine (0.37g, 0.9mmol) was stirred in dioxane (60ml) and water (6 ml). After 10 minutes, the Pd was added portionwise at room temperature2(dba)3(0.408g, 0.446mmol), andthe mixture was heated at 80 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc was added and the mixture was filtered through a layer of celite. The celite was washed with EtOAc, then the filtrate was extracted with EtOAc, washed with brine, and dried (MgSO)4) Filtered and the solvent evaporated. The residue was chromatographed on silica gel (random SiOH, 15/40 μm, 30g MERCK; mobile phase: gradient from 100% DCM to 97% DCM, 3% MeOH). The fractions of the desired product were collected and the solvent was evaporated, yielding 3.30g (73%) of compound 17.
Example B10
Preparation of Compound 18
HCl/i-PrOH (5/6N, 213 μ l; 1.06mmol) was added to CH of intermediate 23(250 mg; 0.53mmol) at 5 deg.C3OH (5mL) solution. The reaction mixture was stirred at 5 ℃ for 3 hours. Water and ice were added. Adding K2CO3Aqueous solution (10%) until pH becomes basic and the product is extracted with DCM. The organic layer was washed with water, brine and dried (MgSO)4) Filtered and the solvent evaporated. The crude product was taken up in diethyl ether, filtered and dried in vacuo to yield 64mg (31%) of compound 18. MP =132 ℃ (Kofler).
Example B11
Preparation of Compound 19
A mixture of intermediate 52(0.99g, 1.8mmol), 3N HCl (3ml) and dioxane (17ml) was heated at 70 ℃ overnight. The reaction mixture was cooled to room temperature, poured into ice water and EtOAc was added. By K2CO3Basified with aqueous solution (10%) and the organic layer separated, brineWashed and dried (MgSO)4) Filtered and the solvent evaporated. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 30g MERCK; mobile phase: gradient from 100% DCM to 98% DCM, 2% MeOH). The pure fractions were collected and evaporated to dryness to yield 782mg (97%) of intermediate 19. MP =130 ℃ (Kofler).
Example B12
Preparation of Compound 20
N3- (Ethylcarboximidoyl) -N1, N1-dimethyl-1, 3-propanediamine hydrochloride (1:1) (0.12g, 0.76mmol) was added portionwise to intermediate 24(0.23g, 0.505mmol), 3-pyrrolidinol (0.061g, 0.76mmol), 1-hydroxybenzotriazole (0.1g, 0.76mmol), Et at room temperature3N (0.105ml, 0.76mmol) in DCM (10 ml). The reaction mixture was stirred for 15 hours. The mixture was poured into water and extracted with DCM. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was crystallized from DIPE, filtered and dried. The product fraction (spherical SiOH, 10 μm60g, PharmPrep MERCK; mobile phase: 0.5% NH) was purified by chromatography on silica gel4OH, 94% DCM, 6% MeOH). The pure fractions were collected and evaporated to dryness. The residue was crystallized from DIPE, filtered and dried to yield 186mg (70%) of compound 20. MP =203.4 c (dsc).
a) Preparation of Compound 21
N3- (ethylcarboximidoyl) -N1, N1-dimethyl-1, 3-propanediamine hydrochloride (1:1) (227 mg; 1.46mmol) was added to intermediate 53(550 mg; 0.98mmol), methylamine hydrochloride (329 mg; 4.88mmol), Et at room temperature3N (0.95 ml; 6.83mmol), 1-hydroxybenzotriazole (198 mg; 1.46mmol) and DCM (40 ml). The reaction mixture was stirred for 20 hours, then stirred for 2 days, poured into water and extracted with DCM. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 30g Merck; mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH, 0.1% NH)4OH). The desired product fractions were collected and the solvent was evaporated to yield 76 mg (17%) of compound 21, which was crystallized from diethyl ether to yield 59 mg (13%) of compound 21. MP =204.5 ℃ (DSC).
The corresponding intermediate-O-Si (CH) can also be prepared by the methods described above, for example, in example B23)2-C(CH3)3Preparation of compound 21.
Example B13
Preparation of Compound 22
Intermediate 25(0.4g, 1.43mmol), 1-bromo-3-isopropoxybenzene (0.46ml, 2.86mmol), sodium tert-butoxide (0.032g, 0.14mmol) and 1,1'- [1, 1' -binaphthyl]-2, 2' -diylbis [1, 1-diphenylphosphine]The mixture (0.413g, 4.30mmol) was degassed with nitrogen in ethylene glycol dimethyl ether (3ml) for 10 minutes. Palladium (II) acetate (47% Pd) (0.032g, 0.14mmol) was then added and the mixture was heated under microwave irradiation at 135 ℃ for 60 minutes. The mixture was cooled to room temperature and poured into water/K2CO3In (1), extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.1% NH)4OH, 99% DCM, 1% MeOH). The pure fractions were collected and the solvent was evaporated. The residue was purified by chromatography on silica gel (X-Bridge-C18, 5 μm, 30X 150 mm; mobile phase: gradient from 40% of 0.5% NH4HCO3Aqueous solution, 60% CH3CN to 100% CH3CN). The pure fractions were collected and the solvent was evaporated. The residue (0.187 g) was crystallized from DIPE/pentane (80/20), and the precipitate was filtered and dried in vacuo to yield 0.128 g (22%) of Compound 22. MP =109 ℃ (DSC).
Example B14
Preparation of Compound 23
A solution of intermediate 54(0.4g, 0.666mmol) and tetrabutylammonium fluoride (0.73mL, 0.73mmol) in THF (10mL) was stirred at 0 deg.C for 2 hours. Water and EtOAc were added, the organic layer was separated, washed with water, then brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (0.4g) was first chromatographed on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase gradient from 98% DCM, 2% MeOH to 95% DCM, 5% MeOH). The pure fractions were collected and the solvent was evaporated. The residue was then purified by achiral supercritical fluid chromatography (AMINO 6 μm150 X21.2mm; mobile phase: 0.3% 2-propylamine, 80% CO)220% EtOH). The pure fractions were collected and the solvent was evaporated. The residue (0.165 g, 51%) was crystallized from DIPE, the precipitate was filtered off and dried in vacuo to yield 0.150g (46%) of compound 23. MP =134 ℃ (Kofler).
Example B14A
Preparation of Compound 691
A solution of 1M tetrabutylammonium fluoride in THF (12.7 mL; 12.7mmol) was added dropwise to a solution of intermediate 691(5 g; 8.5mmol) in THF (50mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and EtOAc was added. With 10% K2CO3The mixture was basified and the organic layer was separated, washed with brine and dried (MgSO4) Filtering and evaporating the solvent. The residue (3.5g) was crystallized from diethyl ether. The precipitate was filtered off and dried in vacuo to afford 3.2g (80%) of compound 691. MP: 99 ℃ (DS)C)。
Example B15
Preparation of Compound 24
HCl/i-PrOH (276. mu.l, 1.38mmol) was added dropwise to intermediate 55(183mg, 0.35mmol) in CH at 10 deg.C3OH (2ml) solution and the mixture was then stirred for 3 hours. Diethyl ether was added and the precipitate was filtered and dried to yield 126mg (76%) of compound 24. MP =80 ℃.
Example B16
Preparation of Compound 25Of HCl salt of
A mixture of intermediate 16(1.37g, 2.5mmol) and pyrrolidine (30ml) was heated at 80 ℃ for 3 h. The mixture was cooled to room temperature and evaporated until dryness. The residue was taken up in DCM and water. The organic layer was extracted with DCM and dried (MgSO)4) Filtering and evaporating to dryness. The residue (3 g) was chromatographed on silica gel (random SiOH, 15-40 μm, 90g MERCK; mobile phase: gradient from 98% DCM, 2% MeOH to 95% DCM, 5% MeOH). The pure fractions were collected and the solvent was evaporated to give the free base. The residue was dissolved in i-PrOH and 1.04 mL of 5N HCl/i-PrOH (4 eq.) was added dropwise at 5 ℃. The salt was filtered, washed with DIPE and dried under vacuum at 60 ℃ to give 0.53g (40%) of compound 25. MP =259 ℃ (DSC).
Example B17
Preparation of Compound 26
3N HCl (2ml) was added dropwise to a solution of intermediate 56(0.3g, 0.484mmol) in dioxane (8 ml). The solution was heated at 70 ℃ for 3 hours. The reaction was cooled to room temperature and poured into ice water. EtOAc is added and the mixture is taken over with K2CO3The aqueous solution (10%) was basified. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.19g) was taken up in DIPE/CH3And (4) crystallizing CN. The precipitate was filtered and dried in vacuo to yield 0.112g (56%) of compound 26. MP =202 ℃ (DSC).
Example B18
Preparation of Compound 27
Intermediate 57(0.425 g; 0.88mmol), 3N HCl (3mL) and dioxane (8mL) were heated to 60 ℃ overnight. Cooling the mixture to room temperature, pouring it into water and dissolving it with K2CO3Alkalizing. The product was extracted with EtOAc and dried (MgSO)4) Filtration and evaporation to dryness gave 322mg (95%) of compound 27. MP =178 ℃ (DSC).
Example B19
Preparation of Compound 28
A mixture of intermediate 58(0.3g, 0.486mmol) and amberlyst 15 ion exchange resin (0.03g) was stirred in MeOH (8mL) at 45 deg.C for 3 h. The resin was filtered. The filtrate was poured into water and washed with K2CO3The aqueous solution (10%) was basified. EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.2g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 3)0g MERCK; mobile phase: gradient from 98% DCM, 2% MeOH to 95% DCM, 5% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (0.18g) was taken up in DIPE/CH3CN (80/20) crystal. The precipitate was filtered off and dried in vacuo to yield 0.114g (52%) of compound 28. MP =142 ℃ (DSC).
Example B20
Preparation of Compound 29
A solution of 2M methylamine in THF (4.8ml, 0.0097mol) was added to intermediate 26(0.14g, 0.0003mol) and K2CO3(0.1g, 0.0007mol) in THF (5 mL). In a sealed tube, the solution was heated to 100 ℃, held for 24 hours, then cooled to room temperature, and poured into water/NaCl. The mixture was extracted with DCM. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 95% DCM-5% MeOH, 0.1% NH)4OH). The product fractions were collected and the solvent was evaporated, yielding 103mg (86%) of compound 29. MP =80 ℃ (Kofler).
Example B21
Preparation of Compound 30
HCl/i-PrOH (0.4ml, 0.002mol) was added dropwise to intermediate 59(0.31g, 0.0005mol) in CH at 10 deg.C3OH (5mL) solution and the mixture was stirred for 2 hours. The solution is evaporated to dryness and the residue is taken up in ice-water and taken up with NH4The OH was basified and the product was extracted with DCM. The organic layer was dried (MgSO4) And (5) drying by distillation. The residue was purified by chromatography on silica gel (Sunfire silica 5 μm150 X30.0mm; mobile phase: gradient from 0.2% NH)4OH、98% DCM, 2% MeOH to 1.1% NH4OH, 89% DCM, 11% MeOH). The product fractions were collected and the solvent was evaporated, yielding 106mg (47%) of compound 30. MP =80 ℃ (Kofler).
Example B22
Preparation of Compound 31
To intermediate 28(0.4g, 0.92mmol) in dioxane (8ml) was added cyanogen bromide (0.099g, 0.93mmol) at room temperature. Then, sodium bicarbonate (0.0775g, 0.94.8mL) was added (in 4.8mL distilled water). The mixture was stirred at room temperature for 5 hours. The mixture was extracted with EtOAc and dried (MgSO)4) Filtered and evaporated to dryness. The residue was taken up in diethyl ether, filtered and dried to yield 0.42g (99%) of compound 31. MP =254 ℃ (Kofler).
Example B23
Preparation of Compound 32
Hydrazine monohydrate (81 μ L, 2.58mmol) was added to a solution of intermediate 27(0.21g, 0.37mmol) in EtOH (10 mL). The mixture was heated at 80 ℃ for 5 hours. The mixture was cooled to room temperature, evaporated and the residue poured into water. The aqueous layer was extracted with DCM, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue was purified by silica gel chromatography (random SiOH, 15-40 μm, 10 g; mobile phase: 95% DCM-5% MeOH-0.5% NH)4OH). The pure fractions were collected and the solvent was evaporated, yielding 97mg (59%) of compound 32. MP =80 ℃ (Kofler).
Example B24
Preparation of Compound 33
Intermediate 31(270mg, 0.59mmol), sodium triacetoxyborohydride (312mg, 1.475mmol) and isopropylamine (100. mu.l, 1.2mmol) were placed in CH3CN (6ml), and stirred at room temperature for 24 hours. Isopropylamine (500 μ l, 5.8mmol) was added and the reaction mixture was stirred at room temperature for 12 hours, then sodium triacetoxyborohydride (312mg, 1.5mmol) was added and the reaction mixture was stirred for 24 hours. Adding 10% of K2CO3An aqueous solution. The reaction mixture was extracted twice with DCM and dried (MgSO)4) Filtering and evaporating. The residue (437mg) (Sunfire silica, 5 μm150X30.0mm, mobile phase: gradient from 0.2% NH) was purified by silica gel chromatography4OH, 98% DCM, 2% MeOH to 0.8% NH4OH, 92% DCM, 8% MeOH). The fractions of the desired product were collected and the solvent was evaporated, yielding 113mg of compound 33 (cis).
Example B25
Preparation of Compound 34
Intermediate 29(0.5g, 0.8mmol) and 40% methylamine in water (28ml, 0.33mol) were heated in dioxane (20ml) at 120 ℃ for 5 hours in a sealed tube. The solution was cooled and evaporated to dryness. The residue was purified by chromatography on silica gel (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0.2% NH)4OH, 98% DCM, 2% MeOH to 1.4% NH4OH, 86% DCM, 14% MeOH). The pure fractions were collected and the solvent was evaporated. The product was crystallized from diethyl ether. The precipitate was filtered and dried to yield 118mg (31%) of compound 34. MP =174 ℃ (DSC).
Example B26
Preparation of Compound 35
To a mixture of intermediate 60(268mg, 0.51mmol) was added THF (20ml) followed by tetrabutylammonium fluoride (2.53ml, 1M in THF; 2.53 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. EtOAc and water were added and the two phases were separated. Drying (MgSO)4) The organic phase was filtered and concentrated. The residue was purified by chromatography on silica gel (Hyperprep C18 HS BDS 100A 8mu (Shandon); mobile phase gradient: 90% 0.25% aqueous ammonium bicarbonate, 10% CH3CN to 100% CH3CN). The product fractions were collected and the solvent was evaporated. The residue was dissolved in CH3CN/Water, lyophilized to give 55mg of Compound 35.
Example B27
Preparation of Compound 36
A mixture of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline (521mg, 1.8mmol), intermediate 38(377mg, 1.8mmol), sodium tert-butoxide (520mg, 5.4mol) was degassed in dioxane (10ml) at room temperature under a nitrogen atmosphere. After 10 minutes at room temperature, palladium (II) acetate (47% Pd) (20mg, 0.09mmol) and 1,1'- [1, 1' -binaphthyl ] were added portionwise under nitrogen at room temperature]-2, 2' -diylbis [1, 1-diphenylphosphine](56mg, 0.09 mmol). The reaction mixture was heated at 90 ℃ overnight, then cooled to room temperature and partitioned between water and DCM. Drying (MgSO)4) The organic layer was filtered and concentrated. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 30 g; mobile phase: 98% DCM, 2% MeOH). The product fractions were collected and the solvent was evaporated. The residue was again purified by achiral supercritical fluid chromatography (2 ethyl pyridine,6μm150 x21.2mm; mobile phase: 0.3% 2-propylamine, 15% MeOH, 85% CO2). The product fractions were collected and the solvent was evaporated. The residue was taken up in diethyl ether, filtered and dried to yield 0.209g (27%) of compound 36. MP =164 ℃ (Kofler).
Example B27A
Preparation of Compound 920
The intermediate is reacted with a catalyst(see A52) (0.5 g; 1.5mmol), a mixture of intermediate 2(0.36 g; 1.3mmol) and sodium tert-butoxide (0.36 g; 1.3mmol) was degassed in anhydrous dioxane (40ml) at room temperature under a nitrogen atmosphere. After 10 min, 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (50 mg; 0.13mmol) and tris (dibenzylideneacetone) dipalladium (0) (115 mg; 0.13mmol) were added and the reaction mixture was heated at 100 ℃ for 4 h. The reaction mixture was cooled to room temperature, poured into a mixture of water and brine, filtered through a pad of celite, extracted with EtOAc, washed with water, and dried (MgSO)4) Filtered and evaporated to dryness to give 1.1g of residue. The residue was purified by chromatography on silica gel (5 μm, mobile phase: gradient from 71% heptane, 1% MeOH, 28% AcOEt to 20% MeOH, 80% AcOEt). The target fraction was collected and evaporated to yield 240 mg of residue. The residue was taken up in Et2O, filtered and dried to give 144mg of compound 920. MP: 123 Deg.C (DSC).
Example B28
Preparation of Compound 37
At 0 deg.C, will be highPotassium manganate (0.117g, 0.738mmol) was added to a solution of compound 51(0.326g, 0.738mmol) in acetone (10ml) and water (2.5 ml). The solution was stirred at room temperature overnight and then poured into ice water. DCM was added and the mixture was filtered through a layer of celite. The organic layer was extracted and dried (MgSO)4) And (5) drying by distillation. The residue (0.23g) was chromatographed on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 95% DCM, 5% MeOH, 0.1% NH)4OH). The desired product fraction was collected and the solvent was evaporated to yield 0.150g of compound 37, which was crystallized from DIPE, filtered and dried to yield 0.139g (40%) of compound 37. MP =154 ℃ (DSC).
Example B29
Preparation of Compound 38
Intermediate 62(3.9g, 8.3mmol) and K2CO3(1.15g, 8.3mmol) of the mixture was stirred in MeOH (150ml) at room temperature for 18 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was decanted, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The solid residue is taken up in diethyl ether and the precipitate is filtered off and dried to yield 2.84g (85%) of compound 38. MP =168 ℃ (Kofler).
Example B30
Preparation of Compound 39And the HCl salt of Compound 40
Intermediate 10(365mg, 0.75mmol) was heated to 80 ℃ in 3, 5-dimethylpiperidine (5mL) overnight. Then 5mL of 3, 5-dimethylpiperazine are addedPyridine was added to the solution and heated at 80 ℃ for 5 hours. The solution was evaporated to dryness and the residue was poured into water and extracted with EtOAc. Drying (MgSO)4) The organic layer was filtered and evaporated. The residue (853mg) was purified by chromatography on silica gel (Sunfire silica, 5 μm150X30.0 mm; mobile phase: gradient from 0.1% NH)4OH, 99% DCM, 1% MeOH to 0.8% NH4OH, 92% DCM, 8% MeOH). The fractions of the desired product were collected and the solvent was evaporated, yielding 41.8mg (11%) of fraction I and 115.7 mg (31%) of Compound 39. MP =80 ℃ (Kofler) (gum). Fraction I was dissolved in isopropanol. The mixture was stirred at 0 ℃ and then 67 μ L (4 eq) of 5N HCl/isopropanol was added dropwise to the mixture. Diethyl ether was added to the solution and stirred at 0 ℃ for 1 hour. The precipitate was filtered and dried to yield 38.3mg (10%) of compound 40. MP =80 ℃ (Kofler) (gum).
Example B31
Preparation of Compound 41
A mixture of intermediate 37(0.22g, 0.39mmol), hydrazine monohydrate (0.085 mL, 2.72mmol) was heated in EtOH (5mL) at 80 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc was added and the organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (0.250g) was chromatographed on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 0.1% NH)4OH, 96% DCM, 4% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.120g, 70%) was taken up in diethyl ether/CH3CN crystallized, filtered and dried under vacuum at 60 deg.C to give 0.110g (65%) of Compound 41. MP: 168 deg.C (Kofler); 169 Deg.C (DSC).
Example B32
Preparation methodCompound 33And compound 43
Intermediate 31(270mg, 0.59mmol), sodium triacetoxyborohydride (312mg, 1.48mmol) and isopropylamine (100 μ l, 1.2mmol) in CH3CN (6ml), and stirred at room temperature for 24 hours. Isopropylamine (500 μ l, 5.8mmol) was added and the reaction mixture was stirred at room temperature for 12 hours, then sodium triacetoxyborohydride (312mg, 1.5mmol) was added and the mixture was stirred for 24 hours. Adding 10% of K2CO3An aqueous solution. The reaction mixture was extracted twice with DCM and dried (MgSO)4) Filtering and evaporating. The residue (437mg) (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0.2% NH) was purified by silica gel chromatography4OH, 98% DCM, 2% MeOH to 0.8% NH4OH, 92% DCM, 8% MeOH). The product fractions were collected and the solvent was evaporated, yielding 113mg (38%) of compound 33 and 42mg (14%) of compound 43.
