CN104672214A - Compound with ALK inhibition activity as well as preparation method and use of compound - Google Patents

Compound with ALK inhibition activity as well as preparation method and use of compound Download PDF

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CN104672214A
CN104672214A CN201310641552.6A CN201310641552A CN104672214A CN 104672214 A CN104672214 A CN 104672214A CN 201310641552 A CN201310641552 A CN 201310641552A CN 104672214 A CN104672214 A CN 104672214A
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compound
alkyl
group
cycloalkyl
acceptable salt
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CN104672214B (en
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仝朝龙
孙兴义
盛锡军
张秀春
喻红平
徐耀昌
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Shanghai Hansen Biological Medicine Technology Co Ltd
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Shanghai Hansen Biological Medicine Technology Co Ltd
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Priority to PCT/CN2014/092492 priority patent/WO2015081813A1/en
Priority to CN201480055111.0A priority patent/CN105612151B/en
Priority to TW103141352A priority patent/TW201609699A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention relates to a compound with ALK inhibition activity as well as a preparation method and use of the compound and specifically relates to a compound expressed by a general formula (I) as shown in the specification or a pharmaceutical salt thereof, as well as a preparation method and the use of the compound or the pharmaceutical salt thereof. The compound has the ALK inhibition activity, can be applied to treating ALK positive related cancers and has a wide pharmaceutical prospect.

Description

There is the compound of ALK inhibit activities and preparation thereof and purposes
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to have the compound of ALK inhibit activities and preparation thereof and purposes.
Background technology
Nucleophosmin-anaplastic lymphoma kinase (ALK) is a kind of receptor tyrosine protein kinase; be found in a hypotype of primary cutaneous type (ALCL) the earliest; therefore name as Nucleophosmin-anaplastic lymphoma kinase (anaplastic lymphoma kinase; ALK) (Morris; S.W. etc., Science, 1994; 263,1281-1284; Shiota, M. etc., Oncogene, 1994,9,1567-1574).Alk protein contains 1620 amino acid, and molecular weight is 177 kilodaltons (kDa), and 254 kinase amino acid structural domains are made up of 1123 to 1376 amino acids residues, is a short cross-film district be made up of amino acid before this.Expression-form in Mice Body points out it to work in the growth of maincenter and peripheral nervous system; In fruit bat, find with the form of ligand binding, ALK promotes that intestinal tube muscle tissue is formed, mammalian ligands is not yet determined; Alk protein matter is detected in human retina.The Bearing Mice Life cycle that ALK gene knocks out and vital movement show no obvious abnormalities (Webb, T.R. etc., Expert Rev.Anti-cancer Ther., 2009,9,331-356), imply that ALK suppresses to cause serious injury body.
2007 Nian Liangge independent studies groups identify ALK gene respectively and reset in nonsmall-cell lung cancer.Wherein one group of researchist develops retrovirus cDNA expression library for screening new oncogene.The cDNA library from 62 years old negative Japanese male smoker adenocarcinoma of lung of KRAS and EGFR of screening display in advance sudden change is extracted in