Example B33
Preparation of Compound 604
N, N-diisopropylethylamine (0.86 mL; 5.2 mmol) and triethylamine (0.73 mL; 5.2 mmol) were added to a solution of intermediate 73(0.6 g; 0.87mmol) in methanol (7.5 mL). The reaction was stirred at 80 ℃ for 15 h, cooled to room temperature, and diluted with DCM and water. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (0.25g, 59%) was taken up in diethyl ether/CH3And (4) crystallizing CN. The precipitate is filtered offDrying in vacuo afforded 215mg (51%) of compound 604. MP: 157 Deg.C (DSC).
Example B34
Preparation of Compound 605
NaH (1.1 g; 27.7mmol) was added portionwise to N, N-dimethylformamide (100mL) and after a few minutes, intermediate 3(5 g; 13.8 mmol) was added portionwise at 5 ℃ under nitrogen. The reaction mixture was stirred at 5 ℃ for 30 minutes. Then, a solution of ethyl 2-bromopropionate (3.6 mL; 27.7mmol) in N, N-dimethylformamide (7mL) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was poured into ice water. The precipitate was filtered off and washed with water. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (7.51g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and concentrated to yield 5.3g (84%) of intermediate 605.
Example B35
Preparation of Compound 607 (mixture of enantiomers)
Intermediate 74(8 g; 16.08 mmol) and potassium phthalimide (phtalimide) (6 g; 32.16 mmol) in CH were reacted using a monomode microwave3The CN (110 mL) solution was heated at 120 ℃ for 2 hours. The reaction mixture was cooled to room temperature and poured into ice water. The precipitate was filtered off and washed with water and DCM. The organic layer was separated, washed with water and dried (MgSO)4) Filtration and evaporation of the solvent gave 7.4g of compound 607 which was used in the next step without further purification.
Example B36
Preparation of Compound 313
A solution of 1M tetrabutylammonium fluoride in THF (7.7 mL; 7.7mmol) was added dropwise to a solution of intermediate 76(3.5 g; 5.9 mmol) in THF (75 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and EtOAc was added. With 10% K2CO3The mixture was basified and the organic layer was separated, washed with brine and dried (MgSO4) Filtering and evaporating the solvent. The residue (4.4g) was crystallized from diethyl ether. The precipitate was filtered off and dried in vacuo to afford 2.62g (93%) of compound 313. MP: 176 Deg.C (DSC).
Example B37
Preparation of Compound 615
A mixture of intermediate 77(2 g; 3.6 mmol) and isopropylamine (1.55 g; 18mmol) was heated in acetonitrile (30mL) at 100 ℃ for 18 hours in a sealed vessel. The reaction mixture was cooled to room temperature. The reaction was poured into ice water and EtOAc was added. Separating the organic layer with NaHCO3The solution was washed and dried (MgSO)4) Filtered and evaporated to dryness. The residue (2.5g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.5% NH)4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated. The residue was crystallized from diethyl ether (0.85 g), the precipitate was filtered off and dried in vacuo to afford 0.76g (41%) of compound 615. MP: 134 Deg.C (DSC).
Example B38
Preparation of Compound 616
Trifluoroacetic acid (6.5 mL; 84.8 mmol) was added to a solution of intermediate 82 in DCM (50mL) at 10 ℃. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, the residue was taken up in DCM and taken up with 10% K2CO3And (6) washing. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried in vacuo to afford 0.65g (65%) of compound 616. MP: 170 deg.C (Kofler).
Example B39
Preparation of Compound 617
A solution of 1M tetrabutylammonium fluoride in THF (1.82 mL, 1.8mmol) was added dropwise to a solution of intermediate 85(0.88 g, 1.65 mmol) in THF (20mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into ice water and EtOAc was added. With 10% K2CO3The mixture was basified and the organic layer was separated, washed with brine and dried (MgSO4) Filtering and evaporating the solvent.
The residue (0.68g) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated. The residue (0.54g) was crystallized from diethyl ether. The precipitate was filtered off and dried in vacuo to afford 0.444g (65%) of compound 617. MP: 149 Deg.C (DSC).
Example B40
Preparation of Compound 618
A mixture of intermediate 86(0.446 g; 0.91mmol) and isopropylamine (6.2 mL; 72.3 mmol) was heated in acetonitrile (14mL) at 140 ℃ for 1 hour in a sealed vessel using a single mode microwave. The reaction mixture was cooled to room temperature. The reaction was poured into ice water and EtOAc was added. Separating the organic layer with NaHCO3The solution was washed and dried (MgSO)4) Filtered and evaporated to dryness. The residue (0.423g) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60 g; mobile phase: 0.5% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated. The residue was crystallized from diethyl ether (0.3g), the precipitate was filtered off and dried in vacuo to give 0.21g (52%) of compound 618. MP: 139 ℃ (DSC).
Example B41
Preparation of Compound 619Of HCl salt of
A mixture of intermediate 87(1.26 g; 0.99mmol) and hydrazine monohydrate (0.22 mL, 7.0mmol) was stirred in EtOH (20mL) at 80 ℃ for 3 h. The reaction mixture was cooled to room temperature and poured into ice water. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (0.566g) was purified by silica gel chromatography (SiOH, 5 μm, 150x30 mm; mobile phase gradient: 0.2% NH)4OH, 98% DCM, 2% MeOH to 1.2% NH4OH, 88% DCM, 12% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.385g, 77%) was dissolved in isopropanol. The reaction mixture was stirred at 0 ℃ and then 0.6 mL of 5N HCl/isopropanol was added dropwise to the solution. Adding diethyl ether to the solutionAnd stirred at 0 ℃ for 1 hour.
The precipitate was filtered off and dried in vacuo to afford 0.42g (69%) of compound 619. MP: 210 deg.C (Kofler).
Example B42
a) Preparation of Compound 620
Intermediate 10(1.4 g; 2.9 mmol), (1S, 4S) - (-) -2, 5-diazabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl ester (0.69 g; 3.5 mmol) and K2CO3(0.8 g; 5.8mmol) in CH3CN (20mL) was stirred at 80 ℃ for 48 hours.
The reaction mixture was cooled to room temperature, poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (1.6g) was purified by silica gel chromatography (random SiOH, 20-45 μm, 450 g; mobile phase: 0.1% NH)4OH, 94% DCM, 6% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.74 g) (Amino 6 μm, 150x21.1 mm; mobile phase: 90% CO) was purified by supercritical fluid chromatography210% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.6g, 36%) was crystallized from diethyl ether. The precipitate was filtered off and dried in vacuo to afford 0.444g (26%) of compound 620. MP: 114 deg.C (Kofler).
b) Preparation of Compound 621Of HCl salt of
5N HCl/i-PrOH solution (0.48 mL, 2.4 mmol) was added dropwise to CH of compound 620(0.35g, 0.6mmol) at 5 deg.C3OH (10mL), and the mixture was stirred at room temperature for 3 days. Diethyl ether was added and the precipitate was filtered off and dried in vacuo to yield 0.33 g (94%) of compound 621. MP：>260℃(Kofler)。
Example B43
Preparation of Compound 622
A solution of 1M tetrabutylammonium fluoride in THF (1.1 mL; 1.1mmol) was added dropwise to a solution of intermediate 88(0.43 g; 0.79mmol) in THF (6mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured into ice water. The precipitate is filtered off, water and CH3CN washing and drying gave 0.13g (40%) of Compound 622. MP: 190 deg.C (Kofler).
Example B44
Preparation of Compound 623Of HCl salt of
A mixture of intermediate 89(0.26 g; 0.43mmol) and isopropylamine (5mL) was heated in acetonitrile (2mL) at 90 ℃ for 18 hours in a sealed vessel. The reaction mixture was cooled to room temperature. The reaction was poured into ice water and DCM was added. The organic layer was separated, washed and dried (MgSO)4) Filtered and evaporated to dryness. The residue (0.28g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.4% NH)4OH, 96% DCM, 4% MeOH). The pure fractions were collected and concentrated. The residue (0.156g, 77%) was dissolved in CH3In CN. 5N HCl/isopropanol was added dropwise to the solution. Evaporation of the solvent and drying in vacuo gave 0.162 g (70%) of compound 623. MP: 133 ℃ (Kofler).
Example B45
Preparation of compoundsObject 630
NaH (0.54 g; 13.3 mmol) was added portionwise to intermediate 3(2.4 g; 6.66 mmol) in N, N-dimethylformamide (36 mL). The reaction mixture was stirred at 0 ℃ for 30 minutes. Then, intermediate 91(2.2 mL; 10 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (4.2g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 300 g; mobile phase: 0.1% NH)4OH, 98.5% DCM, 1.5% MeOH). The pure fractions were collected and concentrated to yield 0.793 g (21%) of compound 630. MP: 67 deg.C (Kofler).
Example B46
Preparation of Compound 632
Trifluoroacetic acid (0.073 mL; 0.25mmol) was added to a solution of intermediate 92(0.135 g; 0.25mmol) in THF (5 mL). The reaction was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.151g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm; mobile phase gradient: 70% heptane, 2% MeOH, 28% EtOAc to 20% MeOH, 80% EtOAc). The pure fractions were collected and concentrated. The residue (0.04g) was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.033g (31%) of compound 632. MP: 156 Deg.C (DSC).
Example B47
Preparation of Compound 638
NaH (0.65 g; 16.6 mmol) was added portionwise to intermediate 3(3 g; 8.3mmol) in N, N-dimethylformamide (25 mL). The reaction mixture was stirred at 10 ℃ for 30 minutes. Then, 3-chloro-3-methyl-1-butyne (1.2 g; 10.8 mmol) was added dropwise under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 48 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (4g) was purified by silica gel chromatography (mobile phase gradient: 71% heptane, 1% MeOH, 28% EtOAc to 20% MeOH, 80% EtOAc). The pure fractions were collected and concentrated to yield 0.152 g (4%) of compound 638, which was used in the next step without further purification.
Example B47A
Preparation of Compound 919
Sodium hydride (0.24 g; 6.1mmol) was added portionwise to a solution of intermediate 3(1.1 g; 3mmol) in DMF (10mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 30 minutes. Then, a solution of (4-chloro-2-butyn-1-yl) -benzene (1 g; 6.1mmo) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and then at room temperature overnight. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue was purified by chromatography on silica gel (SiOH, 15-40 μm, 300 g; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The target fraction was collected, evaporated to give 0.66g of residue, which was then purified by achiral supercritical fluid chromatography (5 μm, mobile phase, 60% CO)240% MeOH/iPrOH 50/50 v/v mixture). Collecting the target fractionAnd the solvent was evaporated to give 282mg (19%) of compound 919. The fraction was treated with Et2Crystallization of O afforded 143mg compound 919(MP =130 ℃).
Example B48
Preparation of Compound 641
A mixture of intermediate 17a (0.3 g; 0.6mmol), glycylamine hydrochloride (0.2 g; 1.8mmol), potassium iodide (0.1 g; 0.6mmol), and sodium carbonate (0.32 g; 3.0mmol) was stirred in 1-BuOH (12mL) at 85 deg.C for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.28g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm; mobile phase gradient: 0.2% NH)4OH, 98% DCM, 2% MeOH to 0.9% NH4OH, 91% DCM, 9% MeOH). The pure fractions were collected and concentrated. The residue (0.100g) was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.081g (28%) of compound 641. MP: 155 Deg.C (DSC).
Example B49
Preparation of Compound 137
A mixture of intermediate 93(12.8 g; 23.4 mmol) and isopropylamine (61 mL; 500 mmol) was heated in acetonitrile (500 mL) at 100 ℃ for 18 hours in a sealed vessel. The reaction mixture was cooled to room temperature. The reaction was poured into ice water and EtOAc was added. The organic layer was washed with brine and dried (MgSO)4) It was filtered through silica gel and evaporated to dryness. The residue (13g) was chromatographed on silica gel (random SiOH, 20-40 μm, 1000 g; mobile phase: 0.5% NH)4OH，95%DCM，10%MeOH) In that respect The pure fractions were collected and concentrated to give 8g (55%) of the free base, which was converted to the HCl salt of compound 137.
Example B50
Preparation of Compound 2
A solution of 1M tetrabutylammonium fluoride in THF (30.3 mL; 30.3 mmol) was added dropwise to a solution of intermediate 94(10.2 g; 20.2 mmol) in THF (70mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and washed with 10% K2CO3Basified and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 5.9g (75%) of compound 2. MP: 169 Deg.C (DSC).
Example B51
Preparation of Compound 644Of HCl salt of
Intermediate 100(0.09 g; 0.14mmol) and K2CO3(0.058 g; 0.42mmol) of the mixture is stirred in MeOH (1.1mL) at room temperature for 1 h. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The residue (0.2g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.5% NH)4OH, 93% DCM, 7% MeOH). The pure fractions were collected and concentrated. The residue was dissolved in EtOH/CH3In CN, and acidified with 5N HCl/i-PrOH. The precipitate was filtered off and dried to yield 0.053g (46%) of compound 644 hydrochloride.
Example B52
Preparation of Compound 93Alternative methods of
Intermediate 3(10 g; 27.7mmol) was added to a solution of potassium hydroxide (27.4 g; 415 mmol), tetrabutylammonium bromide (1.34 g; 4.0 mmol) in 280 mL and water (3 mL). The reaction mixture was stirred at 50 ℃ for 30 minutes, then 3-bromopropylamine hydrochloride (9.7 g; 44.3 mmol) was added portionwise and stirred at 50 ℃ for 2 hours. The reaction mixture was cooled to room temperature. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (20g) was purified by chromatography (random SiOH, 20-45 μm, 1000 g; mobile phase: 1% NH)4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 10.5 g (90%) of compound 93. MP: 178 Deg.C (DSC).
Example B53
Preparation of Compound 645
A5N HCl/i-PrOH solution (2.5 mL; 12.5 mmol) was added dropwise to intermediate 105(0.8g, 1.54 mmol) in CH at 10 deg.C3OH (25mL) solution, and the mixture was then stirred at room temperature for 18 hours. The red precipitate was filtered, washed with diethyl ether and dried. The precipitate was taken up in DCM and washed with 1M NaOH solution. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness. The residue was crystallized from diethyl ether. The precipitate was filtered and dried in vacuo to yield 0.22g (34%) of compound 645. MP: 188 Deg.C (DSC).
Example B54
Preparation of Compound 646
5N HCl/i-PrOH solution (1.1 mL; 5.7 mmol) was added dropwise to the intermediate at 10 deg.C(0.8 g; 1.4mmol) (prepared as described for intermediate 103 in A42 a-c) of CH3OH (20mL) solution, and the mixture was stirred for 18 hours. The reaction mixture was taken up in DCM, washed with 1M sodium hydroxide solution, the organic layer washed with water, MgSO4Dried, filtered and evaporated to dryness. The residue (1.3g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 300 g; mobile phase: 0.5% NH)4OH, 93% DCM, 7% MeOH to 1% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated. The residue was crystallized from diethyl ether, the precipitate was filtered off and dried in vacuo to yield 0.11g (19%) of compound 646. MP: 125 deg.C (Kofler).
Example B55
Preparation of Compound 647Of HCl salt of
5N HCl/i-PrOH solution (0.7 mL; 3.4mmol) was added dropwise to the intermediate at 10 deg.C(0.5 g; 0.8mmol) (prepared as described for intermediate 105 in A42 e) of CH3OH (20mL) solution, and the mixture was stirred for 18 hours. The reaction mixture was evaporated to dryness and the residue was taken up in DCM and basified with 1N sodium hydroxide solution. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness. The residue was crystallized from diethyl ether and 1mL of 3N HCl. The precipitate was filtered off and dried to yield 0.2g of compound 647. MP: 133 ℃ (Kofler).
Example B56
Preparation of Compound 655
Will K2CO3(0.38 g; 2.7mmol) was added to intermediate 109(1.4 g; 2.7mmol) in MeOH (40 mL). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water and EtOAc was added. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to give 1.2g of compound 655.
Example B57
Preparation of Compound 658
Intermediate 110(0.4 g; 0.67 mmol) was hydrogenated with Raney nickel (0.4 g; 6.88mmol) as catalyst in MeOH (20mL) in a pressure vessel (3 bar) at room temperature. After 5 hours, the catalyst was filtered off on a pad of celite and the filtrate was concentrated in vacuo until dry. The residue (0.32g) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60 g; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and evaporated to dryness. The residue (0.19g) was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.16g (42%) of compound 658. MP: 152 Deg.C (DSC).
Example B58
Preparation of compound 659
Will K2CO3(0.17g, 1.19 mmol) was added to intermediate 111(0.66 g, 1.19 mmol) (prepared as described for A44, starting from intermediate 112) (in MeOH (20 mL)). The solution was stirred at room temperature for 3 hours. The reaction mixture was poured into water and EtOAc was added. With MgSO4The organic layer was dried, filtered and evaporated to dryness. By CH3The residue is crystallized from CN and diethyl ether, the precipitate is filtered off and dried, yielding 0.25g (44%) of compound 659. MP: 106 Deg.C (DSC).
Example B59
Preparation of Compounds 660 and 661
NaH (0.19 g; 4.7mmol) was added portionwise to intermediate 118(0.95 g; 2.4 mmol) in N, N-dimethylformamide (1186 mL). The reaction mixture was stirred at 5 ℃ for 1 hour. Then, 1, 2-epoxy-3, 3, 3-trifluoropropane (0.4 mL; 4.7mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature, stirred for 18 hours, and stirred at 60 ℃ for 3 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (1.44g) was purified by silica gel chromatography (random SiOH, 20-45 μm, 450g, mobile phase gradient: from 0.5% NH)4OH, 98% DCM, 2% MeOH to 1% NH4OH, 88% DCM, 12% MeOH). The pure fractions were collected and evaporated to give 1.44g of residue. Separation of the enantiomers (CHIRALPAK AD-H5 μm250x20 mm; mobile phase: 0.3% 2-propylamine, 55% CO) by manual supercritical fluid chromatography245% MeOH). The desired product fraction was collected and the solvent was evaporated. The first eluted enantiomer (0.15g) was crystallized from diethyl ether. The precipitate is filtered off and dried, yielding 0.11g (9%) of compound 660 (R)*MP =154 ℃ (DSC)). The second eluted enantiomer (0.15g) was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.116 g (10%) of compound 661 (S)*，MP=151℃(DSC))。
Example B59A
Preparation of Compounds 926 (free base) and 892(HCl salt)
The following reaction was carried out twice:
sodium hydride (2.0g, 49.8mmol) was added portionwise to a solution of intermediate 3(9g, 24.9mmol) in DMF (140mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, then 1.2-epoxy-3-methylbutane (5.3 mL, 49.8mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and then at 80 ℃ for 3 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to give a brown oil. The residue was purified by chromatography on silica gel (SiOH, 20-45 μm, mobile phase: 0.1% NH)4OH, 97.5% DCM, 2.5% MeOH). The desired product fractions were collected and evaporated to afford 1.2g (11%) of compound 389 and 3.36g (25%) of compound 926. The latter fraction was purified again by chromatography on silica gel (SiOH, 20-45 μm, 450g, mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The product fractions were collected and evaporated to afford 1.1g (8%) of compound 926. The fractions (300 mg) were converted to the HCl salt in MeOH. The solid was filtered and washed with Et2O wash and dry to give 159 mg of compound 892 as a red powder.
Example B60
Preparation of Compound 664
NaH (0.11 g; 2.8mmol) was added portionwise to intermediate 3(0.5 g; 1.4mmol) in N, N-dimethylformamide (3 mL). The reaction mixture was stirred at 5 ℃ for 1 hour. Then, at 5 ℃ under a nitrogen atmosphere, dimethylsulfamoyl chloride (0.3 mL; 2.8mmol) was added dropwise. The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature and stirred for 6 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.8g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm; mobile phase: gradient from 100% DCM to 0.4% NH)4OH, 96% DCM, 4% MeOH). The pure fractions were collected and evaporated. The residue (0.05g) was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.046g (7%) of compound 664. MP: 80 deg.C (Kofler).
Example B61
Preparation of Compounds 667 and 668
Intermediate 10(1 g; 2mmol), 3-methyl-1H-1, 2, 4-triazole (0.35g, 4.2 mmol) and K2CO3A solution of (0.72 g; 5.2 mmol) 1-methyl-2-pyrrolidone (35mL) was stirred at 135 deg.C for 18 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and evaporated to dryness. The residue (1.8g) was purified by silica gel chromatography (SiOH, 20-45 μm, 450 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). Harvesting machineThe pure fractions were pooled and the solvent was evaporated. The residue (0.72g) was separated by hand supercritical fluid chromatography (CHIRALPAK AD-H5 μm250x20 mm; mobile phase: 0.3% 2-propylamine, 50% CO)250% isopropyl alcohol). The desired product fraction was collected and the solvent was evaporated. The first product was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.25g (26%) of compound 667. MP: 181 Deg.C (DSC).
The second product was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.27g (28%) of compound 668. MP: 137 Deg.C (DSC).
Example B62
Preparation of Compound 669
The experiment was performed 6 times with the following numbers.
A mixture of intermediate 3(0.5 g; 1.4mmol), (vinyl) phosphonic acid diethyl ester (0.5 mL; 3mmol) and tri-N-butylphosphine (0.035 mL; 0.1 mmol) in CH was placed in a sealed tube3CN (2mL) at 140 ℃ for 15 hours. The reaction mixture was cooled to room temperature and diluted with DCM and water. The organic layers were separated, combined and dried (MgSO)4) Filtered and evaporated to dryness. The residue (7g) was purified by chromatography on silica gel (SiOH, 20-45 μm, 450 g; mobile phase: 0.1% NH)4OH, 95% DCM, 5% iPrOH). The pure fractions were collected and the solvent was evaporated. By CH3The residue (3.1 g) is crystallized from CN and diethyl ether, the precipitate is filtered off and dried to yield 0.88 g (21%) of compound 669. MP: 122 Deg.C (DSC).
Example B63
Preparation of Compound 693Of HCl salt of
Trifluoroacetic acid (7 mL; 94.7 mmol) was added(prepared according to the protocol described in B3B) (1.2 g; 2mmol) in DCM (60 mL). The solution was then stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and washed with NH4Basifying OH. The product was extracted with DCM. Drying (MgSO)4) The organic layer was filtered and the solvent was evaporated. The residue is crystallized from diethyl ether and the precipitate is filtered off.
The precipitate was dissolved in isopropanol, stirred at 0 ℃ and then 0.8 mL of 5N HCl/i-PrOH was added dropwise. Diethyl ether was added and the solution was stirred at 0 ℃ for 1 hour. The precipitate is filtered off and dried to yield 0.48 g (35%) of compound 693. MP: 151 Deg.C (DSC).
Example B64
Preparation of Compound 846
Lithium hydroxide monohydrate (0.085 g; 2.0 mmol) was added portionwise to a solution of intermediate 142(0.72 g; 1.4mmol) in THF (20mL) and water (6mL) at room temperature. The reaction mixture was stirred at 70 ℃ for 24 hours. The reaction mixture was evaporated until dryness. The residue was taken up in diethyl ether. The precipitate was filtered off and dried in vacuo to yield 0.577g (88%) of compound 846. MP =170 ℃ (Kofler).
Example B65
Preparation of compound 763
The reaction was carried out in a microwave apparatus (biotage) in a sealed tube.
Intermediate 88a (198.6 mg, 0.552 mmol), intermediate 131(520 mg, 1.21mmol) and tetrakis (triphenylphosphine) palladium (0) (31.89 mg, 0.028 mmol) were stirred in toluene (2.6 mL) at 160 ℃ for 40 min. Toluene (2.6 mL) was added and the reaction mixture was stirred at 160 ℃ for 40 minutes. Water was added and the reaction mixture was extracted with AcOEt. The organic layer was dried (MgSO4) Filtered and dried to give a yellow oil. Using the oil with CH3And (4) crystallizing CN. The crystals were dried (room temperature) to give compound 763 as a yellow powder. MP of 176 ℃.
C. Conversion reaction
Transformation 1
Preparation of Compound 44aAnd
compound 44HCl
HCl (5.53 ml; 27.65mmol) was added to CH of Compound 6(3.2 g; 5.53mmol)3OH (70ml) solution and heated to 60 ℃ for 8 hours. The reaction mixture was cooled to room temperature, poured into water and washed with K2CO3Basified and extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 30g MERCK; mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH, 0.1% NH)4OH). The target fraction was collected and the solvent was evaporated. Compound 44a (1.95g, 71%) was dissolved in diisopropyl alcohol and HCl (5 to 6N in alcohol) (3ml), stirred for 30 minutes and evaporated to dryness. The residue was crystallized from diethyl ether to yield 1.537g (47%) of compound 44. MP =215.29 ℃ (DSC).
Transformation 2
Preparation of Compound 45
Compound 9(3.02 g; 5.95mmol) was heated in pyrrolidine (50ml) at 70 ℃ for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (4.04g) (random SiOH, 15-40 μm, 90 g; mobile phase: gradient from 100% DCM to 90% DCM/10% MeOH/0.1% NH)4OH). The desired fraction was collected and the solvent was evaporated to yield 1.83g (57%) of compound 45.
Transformation of 2A
Preparation of Compound 344Of HCl salt of
Mixing compound 310(0.93 g; 2.1 mmol), pyrrolidine (0.52 mL; 6.4 mL), K2CO3(0.3 g; 2.2mmol) of CH3The CN (50mL) solution was stirred at 80 ℃ for 24 hours. The reaction mixture was cooled to room temperature, poured into ice water and extracted with EtOAc. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.9g) was purified by chromatography on silica gel (SiOH, 5 μm; mobile phase gradient: from 0.2% NH)4OH, 98% DCM, 2% MeOH to 1.3% NH4OH, 87% DCM, 13% MeOH). The pure fractions were collected and concentrated. The residue (0.52g) was dissolved in MeOH and converted to the hydrochloride salt with HCl/2-propanol. Et was added2O and the precipitate was stirred for 30 minutes, filtered off and dried to yield 0.55g (47%) of compound 344. MP: 162 Deg.C (DSC)
Transformation of 2B
Preparation of Compounds 692 and 563
Of HCl salt ofOf HCl salt of
NaH (0.13 g; 3.3 mmol) was added portionwise to 2, 4-dimethylimidazole (0.3 g; 3mmol) in N, N-dimethylformamide (25mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 30 minutes, then compound 236(1 g; 2.4 mmol) was added at 5 ℃ under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was poured into ice water. The organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated. The residue (1.8g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 300 g; mobile phase: 0.5% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated. The residue (1g) (Amino 6 μm; mobile phase: 0.3% isopropylamine, 15% MeOH, 85% CO) was purified by achiral supercritical fluid chromatography2). The pure fractions were collected and the solvent was evaporated to dryness. The first fraction (0.44g) was further purified by silica gel chromatography (SiOH, 5 μm; mobile phase gradient: from 0.4% NH)4OH, 96% DCM, 4% MeOH to 1.5% NH4OH, 85% DCM, 15% MeOH). The pure fractions were collected and concentrated. The residue (0.38g) was dissolved in acetone and 4N HCl/dioxane was then added dropwise. Diethyl ether was added and the precipitate was filtered and dried to yield 0.39g (27%) of compound 692. MP: 157 Deg.C (DSC).
Dissolving the second fraction in CH3CN, then 4N HCl/dioxane was added dropwise. The precipitate was filtered off and dried to yield 0.11g (8%) of compound 563. MP: 201 Deg.C (DSC).
Can be prepared according to the scheme.
Transformation 3
Preparation of Compound 46
Hydrazine monohydrate (0.15 ml; 4.8mmol) was added to a solution of compound 47(0.420 g; 0.7mmol) in EtOH (20 ml). The mixture was heated at 80 ℃ for 24 hours. The mixture was cooled to room temperature, evaporated and the residue poured into water. The organic layer was extracted with DCM, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The crude product was purified by silica gel chromatography (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0% NH)4OH, 100% DCM, 0% MeOH to 0.8% NH4OH, 92% DCM, 8% MeOH). The pure fractions were collected and the solvent was evaporated to dryness to yield 56mg (71%) of compound 46.
Transformation 4
Preparation of Compound 48
Methanesulfonyl chloride (0.093ml, 1.2mmol) was added to compound 93(250mg, 0.6mmol) and Et at 5 deg.C3N (0.25ml, 1.8mmol) in DCM (10 ml). The mixture was stirred at room temperature for 24 hours. The reaction was poured into ice water and DCM was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The crude product was crystallized from diethyl ether. The precipitate was filtered and dried in vacuo to yield 118mg (40%) of compound 48. MP: 189 Deg.C (DSC).
Transformation 5
a) Preparation of Compound 50
NaH (44.8 mg, 1.12mmol) was added portionwise to a solution of compound 17(0.3g, 0.75mmol) in DMF (5mL) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes, then 1, 2-dibromoethane (0.194ml, 2.24mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 hours and then poured into water/K2CO3And extracted with EtOAc. The organic layer was dried (MgSO4)，Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, MERCK; mobile phase gradient: 100% DCM to 97% DCM, 3% MeOH, 0.1% NH)4OH). The pure fractions were collected and evaporated to dryness to yield 0.236g (63%) of compound 50.
b) Preparation of Compound 52
Mixing compound 17(214 mg; 0.53mmol), 1-chloro-2-methyl-2-propanol (0.13 ml; 1.28mmol), K2CO3(147 mg; 1.1mmol) was heated to 120 ℃ in DMF (9ml) and held for 72 hours. The reaction mixture was cooled to room temperature and poured into water/K2CO3In (1), extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (277mg) (random SiOH, 15-40 μm, 30 g; mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH, 0.1% NH)4OH). The pure fractions were collected and evaporated to dryness. The residue (226mg) was crystallized from diethyl ether to yield 178mg (90%) of compound 52. MP =159 ℃ (DSC).
c) Preparation of Compound 53
Compound 54(130 mg; 0.38mmol), methyl iodide (23.7. mu.l; 0.38mmol) and K2CO3(105.3 mg; 0.76mmol) in CH3CN (10mL) at reflux overnight. More methyl iodide (23.7. mu.l; 0.38mmol) and K were added2CO3(105.3 mg; 0.76mmol) and the reaction mixture is refluxed for a further 8 hours. The reaction mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and the solvent was evaporated to dryness. The residue was crystallized from diethyl ether, filtered and dried to yield 29mg (21%) of compound 53.
d) Preparation of Compound 55
NaH (0.59g, 1.495mmol) was added portionwise to a solution of compound 17(0.3g, 0.75mmol) in DMF (6 ml). The mixture was stirred at 0 ℃ for 1h, then 1- (2-oxiranylmethyl) -piperidine (0.316mg, 2.24mmol) was added. The resulting mixture was stirred at 5 ℃ for 1 hour and at 90 ℃ overnight. The mixture was poured into water and extracted with DCM. The organic layer was dried, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm60g, PharmPrep MERCK; mobile phase: 0.7% NH)4OH, 93% DCM, 7% MeOH). The pure fractions were collected and the solvent was evaporated. The pure fractions were collected and the solvent was evaporated, yielding 0.045g (11%) of compound 55.
e) Preparation of Compound 56
NaH (179.3mg, 4.5mmol) was added portionwise to a solution of compound 17(1.5g, 3.7mmol) in DMF (20 ml). The mixture was stirred at 0 ℃ for 1h, then (2-bromoethoxy) -tert-butyldimethylsilane (0.96ml, 04.5mmol) was added. The resulting mixture was stirred at room temperature for 4 hours. The mixture was poured into water and extracted with DCM. The organic layer was dried, filtered and concentrated to dryness to give 2.1g of a crude residue. Tetrabutylammonium fluoride (3.75ml of a 1M solution in THF, 3.75mmol) was added dropwise to a solution of the above residue in THF (25ml) at room temperature and stirred for 5 hours at room temperature. The reaction mixture was poured into ice water and washed with K2CO3Basified and extracted with EtOAc. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and concentrated to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 50 g; mobile phase gradient: 100% DCM to 97% DCM, 3% MeOH, 0.1% NH)4OH). The fractions of the desired product were collected and the solvent was evaporated, yielding 1.3g (77%) of compound 56, which was then purifiedIn Et2Trituration in O, filtration and drying in vacuo at 60 ℃ gave 1.22g (73%) of compound 56. MP =147.5 ℃ (DSC).
f) Preparation of Compound 57
Under microwave irradiation, compound 16(0.02g, 0.046mmol), methyl vinyl sulfone (33 μ L, 0.4mmol), Et3N (15.5ml, 0.11mmol) in CH3OH (2mL) was heated to 120 ℃ for 30 minutes. The mixture was evaporated to dryness and purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 95% DCM, 5% MeOH, 0.5% NH)4OH). The desired fraction was collected and the solvent was evaporated, yielding 22.3mg (90%) of compound 57. MP =80 ℃ (Kofler).
g) Preparation of Compound 58
Dimethylsulfamoyl chloride (0.06 mL, 0.56mmol) was added dropwise to compound 17(0.15g, 0.37mmol), 4-methylaminopyridine (0.0045g, 0.037mmol), Et at 5 ℃ under a nitrogen atmosphere3N (0.104mL, 0.75mmol) in DCM (5 mL). The reaction mixture was stirred at 5 ℃ for 1 hour and then at room temperature overnight. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue was chromatographed on silica gel (random SiOH, 15/40 μm, 30g MERCK; mobile phase: gradient 100% DCM to 97% DCM, 3% MeOH). The target fraction was collected and the solvent was evaporated. The compound was crystallized from diethyl ether, filtered and dried in vacuo at 60 ℃ to give 0.065g (34%) of compound 58. MP =163 ℃ (DSC).
h) Preparation of Compound 59
Compound 60 (prepared from compound 127 following the reaction to convert 7) (0.073g, 0.15mmol) was dissolved in DCM (5mL) and N, N-diisopropylethylamine (0.037mL, 0.23mmol) was added. To this solution methanesulfonyl chloride (0.035ml, 0.23mmol) was added dropwise at 0 ℃, and the mixture was stirred overnight. Water and DCM were added. The organic layer was extracted with DCM. The organic layer was dried, filtered and concentrated. The residue (0.1g) was purified by chromatography on silica gel (random SiOH, 15-40 μm, 30g MERCK; mobile phase: 98% DCM, 2% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (0.089g) was crystallized from DIPE. The precipitate was filtered and dried in vacuo to yield 0.04g (47%) of compound 59. MP =200 ℃ (Kofler).
i) Preparation of Compound 51
NaH (0.25mmol) was added portionwise to a solution of compound 17(0.125mmol) in DMF (4 mL). The mixture was stirred at 5 ℃ for 30 minutes, then allyl bromide (0.19 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with water, brine and dried (MgSO)4) Filtration and evaporation to dryness gave 60mg (100%) of compound 51.
Transformation 6
Preparation of Compound 61
Mixing compound 50(0.319g, 0.63mmol), K2CO3(0.347g, 2.51mmol), methylamine (0.94 mL, 1.88mmol in 2M THF) in CH3CN (25ml) at 80 ℃ for 15 hours. The mixture was cooled to room temperature and poured into water/K2CO3In (1), extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm60g, PharmPrep MERCK; mobile phase: gradient from 0.2% NH)4OH, 95% DCM, 5% MeOH to 0.2% NH4OH、90% DCM、10%MeOH). The pure fractions were collected and evaporated to dryness. The product was crystallized from DIPE and pentane, filtered off and dried to yield 157mg (55%) of compound 61. MP =103 ℃ (DSC).
Transformation 7
Preparation of Compound 62
Compound 63(0.280g, 0.46mmol), 3N HCl (4ml) and dioxane (4ml) were heated to 60 ℃ for 5 hours. Cooling the mixture to room temperature, pouring it into water and dissolving it with K2CO3Alkalizing. The product was extracted with EtOAc and dried (MgSO)4) Filtering and evaporating to dryness. The residue was crystallized from DIPE and diethyl ether, filtered and dried to yield 100mg (43%) of compound 62. MP =221 ℃ (DSC).
Transformation 8
Preparation of Compound 64
Lithium hydroxide monohydrate (43 mg; 1.0mmol) was added portionwise at room temperature to a solution of compound 65(230 mg; 0.5mmol) in THF (5mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The residue was taken up in water and the mixture was acidified with 3N HCl. After stirring, the precipitate was filtered, washed with water and dried in vacuo to give 0.206g (88%) of compound 64.
Transformation 9
Preparation of Compound 66
Under microwave irradiation, compound 67(0.245g, 0.53mmol), zinc cyanide (0.093g, 0.79mmol), Pd2(dba)3(0.024g, 0.026mmol), zinc (0.017g, 0.26mmol) and 1,1' -bis (diphenylphosphine)Yl) ferrocene (0.036g, 0.066mmol) was heated in N, N-dimethylacetamide (2ml) at 140 ℃ for 1 hour. The reaction was poured into ice water and DCM was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was chromatographed on silica gel (0.27g) (random SiOH, 15-40 μm, 30g MERCK; mobile phase: gradient from 98% DCM, 2% MeOH to 94% DCM, 6% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (0.2g, 92%) was crystallized from DIPE. The precipitate was filtered and dried in vacuo to yield 0.046g (21%) of compound 66. MP =143 ℃.
Transformation 10
Preparation of Compound 68Of HCl salt of
H at 2 atmospheres at room temperature2A solution of compound 66(0.1g, 0.24mmol) and nickel (0.1g, 1.70mmol) in ammonia and MeOH (4ml, 7N solution) was hydrogenated using nickel as a catalyst for 3 hours under conditions. The catalyst was removed by filtration through celite, washed with DCM, and the filtrate was concentrated. The residue was chromatographed on silica gel (0.1g) (random SiOH, 15-40 μm, 30g MERCK; mobile phase: gradient from 98% DCM, 2% MeOH to 94% DCM, 6% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (0.075g, 74%) was dissolved in iPrOH and 0.11 mL of 5N HCl/iPrOH was added dropwise at 5 ℃. The salt was filtered, washed with DIPE and dried under vacuum at 60 ℃ to give 0.032g (29%) of Compound 68.
Transformation 11
Preparation of Compound 69
Compound 64(Li salt) (500mg, 1.18mmol), 1,1, 1-trimethyl-N- (trimethylsilyl) silanylamine (silamine, 0.5ml, 2.35mmol), N3- (ethylcarboximidoyl) -N1, N1-dimethyl-1, 3-propanediamine hydrochloride (1:1) (365mg, 2.35 m)mol)、HOBt(318mg，2.35mmol)、Et3A mixture of N (0.33ml, 2.35mmol) was stirred in DMF (80ml) at room temperature overnight. The mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue was triturated with diethyl ether (167mg), filtered and dried in vacuo to give 141mg (29%) of compound 69. MP =264 ℃ (DSC).
Transformation 12
Preparation of Compound 70Of HCl salt of
HCl (0.496 ml; 2.5mmol) was added dropwise to a solution of compound 71(277 mg; 0.50mmol) in isopropanol (20 ml). The reaction mixture was heated at 50 ℃ for 4 hours and then at 70 ℃ for 4 hours. Pouring the mixture into water and dissolving with K2CO3Basified and then extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, MERCK; mobile phase: gradient from 100% DCM to 80% DCM, 20% MeOH, 0.1% NH)4OH). The product fractions were collected and the solvent was evaporated. The residue (110mg) was dissolved in diisopropyl alcohol and HCl (0.2ml, 5 to 6N in isopropanol) was added. The mixture was stirred for 30 minutes and evaporated to dryness. The residue was then crystallized from diethyl ether to yield 110mg (39%) of compound 70. MP =163 ℃ (DSC).
Transformation 13
Preparation of Compound 72
Formaldehyde (0.045ml, 0.60mmol) was added to a solution of compound 73 (prepared from compound 128 following the reaction of conversion 7) (0.15g, 0.30mmol) in MeOH (2ml) and THF (2ml) at room temperature. Sodium cyanoborohydride (0.028g, 0.45mmol) was then added, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into ice. The organic layer was extracted with DCM and dried (MgSO)4) Filtered and evaporated to dryness. The residue was chromatographed on silica gel (0.1g) (random SiOH, 15-40 μm, 30g MERCK; mobile phase: gradient from 95% DCM, 5% MeOH to 80% DCM, 20% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (60mg, 39%) was crystallized from DIPE/diethyl ether. The precipitate was filtered and dried in vacuo to yield 0.046g (30%) of compound 72. MP =120 ℃ (Kofler).
Transformation 14
Preparation of Compound 74
A mixture of compound 64(0.14g, 0.33mmol), methylamine hydrochloride (0.052g, 1.67mmol), N3- (ethylcarboximidoyl) -N1, N1-dimethyl-1, 3-propanediamine hydrochloride (1:1) (0.077g, 0.50mmol), 1-hydroxybenzotriazole (0.068g, 0.50mmol), triethylamine (0.325ml, 2.34mmol) was stirred in DCM (14ml) at room temperature overnight. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (Stability silica, 5 μm 150x30.0mm; mobile phase: gradient from 0% NH)4OH, 100% DCM, 0% MeOH to 0.7% NH4OH, 93% DCM, 7% MeOH). The product fractions were collected and the solvent was evaporated. The residue was triturated with diethyl ether, filtered and dried under vacuum at 60 ℃ to give 0.078g (54%) of compound 74. MP =252 and 254 ℃ (Kofler).
Transformation 15
Preparation of Compound 75
Trifluoroacetic acid (1.07 ml; 14.37mmol) was added to a solution of compound 76(2 g; 4.79mmol) in water (19.5ml) and dioxane (80 ml). The reaction mixture was heated under reflux for 5 hours, poured into water,by K2CO3Basified and extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 35-40 μm, 80gGrace Resolv; mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH, 0.1% NH)4OH). The product fractions were collected and the solvent was evaporated. The residue (2.1g) was taken up in Et2O and CH3Crystallization in CN afforded 1.61g (77%) of Compound 75. MP =187 ℃ (DSC).
Transformation 16
Preparation of Compound 75
Potassium permanganate (0.11g, 0.7mol) was added to a solution of compound 121(0.28g, 0.0007mol) in acetone (8 ml)/water (2.5ml) at 0 ℃. The solution was stirred at room temperature for 4 hours, and then poured into ice water. DCM was added and the mixture was filtered through a layer of celite. The organic layer was extracted and dried (MgSO)4) And (5) drying by distillation. The residue (200mg) was chromatographed on silica gel (5 μm150 X30.0mm; mobile phase: gradient from 0.2% NH)4OH, 98% DCM, 2% MeOH to 1.1% NH4OH, 89% DCM, 11% MeOH). The pure fractions were collected and the solvent was evaporated. The residue (100mg, 33%) was taken up in CH3Crystallization from CN/diethyl ether gave 77mg (25%) of intermediate 75. MP =186 ℃ (DSC).
Transformation 17
Preparation of Compound 78
Methyl iodide (0.5ml, 8.0mmol) was added very slowly to a suspension of Mg (0.196g, 8.0mmol) in diethyl ether (2ml) at room temperature under a nitrogen atmosphere. When the grignard reagent was initiated, diethyl ether (10mL) was added and the reaction was stirred for 30 minutes. The mixture was added dropwise to a solution of compound 65(0.240g, 0.54mmol) in THF (12ml) at room temperature under a nitrogen atmosphere. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. The mixture is poured into water/NH4Cl and extracted with EtOAc. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to give a crude residue (0.248g) which was purified by supercritical fluid chromatography (CYANO 6 μm150x 21.1 mm; mobile phase: 0.3% isopropylamine, 7% MeOH, 93% CO2). Evaporation of the pure fractions gave 90mg of Compound 78, which was purified in Et2Crystallization in O afforded 57mg (24%) of compound 78. MP =162 ℃ (DSC).
Transformation 18
Preparation of Compound 79aAnd
compound 79Of HCl salt of
In a sealed vessel, a mixture of compound 76(0.505 gg; 1.21mmol) and methylamine in 2M THF (6.05ml, 12.1 mmol) was heated in DMF (8ml) at 100 ℃ for 15 h, cooled to room temperature, poured over water and K2CO3In (1), extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was chromatographed on silica gel (random SiOH, 15-40 μm, 30g MERCK; mobile phase: gradient from 100% DCM to 90% DCM, 10% MeOH, 0.1% NH)4OH). The pure fractions were evaporated, yielding 0.406g (75%) of compound 79a, which was dissolved in diisopropyl alcohol. HCl (5 to 6N) was added. The mixture was stirred for 30 minutes and evaporated to dryness. The residue was then taken up in Et2Crystallization in O gave 0.4g (62%) of compound 79. MP =224 ℃ (DSC).
Transformation 19
Preparation of Compound 80(E-isomer)
And Compound 81(Z-isomer)
Hydroxylamine hydrochloride (0.043g, 0.62mmol) was added to a solution of compound 82(0.13g, 0.31mmol) and pyridine (0.13ml) in EtOH (4ml) at room temperature. The mixture was stirred at room temperature overnight. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm60g, PharmPrep MERCK; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). Two different residues were collected and their solvents were evaporated separately. The first residue was taken up in DIPE/CH3CN (90/10) crystal. The precipitate was filtered off and dried in vacuo to yield 0.087g (64%) of compound 80 (E-isomer). MP =144 ℃ (Kofler).
The second residue (0.068g) was taken up in DIPE/CH3CN (90/10) crystal. The precipitate was filtered off and dried in vacuo to yield 0.051g (38%) of compound 81 (Z-isomer). MP =199 ℃ (Kofler).
Transformation 20
Preparation of Compound 83
N3- (ethylcarbonamido) -N1, N1-dimethyl-1, 3-propanediamine hydrochloride (1:1) (129 mg; 0.83mmol) was added to a solution of compound 84(223 mg; 0.55mmol), 1-methyl-3-piperidinecarboxylic acid hydrochloride (1:1) (148.8 mg; 0.82mmol), 1-hydroxybenzotriazole (112 mg; 0.615mmol), 4-methylmorpholine (porpholine) (182. mu.l; 1.66mmol) in DMF (8ml) at room temperature. The reaction mixture was stirred for 24 hours and then poured into water/K2CO3And extracted with EtOAc. The organic layer was dried (MgSO4) Filtering and evaporating to dryness. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm60g, PharmPrep MERCK; mobile phase: 0.5% NH)4OH，97% DCM，3% MeOH)。The product fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether to yield 122mg (42%) of compound 83. MP =142 ℃ (DSC).
Transformation 21
Preparation of Compound 85
Diethylaminosulfur trifluoride (0.224 mL, 1.68mmol) in DCM (2mL) was added dropwise to a solution of compound 56(0.250g, 0.56mmol) in DCM (4mL) at 0 ℃ under a nitrogen atmosphere. The mixture was stirred at room temperature overnight. Adding K2CO3Aqueous solution (10%). The mixture was extracted with DCM. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (246mg) was purified by chromatography on silica gel (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0% NH)4OH, 100% DCM, 0% MeOH to 0.3% NH4OH, 97% DCM, 3% MeOH). The pure fractions were collected and evaporated to dryness. The residue (58mg) was crystallized from DIPE, filtered and dried to yield 36mg (14%) of compound 85.
Transformation 22
Preparation of Compound 86
A mixture of compound 122(0.5g, 1.21mmol), sodium azide (0.235g, 3.62mmol) and ammonium chloride (194 mg; 3.62mmol) was heated in N, N-dimethylformamide (10ml) at 140 ℃ for 72 hours. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc was added and the organic layer was separated. The aqueous layer was acidified with 3N HCl. EtOAc was added and the mixture was stirred. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.42g) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 93% DCM, 7% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.110g, 20%) was taken up in diethyl ether/CH3CN crystals, filtration and drying in vacuo at 60 ℃ gave 0.070g (12%) of compound 86. MP =196 ℃ (DSC).
Transformation 23
Preparation of Compound 87
Diethylaminosulfur trifluoride (276. mu.l; 2.25mmol) was added dropwise to a solution of compound 88(550 mg; 1.12mmol) in DCM (14ml) at 0 ℃. The reaction mixture was stirred at room temperature for 2 hours and then poured into water/K2CO3In (1). The organic layer was extracted and dried (MgSO)4) Filtering and evaporating to dryness. The residue (629mg) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 0.5% NH)4OH, 97% DCM, 3% MeOH). The product fractions were collected and the solvent was evaporated. The residue (100mg) (2 ethylpyridine 6 μm150 X21.2mm; mobile phase: 0.3% 2-propylamine, 87% CO) was purified by achiral supercritical fluid chromatography213% MeOH). The product fractions were collected and the solvent was evaporated. The residue (0.08g) was taken up in Et2Crystallization in O afforded 72mg (15%) of compound 87.
Transformation 24
Preparation of Compound 89
LiAlH was added at 5 ℃ under a nitrogen atmosphere4(0.031g, 0.82mmol) is added portionwise to a mixture of compound 90(0.2g, 0.41mmol) in THF (10 ml). The mixture was stirred at 5 ℃ for 3 hours. At-5 ℃, EtOAc, and then water were added dropwise to the mixture. The suspension was passed through a thin pad of celite. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0% NH)4OH, 100% DCM, 0% MeOH to 0.8% NH4OH、92% DCM、8% MeOH)。The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered and dried in vacuo to yield 73mg (40%) of Compound 89. MP =126 ℃ (DSC).
Transformation 25
Preparation of Compound 91
Copper (I) iodide (52.697mg, 0.28mmol), then N, N-diisopropylethylamine (0.829ml, 4.75mmol) was added to a solution of compound 38(1.105g, 2.78mmol) and ethyl azidoacetate (1.38ml, 5.53mmol) in THF (35ml) at 5 ℃. The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched with water and extracted with EtOAc. The organic layer was decanted and dried (MgSO)4) Filtering and evaporating to dryness. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300 gMERCK; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The fractions were collected to give 430mg of residue which was further purified by achiral supercritical fluid chromatography (AMINO 6 μm150X 21.2mm; mobile phase: 0.3% 2-propylamine, 90% CO)210% MeOH). The pure fractions were collected and evaporated to dryness to give two fractions.
The first fraction (90mg) was treated with CH3CN/DiPE crystallization. The precipitate was filtered and dried to yield 74mg (5%) of compound 91, MP =88 ℃ (DSC). The second fraction yielded 360mg (25%) of compound 91.
Transformation 26
Preparation of Compound 92
Compound 93(740mg, 1.77mmol), Et3N (0.54ml, 3.89mmol) and trifluoroacetic anhydride (0.37ml, 2.65mmol) in THF (25ml) were stirred at room temperature overnight. The reaction mixture was poured into water and extracted with DCM. The organic layer is treated with K2CO3Aqueous solution (10%) then water and then dryDried (MgSO)4) Filtering and evaporating to dryness. The residue (800mg) was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.2% NH)4OH, 98% DCM, 2% MeOH). The product fractions were collected and the solvent was evaporated. The residue (730mg) was crystallized from diethyl ether/DIPE to give 465mg (51%) of Compound 92. MP =139 ℃ (DSC).
Transformation 27
Preparation of Compound 300
Compound 38(1.38 g; 3.46mmol), 2-iodo-1-methyl-1H-imidazole (0.45 g; 2.16mmol) and Et were placed under a nitrogen atmosphere3A suspension of N (3.0 ml; 21.6mmol) in DMSO (25ml) was degassed. Dichlorobis (triphenylphosphine) -palladium (304 mg; 0.43mmol) and copper (I) iodide (41 mg; 0.22mmol) were added and the reaction mixture was stirred at 90 ℃ for 1.5 h. The reaction mixture was cooled to room temperature, poured into water, and extracted with EtOAc. The organic layer was decanted, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm, 300g MERCK; mobile phase: 0.4% NH)4OH, 96% DCM, 4% MeOH). The pure fractions were collected and evaporated to dryness. The residue (780mg) (2 AMINO 6 μm150X 21.2mm; mobile phase: 0.3% 2-propylamine, 80% CO) was then purified by achiral supercritical fluid chromatography220% MeOH). The pure fractions were collected and evaporated to dryness to yield 430mg (41%) of compound 300. The fraction was absorbed in CH3In CN. The precipitate was filtered and dried to yield 377mg (36%) of compound 300. MP =192 ℃ (DSC).
Transformation 28
Preparation of Compound 94
A mixture of compound 109(2.5g, 5.29mmol) in 3M NaOH (7ml) and THF (40ml) was stirred at room temperature for 18 h. The reaction mixture was washed with 10% NH4The Cl solution was quenched and EtOAc was added. The pH was adjusted to 4.5 by addition of 3N HCl. Decanting the organic layer with saturated NH4Washed with Cl and dried (MgSO)4) Filtered and evaporated to dryness. The residue was crystallized from EtOH. The precipitate was filtered, washed with EtOH, then diethyl ether and dried to yield 2.02g (86%) of compound 94. MP =101 ℃ (DSC).
Transformation 29
Preparation of Compound 95a
And Compound 95Of HCl salt of
Compound 93(0.15g, 0.36mmol), 3,3, 3-trifluoro-2-hydroxy-2-methylpropionic acid (0.085g, 0.54mmol), N3- (ethylcarboximidoyl) -N1, N1-dimethyl-1, 3-propanediamine hydrochloride (1:1) (0.083g, 0.54mmol), 1-hydroxybenzotriazole (0.073g, 0.54mmol), Et3A mixture of N (0.075ml, 0.54mmol) was stirred in DCM (4ml) at room temperature overnight. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.250g) was chromatographed on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The product fractions were collected and the solvent was evaporated. Dissolving compound 95a in CH3In CN, cooled to 5 ℃ and 5N HCl/iPrOH solution (0.3ml) was added dropwise. The mixture was evaporated to dryness at room temperature. The mixture was taken up in diethyl ether and the precipitate was filtered and dried in vacuo at 60 ℃ to yield 0.172g (80%) of compound 95.
Transformation 30
Preparation of Compound 96
Acetone (0.322 mL, 4.361mmol) was added to a solution of compound 70(0.2g, 0.436mmol) in MeOH (5mL) and THF (5mL) at room temperature. Sodium cyanoborohydride (0.055g, 0.872mmol) was then added and the mixture was stirred at room temperature overnight. Acetone (0.129ml, 1.745mmol) and sodium cyanoborohydride (0.055g, 0.872mmol) were added and the mixture was stirred at room temperature over the weekend. The mixture was poured into ice, and the organic layer was extracted with DCM and dried (MgSO)4) Filtered and evaporated to dryness. The residue (254mg) was chromatographed on silica gel (random SiOH, 15-40 μm, 300 gMerck; mobile phase: gradient from 100% DCM to 90% DCM, 10% CH3OH、0.1% NH4OH). The pure fractions were collected and evaporated to dryness. The product (236mg) was crystallized from DIPE, filtered off and dried to yield 186mg (85%) of compound 96. MP =168 ℃ (DSC).
Transformation 31
Preparation of Compound 97And
compound 98
Means relative stereochemistry
Separation of enantiomer (5.4g) of Compound 75 by hand supercritical fluid chromatography (CHIRALPAK AD-H5 μm250x20 mm; mobile phase, 0.3% 2-propylamine, 40% CO260% MeOH). The desired product fraction was collected and the solvent was evaporated. The first eluted enantiomer (2.1g) was crystallized in diethyl ether to yield 1.965g (36%) of compound 97(R ·, MP =188 ℃ (DSC)). The second enantiomer (2.1g) was crystallized in diethyl ether to give 2g (37%) of compound 98(S ×, MP =186 ℃ (DSC)).
Transformation 32
Preparation of Compound 99
Compound 100(0.5g, 0.91mmol), 4M HCl/dioxane (2mL) and CH3A mixture of CN (10mL) was heated at 50 ℃ overnight. The mixture was poured into ice and washed with K2CO3Basified and extracted with DCM. Drying (MgSO)4) The organic layer was filtered and evaporated to dryness to yield 0.4g (99%) of compound 99.
Transformation 33
Preparation of Compound 101
Sodium hydride (0.054g, 1.36 mmol) was added portionwise to a solution of compound 99(0.4g, 0.9mmol) in DMF (4ml) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, and then iodomethane (68 μ L, 1.09 mmol) was added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour and then at room temperature overnight. The reaction was poured into ice and extracted with EtOAc. The organic layer was washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue (0.71g) was chromatographed on silica gel (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0.2% NH)4OH, 98% DCM, 2% MeOH to 0.8% NH4OH, 92% DCM, 8% MeOH). The pure fractions were evaporated to dryness. The residue was crystallized from diethyl ether and dried to yield 0.172g (42%) of compound 101. MP =186 ℃ (Kofler).
Transformation 34
Preparation of Compound 102
3, 3-bis (bromomethyl) oxetane (1.592g, 6.52mmol) was added to compound 84(2.2g, 5.44mmol) and sodium carbonate (0.961g, 9.1mmol) in 1, 4-dioxane (80ml) at room temperature. Will be reversedThe mixture was stirred at reflux for 7 days and then cooled to room temperature. The mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: gradient from 99% DCM, 1% NH)3MeOH solution to 97.5% DCM, 2.5% NH3In MeOH). The pure fractions were collected and concentrated under reduced pressure to yield 880mg (33%) of compound 102.
Transformation 35
Preparation of Compound 103Of HCl salt of
Sodium cyanide (0.094g, 1.92mmol) was added portionwise to a solution of compound 104(0.5g, 0.96mmol) in EtOH (10ml) and water (3ml) at room temperature. The reaction mixture was heated at 60 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc is added and the solution is taken with K2CO3The aqueous solution (10%) was basified. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.63g) was chromatographed on silica gel (spherical SiOH, 10 μm, 60g PharmPrep MERCK; mobile phase: 0.1% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 0.37g of compound (75%). The compound was further purified by hand supercritical fluid chromatography (CHIRALPAKAD-H5 μm250x20 mm; mobile phase, 0.3% 2-propylamine, 60% EtOH, 40% CO)2). The desired product fraction was collected and the solvent was evaporated. The residue (0.240g, 49%) was dissolved in CH3CN, and cooled at 5 ℃. 5N HCl/i-PrOH solution (0.28mL) was added dropwise at 5 ℃. The solution was evaporated to dryness. The residue was triturated with diethyl ether, filtered and dried under vacuum at 60 ℃ to give 0.250g (42%) of compound 103.
Preparation of Compound 105Of HCl salt of
a-1) preparation of intermediate 63
And compound 126
Methanesulfonyl chloride (0.18 mL; 2.31mmol) was added dropwise to compound 108(580 mg; 1.15mmol), Et at 5 ℃ under a nitrogen atmosphere3N (0.4 mL; 2.88mmol) in DCM (10 mL). The reaction mixture was stirred at 5 ℃ for 2 hours. The reaction mixture was poured into ice water and DCM was added. The organic layer was separated, dried (97%), filtered, and the solvent was evaporated to yield 0.65g (97%) of intermediate 63 and compound 126.
a-2) sodium cyanide (0.110g, 2.24mmol) was added portionwise to a solution of intermediate 63(0.65g, 1.12mmol) in EtOH (10ml) and water (3ml) at room temperature. The reaction mixture was heated at 60 ℃ overnight. The reaction mixture was cooled to room temperature and poured into ice water. EtOAc is added and the solution is taken with K2CO3The aqueous solution (10%) was basified. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue was purified by chromatography on silica gel (Sunfire silica, 5 μm150 X30.0mm; mobile phase: gradient from 0% NH)4OH, 100% DCM to 0.5% NH4OH, 95% DCM, 5% MeOH). The fractions were collected and the solvent was evaporated. The residue was further purified by hand supercritical fluid chromatography (CHIRALPAKAD-H5 μm250x20 mm; mobile phase, 0.3% 2-propylamine, 40% EtOH, 60% CO)2). The product fractions were collected and the solvent was evaporated. The residue (0.220g, 38%) was dissolved in CH3CN, and cooled at 5 ℃. 5N HCl/i-PrOH solution (0.258mL) was added dropwise at 5 deg.C, and the mixture was evaporated to dryness. The residue was triturated with diethyl ether, filtered and dried under vacuum at 60 ℃ to yield 0.215g (32%) of compound 105.
Transformation 36
Preparation of Compound 109
Sodium azide (84.1mg, 1.29mmol) was added to a solution of formaldehyde (0.65ml, 8.62mmol) and HOAc (74 μ l, 1.29mmol) in dioxane (1.5ml) at 5 ℃. The reaction mixture was stirred for 15 minutes and a solution of compound 38(310mg, 0.78mmol) in dioxane (1.5ml) was added. The reaction mixture was stirred at 5 ℃ for 10 minutes, then sodium L-ascorbate (34mg, 0.17mmol) was added followed by aqueous copper sulfate (0.53ml, 0.043 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was decanted, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness to yield 367mg (100%) of compound 109.
Transformation 37
Preparation of Compound 110
To a solution of compound 111 (prepared from compound 129 following the conversion 5a reaction) (170mg, 0.29mmol) in DCM (20ml) was added 1-chloroethyl chloroformate (37. mu.l, 0.34mmol), and the reaction was stirred at room temperature for 90 min. The solvent was removed under reduced pressure. MeOH (20ml) was added to the residue and the solution was heated to 40 ℃ for 1 hour. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to give a red solid. The residue was purified by chromatography on silica gel (170mg) (Hyperprep C18 HS BDS 100A 8mu (Shandon); mobile phase: gradient from 80% 0.5% aqueous ammonium carbonate, 20% MeOH to 20% 0.5% aqueous ammonium carbonate, 80% MeOH). The product fractions were collected and the solvent was evaporated, yielding 64mg (44%) of compound 110.
Transformation 38
Preparation of Compound 82
At 0 ℃ under a nitrogen atmosphereDess-martin periodinane (Dess-martin oxidant, 5.16ml, 1.55mmol) was added dropwise to compound 113(0.59g, 1.41mmol) in DCM (10 ml). The mixture was stirred at room temperature for 2 hours, poured into ice and washed with K2CO3The aqueous solution (10%) was basified. The organic layer was extracted with DCM and dried (MgSO)4) Filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (random SiOH, 15-40 μm; mobile phase: gradient from 98% DCM/2% MeOH to 95% DCM/5% MeOH). The pure fractions were collected and the solvent was evaporated, yielding 0.47g (65%) of compound 82.
Transformation 39
Preparation of Compound 114
Sodium hydride (104 mg; 2.61mmol) was added portionwise to a solution of compound 115(500 mg; 0.87mmol) in N, N-dimethylformamide (8ml) at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 5 ℃ for 1 hour, and then, at 5 ℃, a methyl iodide solution (0.16 mL; 2.61mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue obtained (0.55g) was chromatographed on silica gel (random SiOH,15, 15/40 μm, 30 g; mobile phase gradient: 100% DCM to 96% DCM, 4% MeOH). The product fractions were collected and the solvent was evaporated, yielding 0.39g (76%) of compound 114.
Transformation 40
Preparation of Compound 116
Sodium hydride (0.066g, 1.66mmol) was added portionwise to a solution of compound 117(0.51g, 0.83mmol) in N, N-dimethylformamide (10mL) at 5 ℃ under a nitrogen atmosphere. The mixture was stirred at 5 ℃ for 1 hour, and methyl iodide (0.10) was added in portions at 5 ℃3ml, 1.66 mmol). The reaction mixture was stirred at 5 ℃ for 1 hour, then warmed to room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue was chromatographed on silica gel (random SiOH, 15/40 μm, 30g MERCK; mobile phase: gradient from 100% DCM to 98% DCM, 2% MeOH). The product fractions were collected and the solvent was evaporated, yielding 0.400g (76%) of compound 116.
Transformation 41
a) Preparation of Compound 118
To a stirred mixture of ethylenediamine (0.226ml, 3.38mmol) and anhydrous toluene (15ml) cooled on an ice bath was added dropwise trimethylaluminum/heptane (1M, 4ml, 4mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature for 60 minutes, then compound 65(300mg, 0.670mmol) was added (in dry toluene (7 ml)). The mixture was heated to reflux for 3 hours and then cooled to room temperature. MeOH (50mL) was added carefully. The mixture was stirred at room temperature for 5 minutes and then filtered through celite. The organic layer was concentrated and purified by silica gel chromatography. The desired fraction was collected and the solvent was evaporated to give compound 118((4, 5-dihydro-1H-imidazol-2-ylmethyl) - (3, 5-dimethoxy-phenyl) - [3- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-6-yl ] -amine) (100 mg).
b) Preparation of Compound 119
Compound 118 was heated to 100 ℃ overnight in aqueous sodium hydroxide (2N, 5mL) to facilitate the ring-opening reaction. 1, 4-dioxane (5mL) was added and the reaction was allowed to continue for a further 10 hours at 100 ℃. The reaction was cooled and extracted with EtOAc (2 ×). Drying (MgSO)4) Organic layer, and concentrate. Hydrochloric acid/MeOH was added and the product was precipitated with diethyl etherAnd (4) precipitating. The bright red solid was isolated by filtration and dried in a vacuum oven to give compound 119(N- (2-amino-ethyl) -2- { (3, 5-dimethoxy-phenyl) - [3- (1-methyl-1H-pyrazol-4-yl) -quinoxalin-6-yl]-amino } -acetamide) (80 mg).
Transformation 42
Preparation of Compound 120
To a solution of compound 84(36mg, 0.89mol, 1 eq) in dioxane (3ml) and DMF (1.5ml) was added 1-iodo-2-fluoroethane (16mg, 0.89mmol) and K2CO3(25mg, 1.78 mmol). The reaction mixture was heated to 90 ℃ for 5.5 hours, DMF (1.5mL) was further added, and the reaction mixture was heated to 100 ℃ for 1.5 hours. The solvent was removed under reduced pressure and the reaction mixture was partitioned between EtOAc and water. The layers were separated and dried (MgSO)4) And concentrating under reduced pressure. The crude mixture was purified by HPLC to give compound 120(17 mg).
Transformation 43
Preparation of Compound 124
A solution of compound 76(0.254 g; 0.608 mmol), potassium phthalimide (phtalimide) (0.68 g; 3.65mmol) in N-methyl-pyrrolidone (5mL) was heated at 150 ℃ for 1.5 hours under microwave irradiation. The solution was cooled and the mixture was poured into cold water. The product was extracted with EtOAc. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness to give compound 124, which was used in the next step without further purification.
Transformation 44
Preparation of Compound 125
Compound 124 was heated in EtOH (20mL) with hydrazine monohydrate (0.57 mL; 18.25mmol) for 5 hours at 80 ℃. The mixture was cooled to room temperature, evaporated and the residue poured into water. The organic layer was extracted with DCM, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness to obtain 400mg of crude product. The residue was purified by chromatography on silica gel (spherical SiOH, 10 μm60g, PharmPrep MERCK; mobile phase: 0.5% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and evaporated, yielding 140 mg (53%) of compound 125. MP =99 ℃ (DSC).
Transformation 45
Preparation of Compound 606
A solution of compound 605(5.3 g; 11.55 mmol) in dry THF (105 mL) was added dropwise to a solution of lithium aluminum hydride (0.789 g; 20.79 mmol) in dry THF (105 mL) at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 0 ℃ for 2 hours. EtOAc was added dropwise to the reaction mixture, followed by water dropwise. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (5 g) was chromatographed on silica gel (random SiOH, 20-45 μm, 1000 g; mobile phase gradient: from 0.1% NH)4OH, 97% DCM, 3% MeOH to 0.1% NH4OH, 94% DCM, 6% MeOH). The pure fractions were collected and concentrated. The residue (4g, 75%) was crystallized from DIPE. The precipitate was filtered off and dried in vacuo to yield 3.5g (65%) of compound 606. MP: 97 Deg.C (DSC).
Transformation 46
Preparation of Compounds 608, 609, 610, 611
By relative stereochemistry is meant.
Compound 607(7.4 g; 6.74 mmol), hydrazine monohydrate (2.52 mL; 80.94 mmol) were heated in EtOH (240mL) at 80 ℃ for 2 h. The reaction mixture was cooled to room temperature and poured into ice water. DCM was added and the organic layer was separated, washed with water and dried (MgSO)4) Filtered and the solvent evaporated to dryness. The residue (5.1g) was chromatographed on silica gel (random SiOH, 20-45 μm, 450 g; mobile phase: 0.5% NH)4OH, 93% DCM, 7% MeOH). The product fractions were collected and the solvent was evaporated, yielding 1.1g fraction I = compound 896 (enantiomeric mixture) and 1.1g fraction II = compound 897 (enantiomeric mixture).
Separation of the enantiomers of fractions I and II by hand supercritical fluid chromatography (CHIRALPAK AD-H5 μm250x20 mm; mobile phase, 0.3% 2-propylamine, 60% CO)240% isopropanol). The desired product fraction was collected and the solvent was evaporated. The enantiomer of fraction I (0.52g) eluted first was placed in CH3Crystallization in CN gave 0.325g (12%) of Compound 608 (R)*MP =159 ℃ (DSC)). The second enantiomer of fraction I (0.53 g) was placed in CH3Crystallization in CN gave 0.284 g (10%) of compound 609 (S)*，MP=155℃(DSC))。
The enantiomer of fraction II eluted first (0.47g) in CH3Crystallization from CN/diethyl ether gave 0.327g (12%) of Compound 610 (R)*MP =150 ℃ (DSC)). The second enantiomer of fraction II (0.475 g) was placed in CH3Crystallization in CN gave 0.258 g (9%) of Compound 611 (S)*，MP=148℃(DSC))。
Transformation 47
a) Preparation of Compound 612
Boron tribromide (11.55 mL; 11.55 mmol) was added dropwise to a solution of compound 202 in DCM (10mL) at 0 deg.C. The solution was slowly warmed to room temperature and stirred for 3 days. The reaction was quenched with MeOH at 0 ℃. Then, saturated NH was added3In solution, inAnd the reaction mixture. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (1g) (C18, 10 μm, 250g, 5 cm; mobile phase: 0.25% (NH)4)2CO3Aqueous solution, CH3CN). The pure fractions were collected and concentrated to yield 0.160 g (22%) of compound 612.
b) Preparation of Compound 613
Potassium carbonate (0.057 g; 0.41mmol) is added to a solution of compound 612(0.080 g; 0.21 mmol) in N, N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, methyl iodide (0.013 mL; 0.21 mmol) was added to the reaction mixture and stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure to about 1/3 of its initial volume. The residue was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.05g) (RP Vydac Denali C18, 10 μm, 250g, 5 cm; mobile phase 0.25% (NH)4)2CO3Aqueous solution, CH3CN). The pure fractions were collected and concentrated. Separating the residue (0.025g) (CHIRALPAK Diacel OJ-H20X 25 mm; mobile phase: CO) by means of manual supercritical fluid chromatography2MeOH (containing 0.2% 2-propylamine)). The desired product fraction was collected and the solvent was evaporated, yielding 0.007g (9%) of compound 613.
Transformation 48
Preparation of Compound 625
Methyl iodide (0.096 mL; 1.54 mmol) was added to compound 624(0.73 g; 1.54 mmol) and K2CO3(0.213 g; 1.54 mmol) of CH3CN (20 mL). Will be provided withThe reaction mixture was stirred at 60 ℃ for 5 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.666g) was purified by chromatography on silica gel (spherical SiOH, 10 μm, 60 g; mobile phase gradient: from 0.5% NH)4OH, 95% DCM, 5% MeOH to 1% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated to yield 0.3g (38%) of compound 625. MP: 156 Deg.C (DSC).
Transformation 49
a) Preparation of Compound 626
Compound 38(2 g; 5.0 mmol) was dissolved in THF (80mL) and the solution was cooled at-78 deg.C and 1.6M n-butyllithium/hexane (3.1 mL; 5.0 mmol) was added. The reaction mixture was slowly raised to-30 ℃ and stirred for 45 minutes. 1-Boc-azetidinone (0.715 g; 4.17 mmol)/THF (8mL) was added to the reaction mixture at-78 deg.C, stirred for 1 hour, and the reaction mixture was allowed to warm to room temperature for 1 hour. The solution was poured over ice water and NH4Cl and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (2.86g) was purified by silica gel chromatography (random SiOH, 20-45 μm, 450 g; mobile phase: 0.1% NH)4OH, 96% DCM, 4% MeOH). The pure fractions were collected and concentrated to yield 0.343 g (15%) of compound 626.
b) Preparation of Compound 627
Trifluoroacetic acid (1.4 ml; 17.9mmol) was added to a solution of compound 626(0.17 g; 0.3 mmol). The reaction was stirred at 70 ℃ for 2 hours. The reaction mixture was cooled to room temperature and evaporated. The reaction mixture was poured into ice water, DCM was added and NH was added4Basifying OH. The organic layer was separated and dried (MgSO)4) Is filtered, andthe solvent was evaporated. The residue (0.35g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.5% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated to yield 0.048g (34%) of compound 627.
Conversion 50
Preparation of Compounds 628 and 629
NaH (0.22 g; 5.56 mmol) was added portionwise to compound 14(0.5 g; 1.1mmol) in THF (30 mL). The reaction mixture was stirred at 0 ℃ for 1 hour. Acetyl chloride (0.8 mL; 11.1 mmol) was then added dropwise at 5 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 50 ℃ for 18 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.51g) was purified by chromatography on silica gel (SiOH, 5 μm, 250x 30 mm; mobile phase: gradient from 100% DCM to 0.5% NH)4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated to yield 220 mg of product. Separation of the enantiomers (CHIRALPAKAD-H5 μm250x20 mm; mobile phase: 60% CO) by means of manual supercritical fluid chromatography240% isopropanol). The desired product fraction was collected and the solvent was evaporated. The first eluted enantiomer (0.105g) was crystallized from diethyl ether to yield 0.050g (9%) of compound 628 (S)*MP =122 ℃). The second enantiomer (0.096g) was crystallized from diethyl ether to give 0.051g (9%) of compound 629 (R)*，MP=124℃)。
Transformation 51
Preparation of Compound 631Of HCl salt of
Trifluoroacetic acid (0.52 mL; 6.9mmol) was added to a solution of compound 630(0.4 g; 0.7mmol) in DCM (7 mL).The reaction was stirred at room temperature for 24 hours. The reaction mixture was poured into ice water, DCM was added and K was used2CO3Alkalizing. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.5g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 30 g; mobile phase: 0.5% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated. 5N HCl/isopropanol was added dropwise to the residue (0.41 g). Acetone and diethyl ether were added. The precipitate was filtered off and dried in vacuo to yield 0.383g (98%) of compound 631. MP: 189 deg.C (Kofler).
Transformation 52
Preparation of Compound 633
1,1' -carbonyldiimidazole (1.1g, 6.6 mmol) was added portionwise to a solution of compound 297(2.4 g; 5.6mmol) in DCM (60 mL). Then, the reaction mixture was stirred at room temperature for 1 hour. N, O-dimethylhydroxylamine hydrochloride (0.65 g; 6.6 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was decanted and dried (MgSO)4) Filtering and evaporating to dryness. The residue (2.6g) was purified by silica gel chromatography (random SiOH, 15-40 μm, 300 g; mobile phase: 0.3% NH)4OH, 98% DCM, 2% MeOH). The pure fractions were collected and concentrated to yield 0.185 g (11%). The residue (0.5g) was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.28g (11%) of compound 633. MP: 130 Deg.C (DSC).
Transformation 53
Preparation of Compound 635
Compound 634(0.26 g; 0.53mmol) is hydrogenated with Pd/C (0.05g) as catalyst at room temperature in EtOAc (10mL) at atmospheric pressure. After 18 hours, filter out on a pad of celiteThe catalyst was added and the filtrate was concentrated in vacuo until dry. The residue (0.256g) was purified by silica gel chromatography (SiOH, 5 μm, 150x30 mm; mobile phase gradient from 100% DCM to 0.8% NH)4OH, 92% DCM, 8% MeOH). The pure fractions were collected and concentrated. The residue (0.085g) was washed with CH3CN/DIPE crystal. The precipitate was filtered off and dried to yield 0.075g (29%) of compound 635. MP: 110 Deg.C (DSC).
Conversion 54
Preparation of Compounds 637 and 636
Compound 634(0.38 g; 0.78mmol) is hydrogenated with Lindlar catalyst (0.075 g) at room temperature in EtOAc (40mL) at atmospheric pressure. After 9 h, the catalyst was filtered off on a pad of celite, washed with DCM/MeOH and the filtrate was concentrated to dryness in vacuo. The residue (0.474g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm; mobile phase gradient from 100% DCM to 0.8% NH)4OH, 92% DCM, 8% MeOH). The pure fractions were collected and concentrated to give two fractions. The first fraction (0.135g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.099g (26%) of compound 636 (Z). MP:>260 deg.C (Kofler). The second fraction was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.048g (13%) of compound 637 (E). MP: 80 deg.C (Kofler).
Transformation 55
Preparation of Compound 640
Potassium tert-butoxide (0.054 g; 0.48 mmol) is added to a solution of compound 809(0.24 g; 0.48 mmol) in THF (15mL) and the reaction mixture is stirred at 10 ℃ for 2 h. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtering, and dissolvingThe agent evaporates. The residue (0.44g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm; mobile phase gradient: 70% heptane, 2% MeOH, 28% EtOAc to 20% MeOH, 80% EtOAc). The pure fractions were collected and concentrated. The residue (0.132g) was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.087g (37%) of compound 640. MP: 241 Deg.C (DSC).
Conversion 56
Preparation of Compound 642
Compound 137(0.51 g; 1.1mmol), 3-bromopropionitrile (0.11 mL; 1.4mmol) and K2CO3(0.8 g; 5.6mmol) in CH3CN (15mL) was stirred at 80 ℃ for 6 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.5g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm; mobile phase gradient: 0.2% NH)4OH, 98% DCM, 2% MeOH to 0.9% NH4OH, 91% DCM, 9% MeOH). The pure fractions were collected and concentrated. The residue (0.35g) was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.257g (47%) of compound 642. MP: 127 Deg.C (DSC).
Transformation 57
Preparation of Compound 643Of HCl salt of
3-Hydroxytetrahydrofuran (0.19 mL; 2.3mmol) and triphenylphosphine (0.61; 2.3mmol) were added to a solution of compound 137(0.5 g; 1.16 mmol) in THF (14mL) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes, then diisopropyl azodicarboxylate (0.46 mL; 2.3mmol) was added and the reaction mixture was stirred for 24 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtration ofAnd the solvent was evaporated. The residue (2g) (SiOH, 5 μm, 150x30 mm; mobile phase: 0.5% NH) was purified by silica gel chromatography4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated. The residue (0.19g) was dissolved in MeOH, 2.3 mL of HCl/i-PrOH was added, and the hydrochloride salt was then crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.178g (25%) of compound 643. MP: 160 deg.C (Kofler).
Conversion 58
Preparation of Compound 648
A mixture of compound 297(1.65 g, 3.8 mmol), 2,2, 2-trifluoroethylamine (1.4mL, 9.4 mmol), 1-hydroxybenzotriazole (3.6g, 9.4 mmol) and triethylamine (1 mL, 7.5 mmol) was stirred in N, N-dimethylformamide (50mL) at room temperature for 18 hours. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated. The residue (3.2g) was purified by chromatography on silica gel (random SiOH, 20X 40; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The product fractions were collected and the solvent was evaporated. The residue was triturated with diethyl ether, filtered and dried under vacuum at 60 ℃ to give 1.15g (65%) of compound 648. MP =196 ℃ (DSC).
Transformation 59
Preparation of Compound 651
Trifluoroacetic acid (1 mL; 14.3mmol) was added to a solution of compound 650(0.44 g; 0.7mmol) in DCM (5.2 mL) at 0-5 deg.C. The reaction mixture was stirred at room temperature for 2 hours and then with 10% K2CO3And (4) quenching. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness. The residue (0.45g) was purified by chromatography on silica gel (random silica, 15X 40; 30g, mobile phase: 1% NH)4OH，90% DCM, 10% MeOH). The product fractions were collected and the solvent was evaporated. The residue was taken up in diethyl ether/CH3CN crystallized, filtered and dried under vacuum at 60 deg.C to give 0.26g (72%) of compound 651. MP =122 ℃ (Kofler).
Transformation 60
Preparation of Compound 652
Compound 38(1 g; 3.5 mmol), 2-bromo-3-methoxypyridine (0.25 g; 0.35mmol) and Et were added under a nitrogen atmosphere3A suspension of N (3.0 mL; 21.5 mmol) in DMSO (20mL) was degassed. Dichlorobis (triphenylphosphine) -palladium (0.25 g; 0.36mmol) and copper (I) iodide (0.034 g; 0.18mmol) were added and the reaction mixture was stirred at 90 ℃ for 40 min. The reaction mixture was cooled to room temperature, poured into water and EtOAc was added. The mixture was filtered through a pad of celite. The organic layer was decanted, washed with brine and dried (MgSO)4) Filtered and evaporated to dryness. The residue (1.4g) was purified by silica gel chromatography (random SiOH, 20-40 μm, 450 g; mobile phase: 0.1% NH)4OH, 97% DCM, 3% MeOH). The pure fractions were collected and evaporated to dryness. The residue was crystallized from diethyl ether. The precipitate was filtered and dried to yield 0.6g (65%) of compound 652. MP: 144 Deg.C (DSC).
Transformation 61
Preparation of Compounds 656 and 657
Respective HCl salt
Purification of Compound 14a (3.4g) (random SiOH, 15-40 μm, 300 g; mobile phase: 0.1% NH) by silica gel chromatography4OH, 98% DCM, 2% MeOH). The pure fractions were collected and evaporated to dryness. The residue (1g) (CHIRALPAK AD-H5 μm250x20 mm; mobile phase: 40% 2-propylamine, 60% CO) was separated by hand supercritical fluid chromatography2). The desired product fraction was collected and the solvent was evaporated. Will be firstThe eluted enantiomer (0.5g) was dissolved in diethyl ether, 5 equivalents of HCl/i-PrOH were added and stirred at room temperature for 18 hours. The precipitate is filtered off and dried, yielding 0.29 g (8%) of compound 656 (R)*MP =95 ℃ (Kofler)). The second enantiomer (0.55g) was purified by achiral SFC (Amino 6 μm150x 21.2mm, mobile phase: 90% CO210% MeOH). The desired product fraction was collected and the solvent was evaporated. The residue (0.47g) was dissolved in diethyl ether, 5 equivalents of HCl/i-PrOH were added and stirred at room temperature for 18 hours. The precipitate is filtered off and dried, yielding 0.36g (11%) of compound 657 (S)*，MP=110℃(Kofler))。
Transformation 62
Preparation of Compound 663
Compound 662(0.25 g; 0.49 mmol) is stirred in HCl (1M in water) (12.2 mL; 12.2mmol) at 60 ℃ for 24 h. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was then taken up in DCM and taken up with 10% K2CO3And (6) washing. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (0.2g) was purified by chromatography on silica gel (SiOH, 5 μm, 150x30 mm, mobile phase gradient: from 0.2% NH)4OH, 98% DCM, 2% MeOH to 1.1% NH4OH, 89% DCM, 11% MeOH). The pure fractions were collected and evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield 0.1g (41%) of compound 663. MP: 200 Deg.C (DSC).
Transformation 63
Preparation of Compound 670
1,1' -carbonyldiimidazole (0.5g, 3mmol) was added to a solution of compound 125(1.2g, 2.8mmol) in THF (20.5 mL) at 0 deg.C under nitrogen. The reaction mixture was stirred at room temperature for 2 hours. Reacting the reactantsPoured into ice water and EtOAc was added. The organic layer was washed with brine and dried (MgSO)4) Filtering and evaporating. The residue (1.3g) was purified by silica gel chromatography (random SiOH, 20-45 μm, 300 g; mobile phase: 0.2% NH)4OH, 96% DCM, 4% iPrOH). The pure fractions were collected and the solvent was evaporated. The residue (0.98g) was taken up in CH3CN and diethyl ether. The precipitate was filtered off and dried to yield 0.8g (64%) of compound 670. MP: 157 Deg.C (DSC).
Conversion 64
Preparation of Compounds 671 and 672
A mixture of compound 76(1.5 g; 3.6 mmol) and 3-methyl-1H-1, 2, 4-triazole (3.7 mL; 28.9 mmol) was heated in 1-methyl-2-pyrrolidone (4mL) at 140 deg.C for 40 minutes using a single mode microwave (Biotage Initiator EXP 60) in a sealed tube. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. Purification of the crude product (2.1g) (15-40 μm, 300 g; mobile phase: 0.5% NH) by silica gel chromatography4OH, 93% DCM, 7% MeOH). The pure fractions were collected and the solvent was evaporated to dryness. The residue (1g) was purified by silica gel chromatography (Cyano 6 μm150x 21 mm; mobile phase: 90% CO)210% EtOH). The desired product fraction was collected and the solvent was evaporated. The first isomer (0.3g) was placed in CH3Crystallization in CN/diethyl ether gave 0.26g (15%) of compound 671, MP =144 ℃ (DSC). The second isomer (0.34g) was placed in CH3Crystallization in CN/diethyl ether gave 0.26g (15%) of compound 672, MP =194 ℃ (DSC).
Conversion 65
Preparation of Compound 673
A mixture of compound 584(0.64 g; 1.2mmol) and methylamine/2M THF (3 mL; 6mmol) is heated in 1-methyl-2-pyrrolidone (5mL) at 140 ℃ for 24 h in a sealed tube. The reaction mixture was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. Purification of the crude product (1g) (5 μm; mobile phase: gradient from 100% DCM to 0.6% NH) by silica gel chromatography4OH, 94% DCM, 6% MeOH). The pure fractions were collected and the solvent was evaporated to dryness. The residue was crystallized from acetone and diethyl ether. The precipitate was filtered off and dried to yield 0.34g (58%) of compound 673. MP: 180 deg.C (Kofler).
Conversion 66
a) Preparation of Compound 674
Chloroacetyl chloride (0.23 mL; 2.9 mmol) is added dropwise to a solution of compound 409(1.3g, 2.7mmol) and triethylamine (1.14 mL, 8.2 mmol) in acetonitrile (40mL) at 0 ℃ under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then at 110 ℃ overnight. Water was added and the reaction mixture was extracted with DCM and dried (MgSO)4) Filtered and dried to provide 1.5g of compound 674, which is used in the next step without further purification.
b) Preparation of Compound 675
Potassium tert-butoxide was added portionwise to a solution of compound 674(2.6 g; 4.7mmol) in isopropanol (58mL) and THF (58 mL). The reaction mixture was stirred at room temperature for 2 hours, then poured into ice water and DCM was added. The organic layer was separated and dried (MgSO)4) Filtered and the solvent was evaporated to dryness. The crude product (2.1g) (20-45) was purified by silica gel chromatographyMu m, 450 g; mobile phase gradient: from 0.2% NH4OH, 96.5% DCM, 3.5% MeOH to 1% NH4OH, 89% DCM, 10% MeOH). The pure fractions were collected and the solvent was evaporated to dryness. The residue (0.61g) was taken up in diethyl ether and CH3And (4) crystallizing CN. The precipitate was filtered off and dried to yield 0.49g (21%) of compound 675. MP: 187 ℃ (Kofler).
c) Preparation of Compounds 676
Lithium aluminium hydride (0.028 g; 0.73mmol) was added to a solution of compound 674(0.25 g; 0.48 mmol) in THF (20mL) at 0-5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 0-5 ℃ for 1 hour. EtOAc was added dropwise to the reaction mixture, followed by water dropwise. The organic layer was separated, washed with brine and dried (MgSO)4) Filtered and the solvent evaporated to dryness. Purification of the crude product (1g) (5 μm; mobile phase: gradient from 100% DCM to 0.6% NH) by silica gel chromatography4OH, 94% DCM, 6% MeOH). The pure fractions were collected and the solvent was evaporated to dryness. The residue (0.155 g) (2-ethylpyridine, 6 μm; mobile phase: 0.3% isopropylamine, 20% MeOH, 80% CO) was purified by achiral supercritical fluid chromatography2). The pure fractions were collected and the solvent was evaporated to dryness.
The residue (0.053g) (15-40 μm, 10 g; mobile phase: gradient from 100% DCM to 0.6% NH) was purified by chromatography on silica gel4OH, 94% DCM, 6% MeOH). The pure fractions were collected and the solvent was evaporated to dryness to yield 0.043g (18%) of compound 677. MP =88 ℃ (Kofler).
Transformation 67
a) Preparation of Compound 678
The experiment was performed 3 times with the following numbers.
Compound 137(HCl salt) (1 g; 2.3mmol), 2-bromoethyl-methylMethylsulfonyl (0.5 mL; 2.8mmol) and K2CO3(0.6 g; 4.6 mmol) in CH3CN (33 mL) was stirred at 80 ℃ for 2 hours. The reaction was poured into ice water and EtOAc was added. The organic layer was separated, washed with brine, combined and dried (MgSO)4) Filtered and the solvent evaporated. The residue (5.2g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 450; mobile phase gradient: 0.5% NH)4OH, 96% DCM, 4% MeOH to 0.5% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated. The residue (3.2g) was crystallized from diethyl ether. The precipitate is filtered off and dried, yielding 2.2g (78%) of compound 678. MP: 148 Deg.C (DSC).
Conversion 68
a) Preparation of Compound 680
In a sealed tube, compound 681(0.97 g; 1.4mmol) was heated in trifluoroacetic acid (28.5ml) at 100 ℃ for 24 hours. The reaction mixture was evaporated to dryness. The crude product was diluted in DCM and NaHCO3Alkalizing. The organic layer was separated and dried (MgSO)4) Filtered and the solvent evaporated. The residue (1.2g) was purified by silica gel chromatography (SiOH, 15-40 μm, 300 g; mobile phase gradient: 0.5% NH)4OH, 92% DCM, 8% MeOH to 0.5% NH4OH, 90% DCM, 10% MeOH). The pure fractions were collected and concentrated. The residue (0.42g) was purified by chromatography on silica gel (SiOH, 10 μm, 60 g; mobile phase: 0.5% NH)4OH, 93% DCM, 7% MeOH). The pure fractions were collected and concentrated. The residue was taken up in DIPE/CH3And (4) crystallizing CN. The precipitate was filtered off and dried to yield 0.29 g (45%) of compound 680. MP: 167 Deg.C (DSC).
Transformation 69
a) Preparation of Compound 682
10% Palladium on carbon (0.65 g; 6mmol) is addedTo a solution of compound 10(1.5 g; 2.7mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature under 3 bar. After 24 hours, the catalyst was filtered off on a pad of celite and the filtrate was concentrated. The residue (1.2g) was purified by silica gel chromatography (SiOH, 20-40 μm, 450 g; mobile phase gradient: from 0.2% NH)4OH, 96% DCM, 4% MeOH to 0.2% NH4OH, 95% DCM, 5% MeOH). The pure fractions were collected and concentrated. The residue (0.25 g) (2-ethylpyridine, 6 μm; mobile phase: 0.3% isopropylamine, 20% MeOH, 80% CO) was purified by achiral supercritical fluid chromatography2). The pure fractions were collected and the solvent was evaporated to dryness. The residue was taken up with diethyl ether and CH3And (4) crystallizing CN. The precipitate was filtered off and dried to yield 0.15g (12%) of compound 682. MP: 149 deg.C (Kofler).
Conversion 70
a) Preparation of Compound 683
A mixture of compound 84(1 g; 2.5mmol) and 1.2-epoxy-3.3.3-trifluoropropane (0.4 mL; 4.9mmol) was heated in MeOH (15mL) at 60 ℃ for 2 h. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue (1.6g) was purified by chromatography on silica gel (SiOH, 15-40 μm, 300 g; mobile phase gradient: from 0.1% NH)4OH, 98% DCM, 2% MeOH to 0.1% NH4OH, 97% DCM, 3% MeOH). The pure fractions were collected and concentrated. The residue (0.56g) was crystallized from diethyl ether. The precipitate is filtered off and dried to yield 0.2g (16%) of compound 683. MP: 123 Deg.C (DSC).
Conversion 71
Preparation of Compound 685Of HCl salt of
A5N HCl/i-PrOH 5/6N solution (2.4 mL; 12mmol) was added to compound 686(0.9 g; 1.7 mmol) in CH at 5 deg.C3OH (3mL) solution. Mixing the reactionThe mixture was stirred at 5 ℃ for 2 hours and then at room temperature for 15 hours. The precipitate was filtered off and dried in vacuo to yield 0.425g (52%) of compound 685. MP =203 ℃ (Kofler).
Conversion 72
Preparation of Compound 696Of HCl salt of
Hydrochloric acid (4M in dioxane) (6.8 mL; 27.2 mmol) was added to CH of compound 695(1.9 g; 3.4mmol)3CN (37 mL) and stirred at 50 ℃ for 18 h. The reaction mixture was poured into ice water. The precipitate is filtered off and dried to yield 0.3g (15%) of compound 696. MP: 188 deg.C (Kofler).
Conversion 73
Preparation of Compound 902.HBr
A mixture of compound 669(200 mg, 0.38mmol) and bromotrimethylsilane (3.16 mL, 23.975 mmol) was stirred in anhydrous DCM (4mL) at room temperature for 3 h. The solvent was evaporated and the resulting residue diluted with MeOH-water (1:1, 10ml) and stirred for 20 min. The precipitate was filtered off, washed with AcOEt and dried to yield 149mg (82%) of compound 902.
Conversion 74
Preparation of Compound 906
Compound 93(340mg, 0.81mmol) was added to trifluoroacetaldehyde methyl hemiacetal (311 μ L, 3.25mmol) at 0 ℃ and the mixture was stirred at 0 ℃ for 4 hours 30 minutes. The mixture was evaporated and the residue purified by chromatography on silica gel (5 μm, mobile phase: gradient from 0.2% NH)4OH, 98% DCM, 2% MeOH to 1.3% NH4OH、87% DCM、13%MeOH). The fractions of the desired product were collected and the solvent was evaporated, yielding 41 mg. The residue was taken up in Et2In O, filtered and dried to give 29mg of compound 906.
Transformation 75
Preparation of Compound 918
A mixture of compound 584(397 mg; 0.75mmol) and dimethylamine (3mL of a 2.0M solution in tetrahydrofuran; 6mmol) was stirred in 1-methyl-2-pyrrolidone (11 mL) in a sealed tube at 140 ℃ for 24 h. The mixture was poured into ice water and EtOAc was added. The organic layer was separated and dried (MgSO)4) Filtration and evaporation of the filtrate to dryness gave 607mg residue which was purified by silica gel chromatography (15-40 μm, 90g, mobile phase: DCM/CH3OH/NH4OH: 98/2/0.1). The target fraction was collected and evaporated to dryness to give 461 mg of residue which was repurified by silica gel chromatography (5 μm; mobile phase: gradient from 100% DCM to 0.6% NH)4OH, 94% DCM, 6% MeOH). The target fraction was collected and evaporated to dryness to give 390 mg. The residue was purified by achiral supercritical fluid chromatography (diethylaminopropyl, 5 μm, mobile phase: 0.3% isopropylamine, 92% CO)28% MeOH). The target fraction was collected, evaporated to dryness to give 233 mg of residue, which was taken up in Et2And (4) crystallizing the O. The precipitate was filtered off and dried to yield 211 mg (57%) of compound 918.
Conversion 76
Preparation of Compound 757
NaH (447.83 mg, 11.2 mmol) was added to a mixture of compound 4(2g, 4.48mmol) and DMF (40ml) at 5 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at 10 ℃ for 30 minutes, then methyl iodide (0.335 ml, 5.375 mmol) was added dropwise. The reaction mixture was cooled to room temperature and at room temperatureStirred for 2 hours. Pouring into H2O + NaCl and extracted with AcOEt. The organic layer was washed with water and dried (MgSO)4) Filtered and evaporated to dryness to give 2g of residue. Purification of the residue by flash chromatography on silica gel (15-40 μm, 40g, CH)2Cl2/CH3OH/NH4OH: 96/4/0.1). The pure fractions were collected and evaporated to dryness to give 2 fractions: 1.05g of compound 757 and 0.3g of compound 757.
The following compounds were prepared according to the reaction scheme of one of the above examples, using alternative starting materials (as the case may be). Hereinafter, those with NMR have NMR data.
In the table, = CoX (or = BX) indicates that the preparation method of the compound is described in the conversion X (or the method BX).
In this table, CoX (or BX) indicates that the compound was prepared according to transformation X (or method BX).
As will be appreciated by those skilled in the art, the compounds synthesized using the indicated schemes may exist in the form of solvates (e.g., hydrates) and/or contain residual solvents or trace impurities. The compounds isolated in salt form may be in integer stoichiometry, i.e., mono-or di-salts, or intermediate stoichiometry.
Analysis section
LC/GC/NMR
General method A
HPLC measurements were performed using an Alliance HT 2790(Waters) system comprising a quaternary pump with degasser, autosampler, column oven (set at 40 ℃ C. unless otherwise stated), diode-array detector (DAD) and columns as listed in the corresponding methods below. The flow is diverted from the column to the MS spectrometer. The MS detector was configured with an electrospray ionization source. The mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizer gas. Data collection was performed using the Waters-Micromass MassLynx-Openlynx data System.
Method 1
In addition to general method a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100 mm) with a flow rate of 1.6 ml/min. Gradient conditions were run using three mobile phases (mobile phase A: 95% 25mM ammonium acetate +5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol): from 100% a to 1% a, 49% B and 50% C (6.5 min) to 1% a and 99% B (1 min), these conditions were maintained for 1 min and re-equilibrated with 100% a for 1.5 min. An injection volume of 10 μ l was used. The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.
Method 2
In addition to general method a: the column heater was set at 45 ℃. Reverse phase HPLC was performed on an Atlantis C18 column (3.5 μm, 4.6X100 mm) at a flow rate of 1.6 ml/min. Two mobile phases (mobile phase a: 70% methanol +30% water; mobile phase B: 0.1% formic acid-water/methanol 95/5) were used to run the gradient conditions: these conditions were maintained for 3 minutes from 100% B to 5% B + 95% a (9 minutes). An injection volume of 10 μ l was used.
The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.
Method 3
In addition to general method a: reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X100 mm) with a flow rate of 1.6 ml/min. Gradient conditions were run using three mobile phases (mobile phase A: 95% 25mM ammonium acetate +5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol): from 100% a to 50% B and 50% C (6.5 min) to 100% B (1 min), 100% B (1 min) and equilibrated with 100% a for an additional 1.5 min. An injection volume of 10 μ l was used.
The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.
Method 9
In addition to general method a: reverse phase HPLC was performed on a Waters Xterra-RP C18 column (3.5 μm, 4.6X100 mm) at a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 100% 7mM ammonium acetate; mobile phase B: 100% acetonitrile) were used to run the gradient conditions: from 80% a and 20% B (hold 0.5 min) to 90% B (4.5 min), 90% B (4 min), the initial conditions were equilibrated for an additional 3 min. An injection volume of 5ml was used. The cone voltage was 20V for positive and negative ionization modes. The scans were performed from 100 to 1000 in 0.4 seconds using an intermediate scan delay of 0.3 seconds to obtain mass spectra.
Method 10
In addition to general method a: reverse phase HPLC was performed on a Xterra-MS C18 column (3.5 μm, 4.6X100 mm) with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 100% 7mM ammonium acetate; mobile phase B: 100% acetonitrile) were used to run the gradient conditions: from 80% a, 20% B (hold 0.5 min) to 10% a, 90% B (4.5 min), held for 4 min at 10% a and 90% B, and equilibrated for 3 min with initial conditions. An injection volume of 10ml was used. The cone voltage was 20V for positive and negative ionization modes. The scans were performed from 100 to 1000 in 0.4 seconds using an intermediate scan delay of 0.3 seconds to obtain mass spectra.
General method B
LC assays were performed using the Acquity UPLC (Waters) system, which included a binary pump, sample holder, column heater (set at 55 ℃), diode-array detector (DAD) and columns listed in the corresponding methods below. The flow is diverted from the column to the MS mass spectrometer. The MS detector was configured with an electrospray ionization source. The mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 ℃. Nitrogen was used as the atomizer gas. Data collection was performed using the Waters-Micromass MassLynx-Openlynx data System.
Method 4
In addition to general method B: reversed phase UPLC (ultra high performance liquid chromatography) was performed on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1X50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. Two mobile phases (mobile phase a: 0.1% formic acid-water/methanol 95/5; mobile phase B: methanol) were used to run the gradient conditions: from 95% a and 5% B to 5% a and 95% B (1.3 min), hold for 0.2 min. An injection volume of 0.5 μ l was used.
The cone voltage is 10V for the positive ionization mode and 20V for the negative ionization mode.
Method 5
In addition to general method B: reversed phase UPLC (ultra high performance liquid chromatography) was performed on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1X50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. Two mobile phases (25 mM ammonium acetate-water/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run the gradient conditions: from 95% a and 5% B to 5% a and 95% B (1.3 min), hold for 0.3 min. An injection volume of 0.5 μ l was used.
The cone voltage is 30V for positive ionization mode and 30V for negative ionization mode.
General method C
The LC assay was performed using a UPLC (ultra performance liquid chromatography) acquity (waters) system comprising a binary pump with degasser, autosampler, diode-array detector (DAD) and columns as listed in the corresponding methods below, which were maintained at a temperature of 40 ℃. The effluent flows from the column to the MS detector. The MS detector was configured with an electrospray ionization source. The capillary needle voltage was 3kV and the source temperature was maintained at 130 ℃ (on Quattro (triple quadrupole mass spectrometer, from Waters)). Nitrogen was used as the atomizer gas. Data collection was performed using the Waters-Micromass MassLynx-Openlynx data System.
Method 6
In addition to general method C: reverse phase UPLC was performed on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18 column (1.7 μm, 2.1x 100 mm) at a flow rate of 0.35 ml/min. Two mobile phases (mobile phase A: 95% 7mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile) were used to run the gradient conditions: from 90% a and 10% B (hold 0.5 min) to 8% a and 92% B (3.5 min), hold for 2 min, and return to the initial condition (0.5 min), hold for 1.5 min. An injection volume of 2 μ l was used. The cone voltage was 20V for positive and negative ionization modes. The scans were performed from 100 to 1000 in 0.2 seconds using an intermediate scan delay of 0.1 seconds to obtain mass spectra.
Method 7
In addition to general method C: reverse phase UPLC was performed on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18 column (1.7 μm, 2.1x 100 mm) at a flow rate of 0.343 ml/min. Two mobile phases (mobile phase A: 95% 7mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile) were used to run the gradient conditions: from 84.2% a and 15.8% B (hold 0.49 min) to 10.5% a and 89.5% B (2.18 min), hold 1.94 min, and return to the initial condition (0.73 min), hold 0.73 min. An injection volume of 2ml was used. The cone voltage was 20V for positive and negative ionization modes. The scans were performed from 100 to 1000 in 0.2 seconds using an intermediate scan delay of 0.1 seconds to obtain mass spectra.
General method D
HPLC measurements were performed using an Alliance HT 2795(Waters) system comprising a quaternary pump with degasser, autosampler, diode-array detector (DAD) and columns as listed in the corresponding methods below, which were maintained at a temperature of 30 ℃. The effluent was diverted from the column to the MS spectrometer. The MS detector was configured with an electrospray ionization source. The capillary needle voltage was 3kV and the source temperature was maintained at 100 deg.C (on LCT (Time of Flight Zspray Mass spectrometer from Waters)). Nitrogen was used as the atomizer gas. Data collection was performed using the Waters-Micromass MassLynx-Openlynx data System.
Method 8
In addition to general method D: reverse phase HPLC was performed on a Supelco Ascentis Express C18 column (2.7 μm, 3.0 x50 mm) at a flow rate of 0.7 ml/min. Two mobile phases (mobile phase A: 100% 7mM ammonium acetate; mobile phase B: 100% acetonitrile) were used to run the gradient conditions: from 80% a and 20% B (hold 0.5 min) to 5% a and 95% B (2.5 min), hold 4.5 min, return to the initial condition (1.5 min), hold 1 min. An injection volume of 5 μ l was used. The cone voltage was 20V for positive and negative ionization modes. The scans were performed from 100 to 1000 in 0.4 seconds using an intermediate scan delay of 0.3 seconds to obtain mass spectra.
NMR data
The following NMR experiments were performed at room temperature using Bruker Avance 500 and Bruker Avance DRX 400 spectrometers, equipped with reverse triple resonance (with a reverse triple resonance for 500MHz, using intrinsic deuterium locks1H,13C,15N TXI probe, for 400MHz, equipped with inverse dual resonance (A), (B), (C), (1H,13C, SEI) probe. Chemical shifts () are reported in parts per million (ppm).
Compound 131
1H NMR(500 MHz, DMSO-d6)9.01(s, 1H), 8.60(s, 1H), 8.28(s, 1H), 7.79(d, J=9.1 Hz, 1H), 7.27(dd, J=2.5, 9.1 Hz, 1H), 7.16(d, J=2.5 Hz, 1H), 6.38-6.49(m, 3H), 4.82(br. s., 2H), 4.23(t, J=5.7 Hz, 2H), 3.96(t, J=4.9 Hz, 2H),3.80(t, J=5.7 Hz, 2H), 3.71-3.75(m, 5H), 3.69(t, J=4.9 Hz, 2H), 1.05-1.26(m,1H), 0.42-0.51(m, 2H), 0.16-0.25(m, 2H)。
Compound 149
1H NMR(500 MHz, DMSO-d6)9.00(s, 1H), 8.58(s, 1H), 8.22(s, 1H), 7.80(d, J=9.1 Hz, 1H), 7.31(dd, J=2.5, 9.1 Hz, 1H), 7.25(d, J=2.5 Hz, 1H), 6.80(br. s., 1H), 6.49(d, J=1.9 Hz, 2H), 6.42(br. s., 1H), 4.15-4.31(m, 2H),3.89-4.00(m, 4H), 3.74(s, 6H)。
Compound 148
1H NMR(500 MHz, DMSO-d6) 9.00(s, 1H), 8.58(s, 1H), 8.22(s, 1H), 7.80(d, J=9.1 Hz, 1H), 7.31(dd, J=2.5, 9.1 Hz, 1H), 7.25(d, J=2.5 Hz, 1H), 6.80(br. s., 1H), 6.49(d, J=1.9 Hz, 2H), 6.42(br. s., 1H), 4.15-4.31(m, 2H),3.89-4.00(m, 4H), 3.74(s, 6H)。
Compound 147
1H NMR(400 MHz, DMSO-d6) 9.76(br. s., 1H), 9.01(s, 1H), 8.64(s, 1H),8.22(s, 1H), 7.79(d, J=9.3 Hz, 1H), 7.26(dd, J=2.8, 9.3 Hz, 1H), 7.18(d, J=2.8 Hz, 1H), 6.36-6.51(m, 3H), 4.58(spt, J=6.6 Hz, 1H), 4.03-4.19(m, 2H),3.93(t, J=7.3 Hz, 2H), 3.75(s, 6H), 3.09-3.20(m, 2H), 2.08(td, J=7.3, 14.5Hz, 2H), 1.49(d, J=6.6 Hz, 6H)。
Compound 146
1H NMR(400 MHz, DMSO-d6) 8.99(s, 1H), 8.71(s, 1H), 8.65(t, J=1.5 Hz,1H), 8.51-8.56(m, 2H), 8.19(s, 1H), 7.79(d, J=9.1 Hz, 1H), 7.39(dd, J=2.8,9.1 Hz, 1H), 7.22(d, J=2.8 Hz, 1H), 6.55(d, J=2.1 Hz, 2H), 6.37(t, J=2.1 Hz,1H), 5.31(s, 2H), 3.91(s, 3H), 3.72(s, 6H)。
Compound 145
1H NMR(500 MHz, DMSO-d6) 8.98(br. s., 2H), 8.55(s, 1H), 8.20(s, 1H),7.79(d, J=9.1 Hz, 1H), 7.34(dd, J=2.6, 9.1 Hz, 1H), 7.26(d, J=2.6 Hz, 1H),6.55(d, J=1.9 Hz, 2H), 6.43(s, 1H), 4.17(br. s., 1H), 3.88-3.99(m, 6H), 3.75(s, 6H), 3.30(td, J=6.3, 11.9 Hz, 1H), 3.02-3.16(m, 1H), 2.96(q, J=9.6 Hz,1H), 1.22(d, J=6.3 Hz, 6H)。
Compound 144
1H NMR(500 MHz, DMSO-d6) 8.96(s, 1H), 8.55(s, 1H), 8.21(s, 1H), 7.77(d, J=9.5 Hz, 1H), 7.73(br. s., 1H), 7.27(dd, J=2.7, 9.5 Hz, 1H), 7.14(d, J=2.7 Hz, 1H), 6.45(d, J=2.2 Hz, 2H), 6.38-6.41(m, 1H), 3.99(t, J=6.6 Hz, 2H),3.93(s, 3H), 3.73(s, 6H), 3.14(br. s., 2H), 3.01(s, 2H), 2.68(t, J=6.6 Hz,2H), 2.63(t, J=5.2 Hz, 2H)。
Compound 143
1H NMR(500 MHz, DMSO-d6) 8.96(s, 1H), 8.55(s, 1H), 8.21(s, 1H), 7.77(d, J=9.1 Hz, 1H), 7.28(dd, J=2.5, 9.1 Hz, 1H), 7.14(d, J=2.5 Hz, 1H), 6.44(d, J=2.2 Hz, 2H), 6.32-6.42(m, 1H), 3.98(t, J=6.9 Hz, 2H), 3.93(s, 3H), 3.73(s, 6H), 3.35-3.43(m, 4H), 2.63(t, J=6.9 Hz, 2H), 2.44(t, J=4.9 Hz, 2H), 2.38(t, J=4.9 Hz, 2H), 1.97(s, 3H)。
Compound 142
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.75(d, J=9.5 Hz, 1H), 7.34(dd, J=2.7, 9.5 Hz, 1H), 7.22(d, J=2.7 Hz, 1H), 6.49(d, J=1.9 Hz, 2H), 6.38(t, J=1.9 Hz, 1H), 5.16(d, J=5.1 Hz, 1H), 3.83-4.00(m,5H), 3.69-3.78(m, 7H), 3.19-3.31(m, 2H), 2.68-2.78(m, 1H), 2.66(td, J=6.1,12.1 Hz, 1H), 2.30-2.40(m, 1H)。
Compound 141
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.55(s, 1H), 8.21(s, 1H), 7.76(d, J=9.1 Hz, 1H), 7.26(dd, J=2.5, 9.1 Hz, 1H), 7.14(d, J=2.5 Hz, 1H), 6.34-6.44(m, 3H), 4.49(s, 1H), 3.84-3.99(m, 5H), 3.74(s, 6H), 1.66-1.86(m, 2H),1.16(s, 6H)。
Compound 140
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.76(d, J=9.1 Hz, 1H), 7.28(dd, J=2.5, 9.1 Hz, 1H), 7.14(d, J=2.5 Hz, 1H), 6.46(d, J=1.9 Hz, 2H), 6.41(t, J=1.9 Hz, 1H), 3.83-3.96(m, 5H), 3.74(s, 6H), 2.82(t, J=6.7 Hz, 2H), 2.78(t, J=6.7 Hz, 2H), 2.57(t, J=6.7 Hz, 2H), 2.22(br. s.,1H)。
Compound 139
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.75(d, J=9.5 Hz, 1H), 7.34(dd, J=2.7, 9.5 Hz, 1H), 7.22(d, J=2.7 Hz, 1H), 6.49(d, J=1.9 Hz, 2H), 6.38(t, J=1.9 Hz, 1H), 5.16(d, J=5.1 Hz, 1H), 3.83-4.00(m,5H), 3.69-3.78(m, 7H), 3.19-3.31(m, 2H), 2.68-2.78(m, 1H), 2.66(td, J=6.1,12.1 Hz, 1H), 2.30-2.40(m, 1H)。
Compound 137
1H NMR(400 MHz, DMSO-d6) 9.10(br.s., 3H), 8.49(s, 2H), 7.84(d, J=9.6Hz, 1H), 7.39(dd, J=2.7, 9.6 Hz, 1H), 7.29(d, J=2.7 Hz, 1H), 6.52(d, J=2.1Hz, 2H), 6.46(t, J=2.1 Hz, 1H), 4.21(t, J=7.3 Hz, 2H), 3.76(s, 6H), 3.35(m,1H), 3.15(br. s., 2H), 1.25(d, J=6.1 Hz, 6H)。
Compound 98
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.56(s, 1H), 8.21(s, 1H), 7.75(d, J=9.1 Hz, 1H), 7.34(dd, J=2.5, 9.1 Hz, 1H), 7.25(d, J=2.5 Hz, 1H), 6.50(d, J=2.2 Hz, 2H), 6.37(t, J=2.2 Hz, 1H), 5.01(d, J=2.8 Hz, 1H), 4.70-4.79(m,1H), 4.03(dd, J=3.6, 14.9 Hz, 1H), 3.92(s, 3H), 3.81(br. s., 1H), 3.73(s,6H), 3.68(dd, J=8.1, 14.9 Hz, 1H), 3.36-3.48(m, 2H)。
Compound 136
1H NMR(500 MHz, DMSO-d6) 9.03(br.s., 2H), 8.58(s, 1H), 8.25(s, 1H),7.83(d, J=9.5 Hz, 1H), 7.36(dd, J=2.5, 9.5 Hz, 1H), 7.23(d, J=2.5 Hz, 1H),6.52(d, J=1.9 Hz, 2H), 6.46(t, J=1.9 Hz, 1H), 4.19-4.21(m, 2H), 4.10(d, J=6.9Hz, 2H), 3.84(dd, J=2.8, 11.7 Hz, 2H), 3.76(s, 6H), 3.31-3.38(td, J=6.1,11.7, 1H), 3.27(t, J=11.7 Hz, 2H), 3.14-3.18(m, 2H), 2.16-2.08(m, 1H), 1.43(d, J=11.7 Hz, 2H), 1.18-1.37(m, 8H)。
Compound 135
1H NMR(500 MHz, DMSO-d6) 9.03(br.s., 2H), 8.62(s, 1H), 8.23(s, 1H),7.83(d, J=9.5 Hz, 1H), 7.36(dd, J=2.5, 9.5 Hz, 1H), 7.25(d, J=2.5 Hz, 1H),6.51(d, J=2.2 Hz, 2H), 6.46(t, J=2.2 Hz, 1H), 3.76(s, 6H), 4.12-4.27(m, 4H),3.30-3.43(m, 1H), 3.07-3.19(m, 2H), 1.44(t, J=7.2 Hz, 3H), 1.25(d, J=6.3 Hz,6H)。
Compound 134
1H NMR(500 MHz, DMSO-d6) 9.05(s, 1H), 8.93(m, 1H), 8.57(s, 1H), 8.25(s, 1H), 8.18(q, J=4.6 Hz, 1H), 7.83(d, J=9.1 Hz, 1H), 7.33(dd, J=2.5, 9.1Hz, 1H), 7.28(d, J=2.5 Hz, 1H), 6.52(d, J=2.2 Hz, 2H), 6.46(t, J=2.2 Hz, 1H),4.88(s, 2H), 4.19(t, J=7.6 Hz, 2H), 3.75(s, 6H), 3.29-3.42(m, 1H), 3.16(br.s., 2H), 2.64(d, J=4.6 Hz, 3H), 1.25(d, J=6.6 Hz, 6H)。
Compound 5
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.75(d, J=9.1 Hz, 1H), 7.28(dd, J=2.5, 9.1 Hz, 1H), 7.12(d, J=2.5 Hz, 1H), 6.40(s, 3H), 3.93(s, 3H), 3.88(t, J=7.1 Hz, 2H), 3.74(s, 6H), 3.11-3.28(m, 2H),2.68-2.72(m,, 2H), 2.39-2.48(m, 1H), 1.78(quin, J=7.1 Hz, 2H)。
Compound 133
1H NMR(500 MHz, DMSO-d6) 8.97(s, 1H), 8.56(s, 1H), 8.21(s, 1H), 7.77(d, J=9.5 Hz, 1H), 7.27(dd, J=2.5, 9.5 Hz, 1H), 7.12(d, J=2.5 Hz, 1H), 6.29-6.49(m, 3H), 3.96(t, J=6.8 Hz, 2H), 3.93(s, 3H), 3.74(s, 6H), 3.19-3.29(m,1H), 2.70-2.85(m, 5H), 2.42-2.46(m, 1H), 2.10-2.24(m, 1H), 1.88-1.98(m, 1H)。
Compound 132
1H NMR(500 MHz, DMSO-d6) 8.96(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.76(d, J=9.3 Hz, 1H), 7.23(dd, J=2.8, 9.3 Hz, 1H), 7.07(d, J=2.8 Hz, 1H), 6.41(s, 3H), 3.93(s, 3H), 3.81(t, J=7.4 Hz, 2H), 3.74(s, 6H), 3.23-3.32(m, 4H),2.23(t, J=8.1 Hz, 2H), 1.93(m, 2H), 1.84(m,2H)。
Compound 300
1H NMR(400 MHz, DMSO-d6) 9.05(s, 1H), 8.54-8.63(m, 1H), 8.24(s, 1H),7.84(d, J=9.1 Hz, 1H), 7.41(d, J=2.5 Hz, 1H), 7.34(dd, J=2.5, 9.1 Hz, 1H),7.20(s, 1H), 6.88(s, 1H), 6.50(s, 2H), 6.42-6.47(m, 1H), 4.99(s, 2H), 3.93(s,3H), 3.74(s, 6H), 3.53(s, 3H)
Compound 4
1H NMR(500 MHz, DMSO-d6) 8.95(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.76(d, J=9.1 Hz, 1H), 7.27(dd, J=2.8, 9.1 Hz, 1H), 7.13(d, J=2.8 Hz, 1H), 6.46(d, J=2.2 Hz, 2H),6.40(t, J=2.2 Hz, 1H), 3.93(s, 3H), 3.88(t, J=6.9 Hz, 2H),3.74(s, 6H), 2.79(t, J=6.9 Hz, 2H), 2.70(m, 1H), 1.69(br. s., 1H), 0.95(d, J=6.3 Hz, 6H)。
Compound 84
1H NMR(500 MHz, DMSO-d6) 8.94(s, 1H), 8.55(s, 1H), 8.20(s, 1H), 7.75(d, J=9.3 Hz, 1H), 7.28(dd, J=2.5, 9.30 Hz, 1H), 7.15(d, J=2.5 Hz, 1H), 6.45(d, J=2.2 Hz, 2H), 6.38-6.42(m, 1H), 3.93(s, 3H), 3.82(t, J=7.1 Hz, 2H), 3.74(s, 6H), 2.80(t, J=7.1 Hz, 2H), 1.55(br. s., 2H)。
Compound 130
1H NMR(500 MHz, DMSO-d6) 9.00(s, 1H), 8.69(s, 1H), 8.33(s, 1H), 7.79(d, J=9.5 Hz, 1H), 7.28(dd, J=2.7, 9.5 Hz, 1H), 7.14(d, J=2.7 Hz, 1H), 6.38-6.47(m, 3H), 5.55(br.s., 1H), 4.34(t, J=6.6 Hz, 2H), 3.62-3.91(m, 12H), 3.36-3.55(m, 6H), 3.09-3.31(m, 4H), 2.28-2.38(m, 2H), 1.75-1.97(m, 2H), 1.10-1.23(m, 1H), 0.43-0.52(m, 2H), 0.15-0.24(m, 2H)。
The following NMR experiment was performed using a Bruker Avance AV400 spectrometer, equipped with 4 nuclei using an intrinsic deuterium lock (R) ((R))1H，13C，19F，31P) a probe. Chemical shifts () are reported in parts per million (ppm) at 27 ℃.
Compound 138
1H NMR(400 MHz, DMSO-d6): 9.07(1H, s), 8.59(1H, s), 8.56-8.47(1H, m),8.27-8.21(1H, m), 7.87(1H, d), 7.54-7.47(1H, m), 7.43-7.32(3H, m), 7.27-7.18(1H, m), 3.98-3.89(3H, m), 3.83(2H, d), 2.76(3H, d), 1.23-1.13(1H, m), 0.50-0.41(2H, m), 0.22-0.14(2H, m)。
Compound 99
1H NMR(400 MHz, Me-d3-OD): 8.89(1H, s), 8.40(1H, s), 8.23(1H, s),7.79(1H, d), 7.41(1H, dd), 7.30(1H, d), 7.01(2H, s), 6.53(2H, s), 6.47-6.40(1H, m), 4.57(2H, s), 4.01(3H, s), 3.77(7H, s)。
Compound 200
1H NMR(400 MHz, DMSO-d6): 8.96(1H, s), 8.56(1H, s), 8.21(1H, s), 7.76(1H, d), 7.25(1H, dd), 7.11(1H, d), 6.46-6.36(3H, m), 3.99-3.82(5H, m), 3.75(6H, s), 1.23(3H, t)。
Compound 201
1H NMR(400 MHz, DMSO-d6): 8.92(1H, s), 8.54(1H, s), 8.20(1H, s), 7.76(1H, d), 6.99(1H, dd), 6.81(2H, dd), 6.64(1H, d), 3.92(6H, d), 3.88-3.73(5H,m), 1.24(3H, t)。
Compound 11
1H NMR(400 MHz, DMSO-d6): 8.98(1H, s), 8.56(1H, s), 8.22(1H, s), 7.78(1H, d), 7.30(1H, dd), 7.16(1H, d), 6.43(2H, d), 6.40(1H, t), 3.94(3H, s),3.74(6H, s), 3.41(3H, s)。
Compound 202
1H NMR(400 MHz, DMSO-d6): 8.96(1H, s), 8.56(1H, s), 8.21(1H, s), 7.77(1H, d), 7.26(1H, dd), 7.13(1H, d), 6.42(3H, s), 3.93(3H, s), 3.82-3.70(8H,m), 1.24-1.12(1H, m), 0.53-0.43(2H, m), 0.26-0.16(2H, m)。
Compound 12
1H NMR(400 MHz, DMSO-d6): 8.96(1H, s), 8.56(1H, s), 8.21(1H, s), 7.76(1H, d), 7.26(1H, dd), 7.08(1H, d), 6.41(3H, dd), 3.93(3H, s), 3.79(2H, t),3.75(6H, s), 1.73-1.63(2H, m), 0.96(3H, t)。
Compound 204
1H NMR(400 MHz, DMSO-d6): 9.00-8.94(1H, m), 8.59-8.53(1H, m), 8.25-8.18(1H, m), 7.77(1H, d), 7.30(1H, dd), 7.17(1H, d), 6.44(2H, d), 6.40(1H,t), 4.03(2H, t), 3.94(3H, s), 3.74(6H, s), 3.60(2H, t), 3.29(3H, s)。
Compound 13
1H NMR(400 MHz, DMSO-d6): 8.97(1H, s), 8.56(1H, s), 8.21(1H, s), 7.77(1H, d), 7.30(1H, dd), 7.10(1H, d), 6.41(3H, s), 3.93(3H, s), 3.74(6H, s),3.69(2H, d), 2.09-1.97(1H, m), 0.98(6H, d)。
Compound 205
1H NMR(400 MHz, DMSO-d6): 9.02(1H, s), 8.60-8.54(1H, m), 8.22(1H, s),7.82(1H, d), 7.36(1H, dd), 7.24(1H, d), 6.48(2H, d), 6.40(1H, t), 6.32(1H,s), 5.25(2H, s), 3.97-3.89(3H, m), 3.78-3.69(7H, m), 3.29(3H, s), 2.18(3H,s)。
Pharmacological moieties
Biological test A
FGFR1 (enzyme assay)
In a final reaction volume of 30 μ L, in the presence of compound (DMSO final 1%), with 50mM HEPES (pH7.5), 6mM MnCl2、1mM DTT、0.1 mM Na3VO4FGFR1(h) (25) was cultured with 0.01% Triton-X-100, 500 nM Btn-Flt3 and 5 μ M ATPng/ml). After incubation at room temperature for 60 minutes, the reaction was stopped with 2.27 nM EU-anti-P-Tyr, 7mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA (which was present at room temperature for 60 minutes). Time-resolved fluorescence resonance energy transfer (TR-FRET) signals (ex 340 nm, Em 620 nm, Em 655 nm) were then measured, after which the results were expressed in RFU (relative fluorescence units). In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
FGFR2 (enzyme assay)
In a final reaction volume of 30 μ L, in the presence of compound (DMSO final 1%), with 50mM HEPES (pH7.5), 6mM MnCl2、1mM DTT、0.1 mM Na3VO4FGFR2(h) (150 ng/ml) was cultured with 0.01% Triton-X-100, 500 nM Btn-Flt3 and 0.4 μ M ATP. After incubation at room temperature for 60 minutes, the reaction was stopped with 2.27 nM EU-anti-P-Tyr, 7mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA (which was present at room temperature for 60 minutes). Time-resolved fluorescence resonance energy transfer (TR-FRET) signals (ex 340 nm, Em 620 nm, Em 655 nm) were then measured and the results expressed in RFU (relative fluorescence units). In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
FGFR3 (enzyme assay)
In a final reaction volume of 30 μ L, in the presence of compound (DMSO final 1%), with 50mM HEPES (pH7.5), 6mM MnCl2、1mM DTT、0.1 mM Na3VO4FGFR3(h) (40 ng/ml) was cultured with 0.01% Triton-X-100, 500 nM Btn-Flt3 and 25 μ M ATP. After incubation at room temperature for 60 minutes, the reaction was stopped with 2.27 nM EU-anti-P-Tyr, 7mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA (which was present at room temperature for 60 minutes). Time-resolved fluorescence resonance energy transfer (TR-FRET) signals (ex 340 nm, Em 620 nm, Em 655 nm) were then measured and the results expressed in RFU (relative fluorescence units). In this test, the differences were determinedThe inhibitory effect of the compound concentration (in the range of 10. mu.M to 0.1 nM) and used to calculate IC50Values (M) and pIC50Value (-logIC)50)。
FGFR4 (enzyme assay)
In a final reaction volume of 30. mu.L, in the presence of compound (DMSO final 1%), with 50mM HEPES (pH7.5), 6mM MnCl2、1mM DTT、0.1 mM Na3VO4FGFR4(h) (60 ng/ml) was cultured with 0.01% Triton-X-100, 500 nM Btn-Flt3 and 5. mu.M ATP. After incubation at room temperature for 60 minutes, the reaction was stopped with 2.27 nM EU-anti-P-Tyr, 7mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA (which was present at room temperature for 60 minutes). Time-resolved fluorescence resonance energy transfer (TR-FRET) signals (ex 340 nm, Em 620 nm, Em 655 nm) were then measured, after which the results were expressed in RFU (relative fluorescence units). In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
KDR (VEGFR2) (enzyme assay)
In a final reaction volume of 30. mu.L, in the presence of compound (DMSO final 1%), with 50mM HEPES (pH7.5), 6mM MnCl2、1mM DTT、0.1 mM Na3VO40.01% Triton-X-100, 500 nM Btn-Flt3 and 3. mu.M ATP-cultured KDR (150 ng/ml). After incubation at room temperature for 120 minutes, the reaction was stopped with 2.27 nM EU-anti-P-Tyr, 7mM EDTA, 31.25 nM SA-XL-665 and 0.02% BSA (which was present at room temperature for 60 minutes). Time-resolved fluorescence resonance energy transfer (TR-FRET) signals (ex 340 nm, Em 620 nm, Em 655 nm) were then measured and the results expressed in RFU (relative fluorescence units). In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
Ba/F3-FGFR1 (with IL3 removed or IL3 added) (cell proliferation assay)
In 384-well plates100 nl of compound dilution (in DMSO) was sprayed, followed by addition of 50 μ L of cell culture medium (phenol red free RPMI-1640, 10% FBS, 2mM L-glutamine and 50 μ g/ml gentamicin), with 20000 cells per well of Ba/F3-FGFR 1-transfected cells. Cells were placed at 37 ℃ and 5% CO2Incubator under conditions. After 24 hours, 10 μ l of alamar blue solution (0.5 mM K)3Fe(CN)6，0.5 mM K4Fe(CN)60.15mM resazurin and 100 mM phosphate buffer) were added to the wells at 37 deg.C and 5% CO2Incubated for 4 hours under conditions, and then RFU (relative fluorescence units) was measured using a fluorescence plate reader (ex. 540 nm, em.590 nm.).
In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
As a control screen, the same experiment was performed in the presence of 10 ng/ml murine IL 3.
Ba/F3-FGFR3 (with IL3 removed or IL3 added) (cell proliferation assay)
100 nl of compound dilution (in DMSO) was sprayed in 384 well plates, followed by 50 μ L of cell culture medium (phenol red free RPMI-1640, 10% FBS, 2mM L-glutamine and 50 μ g/ml gentamicin), with 20000 cells per Ba/F3-FGFR3 transfected cell well. Cells were placed at 37 ℃ and 5% CO2Incubator under conditions. After 24 hours, 10 μ l of alamar blue solution (0.5 mM K)3Fe(CN)6，0.5 mM K4Fe(CN)60.15mM resazurin and 100 mM phosphate buffer) were added to the wells at 37 deg.C and 5% CO2Incubated for 4 hours under conditions, and then RFU (relative fluorescence units) was measured using a fluorescence plate reader (ex. 540 nm, em.590 nm.).
In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
As a control screen, the same experiment was performed in the presence of 10 ng/ml murine IL 3.
Ba/F3-KDR (removal of IL3 or addition of IL3) (cell proliferation assay)
In 384 well plates, 100 nl of compound dilution (in DMSO) was sprayed, followed by 50 μ L of cell culture medium (phenol red free RPMI-1640, 10% FBS, 2mM L-glutamine and 50 μ g/ml gentamicin), with 20000 cells per Ba/F3-KDR transfected cell well. Cells were placed at 37 ℃ and 5% CO2Incubator under conditions. After 24 hours, 10 μ l of alamar blue solution (0.5 mM K)3Fe(CN)6，0.5 mM K4Fe(CN)60.15mM resazurin and 100 mM phosphate buffer) were added to the wells at 37 deg.C and 5% CO2Incubated for 4 hours under conditions, and then RFU (relative fluorescence units) was measured using a fluorescence plate reader (ex. 540 nm, em.590 nm.).
In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
As a control screen, the same experiment was performed in the presence of 10 ng/ml murine IL 3.
Ba/F3-Flt3 (with IL3 removed or IL3 added) (cell proliferation assay)
100 nl of compound dilution (in DMSO) was sprayed in 384 well plates, followed by 50 μ L of cell culture medium (phenol red free RPMI-1640, 10% FBS, 2mM L-glutamine and 50 μ g/ml gentamicin), with 20000 cells per Ba/F3-Flt3 transfected cell well. Cells were placed at 37 ℃ and 5% CO2Incubator under conditions. After 24 hours, 10 μ l of alamar blue solution (0.5 mM K)3Fe(CN)6，0.5 mM K4Fe(CN)60.15mM resazurin and 100 mM phosphate buffer) were added to the wells at 37 deg.C and 5% CO2Cultured under the conditions for 4 hours, and thenRFU (relative fluorescence units) was determined with a fluorescence plate reader (ex. 540 nm, em.590 nm.).
In this test, the inhibitory effect of different compound concentrations (ranging from 10 μ M to 0.1 nM) was determined and used to calculate the IC50Values (M) and pIC50Value (-logIC)50)。
As a control screen, the same experiment was performed in the presence of 10 ng/ml murine IL 3.
Data for the compounds of the invention in the above tests are provided in table a 2.
Biological test B
FGFR3、VEGFR2 and PDGFR in vitro kinase inhibition Activity assay
Test compounds, biotinylated Flt3 medium (biotin-VASSDNEYFYVDF) (Cell Signalling Technology Inc.) and ATP culture enzyme (from Upstate) (prepared at 2x final concentration) were used in appropriate assay buffers (table 1). The reaction was allowed to proceed on a plate shaker (700 rpm) for 3 hours (FGFR3), 1 hour (VEGFR2, PDGFR-. beta.) at room temperature, and then stopped with 35mM EDTA (pH8) (FGFR3, VEGFR2) or 55mM EDTA (pH8) (PDGFR-. beta.). Then, a5 Xassay mix (for FGFR 3: 50mM HEPES pH7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20) (PerkinElmer), 74 nM SA-XL665 (Cisbio); for VEGFR 2: 50mM HEPES, pH7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (PY20), 187.5 nM SA-XL 665; for PDGFR-beta: 50mM HEPES, pH7.5, 0.1% BSA, 11.34 nM Eu-anti-pY (66) (Perkinmer), 375 nM SA-XL665(Cisbio)) was added to each well and the plates were sealed and incubated for one hour at room temperature on a plate shaker (700 rpm). The plate was then read on a Packard Fusion plate reader or BMG Pherastar (both in TRF mode).
TABLE 1 Final assay conditions for FGFR3, VEGFR2 and PDGFR- β assays
Enzyme 1x assay buffer Flt3 Medium concentration ATP concentration
FGFR3 A 0.125 µM 8 µM
VEGFR2 B 0.5 µM 0.5 µM
PDGFR-β C 1 µM 70 µM
The kinase assay buffer was:
A: 50 mM HEPES pH7.5，6 mM MnCl2，1 mM DTT，0.01% Triton X-100
B: 50 mM HEPES pH7.5，6 mM MnCl21mM DTT, 0.01% Triton X-100, 0.1 mM sodium orthovanadate
C: 20 mM HEPES pH7.5，10 mM MnCl20.01% Triton X-100, 1mM DTT, 0.1 mM sodium orthovanadate
FGFR3 and VEGFR2 data for the compounds of the invention in the above assays are provided in table A3.
Ba/F3-TEL-FGFR3 and Ba/F3(WT) cell proliferation assay
Stably transfected Ba/F3-TEL-FGFR3 cells were plated in clear-bottomed, black 96-well tissue culture plates at a density of 5X 10 in RPMI medium containing 10% FBS and 0.25 mg/ml G4183Individual cells/well (200 μ l per well). In mice containing 10% FBS and 2 ng/ml IL-3 (R)&D Sysems) in RPMI medium, maternal wild-type Ba/F3 cells (DSMZ No.: ACC 300) coated in clear bottom black 96-well tissue culture plates at a density of 2.5 × 103Individual cells/well (200 μ l per well). Plates were placed in the incubator overnight and compounds were added the next day. Dilutions of compounds (starting at 10 mM) were prepared in DMSO and diluted into wells to give a final DMSO assay concentration of 0.1%. The compound was allowed to remain on the cells for 72 hours, after which the plates were removed from the incubator and 20 μ l of alamar blue (Biosource) was added to each well. The plates were placed in the incubator for 4-6 hours, and then read on a Fusion plate reader (Packard) at 535 nm (excitation)/590 nm (emission). If the inhibitory effect is high, IC can be determined50The value is obtained.
Data for the compounds of the invention in the above tests are provided in table a 3.

Claims (18)

1. A compound of formula (VI):
including any tautomeric or stereochemically isomeric form thereof, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, cyano C1-4Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, by-Si (CH)3)3Substituted C1-6An alkyl group;
each R1aIndependently selected from hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino-substituted C1-4Alkyl, and C substituted by one or more fluorine atoms1-4An alkyl group;
each R2Independently selected from: hydroxy, halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy-halogeno-C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13is-NR7R8Substituted C1-4Alkyl radical, by-NR7R8Substituted C1-4Alkoxy, -NR7R8and-C (= O) -NR7R8(ii) a Or when two R are2When groups are attached to adjacent carbon atoms, they may be joined together to form radicals of the formula:
-O-(C(R17)2)p-O-；
wherein R is17Represents hydrogen, p represents 1 or 2;
R4and R5Each independently represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted with one or two hydroxyl groupsSubstituted C1-6Alkoxy radical C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl, or by R13Substituted C1-6An alkyl group;
R6represents C3-8Cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C is3-8Cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl are optionally and each independently substituted with 1,2,3, 4 or 5 substituents each independently selected from: c1-6Alkyl, hydroxy C1-6Alkyl, halogen, C1-6Alkoxy radical, C1-6alkyl-O-C (= O) -, -NR14R15，-S(=O)2-C1-6Alkyl, -S (= O)2-NR14R15；
R7And R8Each independently represents hydrogen or C1-6An alkyl group;
R13represents C3-8Cycloalkyl or a saturated 4-to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C3-8The cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1,2 or 3 substituents each independently selected from C1-6Alkyl, -C (= O) -C1-6Alkyl, or-NR14R15；
R14And R15Each independently represents hydrogen, or C optionally substituted by hydroxy1-4An alkyl group; or
A pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R is1Represents: hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= S)O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6Alkyl, or by-Si (CH)3)3Substituted C1-6An alkyl group; wherein each R1aIs hydrogen.
3. A compound according to claim 1 wherein each R is1aIs hydrogen.
4. A compound according to claim 1, wherein R is1Represents C1-6An alkyl group.
5. A compound according to claim 1, wherein R is1Represents CH3-or CD3-。
6. A compound according to claim 1, wherein R is2Independently selected from: halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13is-NR7R8Substituted C1-4Alkyl radical, by-NR7R8Substituted C1-4Alkoxy, -NR7R8and-C (= O) -NR7R8。
7. A compound according to claim 6, wherein R is2Represents C1-4An alkoxy group.
8. A compound according to claim 7, wherein R is2Represents CH3O-or CD3O-。
9. A compound according to claim 1, wherein R is1Represents C1-6Alkyl radical, each R1aIs hydrogen, n is an integer equal to 2, each R2Represents C1-4An alkoxy group.
10. A compound according to claim 1, wherein R is1represents-CH3Each R1aIs hydrogen, n represents an integer equal to 2, each R2Represents CH3O-。
11. A compound according to claim 1, wherein the compound is
。
12. A compound according to claim 1, wherein the compound is
。
13. The compound according to claim 1, wherein said compound is
。
14. The compound according to claim 1, wherein the compound is selected from
And
。
15. a compound of formula (I) including any tautomeric or stereochemically isomeric form thereof
(I)
Or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of liver cancer in which its ligand expression of FGF19 is frequently increased, for the treatment of t (4;14) migratory positive multiple myeloma, for the treatment of bladder cancer with a chromosomal translocation of FGFR3, for the treatment of bladder cancer with a point mutation of FGFR3, for the treatment of tumors with gain-of-function mutants of FGFR2 or FGFR3, for the treatment of glioblastomas, for the treatment of tumors with mutants of FGFR1, FGFR2, FGFR3 or FGFR4, for the treatment of esophageal cancer, for the treatment of head and neck cancer, for the treatment of urothelial cancer, for the treatment of cervical cancer, for the treatment of small cell lung cancer, for the treatment of lung adenocarcinoma, wherein
n represents an integer equal to 0, 1,2,3 or 4;
R1represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, halo C1-6Alkyl, cyano C1-4Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, by-NR4R5Substituted C1-6Alkyl radical, by-C (= O) -NR4R5Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl radical, by-C (= O) -R6Substituted C1-6Alkyl radical, by R6Substituted hydroxy radical C1-6An alkyl group, a carboxyl group,is-Si (CH)3)3Substituted C1-6An alkyl group;
each R1aIndependently selected from hydrogen, C1-4Alkyl, hydroxy C1-4Alkyl, by amino or mono-or di (C)1-4Alkyl) amino-substituted C1-4Alkyl, and C substituted by one or more fluorine atoms1-4An alkyl group;
each R2Independently selected from: hydroxy, halogen, cyano, C1-4Alkyl radical, C2-4Alkenyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, hydroxy C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, hydroxy-halogeno-C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, R13Is by R13Substituted C1-4Alkoxy, -C (= O) -R13is-NR7R8Substituted C1-4Alkyl radical, by-NR7R8Substituted C1-4Alkoxy, -NR7R8and-C (= O) -NR7R8(ii) a Or when two R are2When groups are attached to adjacent carbon atoms, they may be joined together to form radicals of the formula:
-O-(C(R17)2)p-O-；
wherein R is17Represents hydrogen, p represents 1 or 2;
R3represents C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, optionally substituted by-O-C (= O) -C1-6Alkyl-substituted halogeno C1-6Alkyl, hydroxy C1-6Alkyl, hydroxy C2-6Alkynyl, hydroxy-halogeno-C1-6Alkyl, cyano C1-6Alkyl, C substituted by carboxyl1-6Alkyl radical, by-C (= O) -O-C1-6Alkyl substituted C1-6Alkyl radical, each of which is C1-6The alkyl group may optionally be substituted by one or two hydroxy groups or by-O-C (= O) -C1-6Alkyl substituted C1-6Alkoxy radical C1-6Alkyl radical, by R9Substituted C1-6Alkyl radical, by-C (= O) -R9Substituted C1-6Alkyl, by hydroxy and R9Substituted C1-6Alkyl radical, by R9Substituted C2-6Alkenyl radical, by R9Substituted C2-6Alkynyl radicals, by-NR10R11Substituted C1-6Alkyl, by hydroxy and-NR10R11Substituted C1-6Alkyl, by one or two halogens and-NR10R11Substituted C1-6Alkyl radical, -C1-6alkyl-C (R)12)=N-O-R12is-C (= O) -NR10R11Substituted C1-6Alkyl by-O-C (= O) -NR10R11Substituted C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-C1-6Alkyl substituted C1-6Alkyl radical, by-NR12-S(=O)2-NR14R15Substituted C1-6Alkyl radical, R13Or by-P (= O) (OH)2Substituted C1-6An alkyl group;
R4and R5Each independently represents hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl radical, each of which is C1-6C wherein alkyl may be optionally substituted by one or two hydroxy groups1-6Alkoxy radical C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15quilt-S (= O)2-C1-6Alkyl substituted C1-6Alkyl, or by R13Substituted C1-6An alkyl group;
R6represents C3-8Cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S; said C is3-8Cycloalkyl, phenyl, 4 to 7 membered monocyclic heterocyclyl are optionally and each independently substituted with 1,2,3, 4 or 5 substituents each independently selected from: c1-6Alkyl, hydroxy C1-6Alkyl, halogen, C1-6Alkoxy radical, C1-6alkyl-O-C (= O) -, -NR14R15，-S(=O)2-C1-6Alkyl, -S (= O)2-NR14R15；
R7And R8Each independently represents hydrogen or C1-6An alkyl group;
R9represents C3-8Cycloalkyl, phenyl, or a 3 to 12 membered monocyclic or bicyclic heterocyclic group containing at least one heteroatom selected from N, O or S, said C3-8Cycloalkyl, phenyl, or 3 to 12 membered monocyclic or bicyclic heterocyclyl are each optionally and each independently substituted with 1,2,3, 4, or 5 substituents, each substituent independently selected from: = O, C1-4Alkyl, hydroxy, carboxyl, hydroxy C1-4Alkyl, cyano C1-4Alkyl radical, C1-4alkyl-O-C (= O) -, by C1-4alkyl-O-C (= O) -substituted C1-4Alkyl radical, C1-4alkyl-C (= O) -, halogen, halo-C1-4Alkyl, -NR14R15，-C(=O)-NR14R15is-NR14R15Substituted C1-4Alkyl radical, C1-4Alkoxy, -S (= O)2-C1-4Alkyl, -S (= O)2-NR14R15quilt-NH-S (= O)2-halo C1-4Alkyl substituted C1-4Alkyl radical, R13，-C(=O)-R13Phenyl radical C1-6Alkyl, a 5 or 6 membered aromatic monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S;
or when R is9When the two substituents of (a) are attached to the same atom, they may be taken together to form a 4-to 7-membered saturated monocyclic heterocyclic group containing at least one heteroatom selected from N, O or S;
R10and R11Each independently represents hydrogen, C1-6Alkyl, cyano C1-6Alkyl radical, by-NR14R15Substituted C1-6Alkyl radical, by-C (= O) -NR14R15Substituted C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, R6Is by R6Substituted C1-6Alkyl, -C (= O) -R6，-C(=O)-C1-6Alkyl, -C (= O) -halo C1-6Alkyl, -C (= O) -hydroxyhaloC1-6Alkyl radicals, by-Si(CH3)3Substituted C1-6Alkyl, -S (= O)2-C1-6Alkyl, -S (= O)2-NR14R15；
R12Represents hydrogen or optionally substituted by C1-4Alkoxy-substituted C1-4An alkyl group;
R13represents C3-8Cycloalkyl or a saturated 4-to 6-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O or S, wherein said C3-8The cycloalkyl or monocyclic heterocyclyl is optionally substituted with 1,2 or 3 substituents each independently selected from C1-6Alkyl, -C (= O) -C1-6Alkyl, or-NR14R15；
R14And R15Each independently represents hydrogen, or C optionally substituted by hydroxy1-4An alkyl group.
16. Use according to claim 15, for the treatment of liver cancer wherein its expression of the ligand FGF19 is frequently increased.
17. Use according to claim 15 or 16, wherein the compound of formula (I) is N- (3, 5-dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine.
18. Use according to claim 15 or 16, wherein the compound of formula (I) is a pharmaceutically acceptable salt of N- (3, 5-dimethoxyphenyl) -N' - (1-methylethyl) -N- [3- (1-methyl-1H-pyrazol-4-yl) quinoxalin-6-yl ] ethane-1, 2-diamine.
HK15112661.6A 2010-04-30 2015-12-24 Pyrazolyl quinoxaline kinase inhibitors HK1211922B (en)

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US32988410P 2010-04-30 2010-04-30
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US61/329884 2010-04-30
GB201007286A GB201007286D0 (en) 2010-04-30 2010-04-30 New compounds

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HK1211922B true HK1211922B (en) 2018-05-04

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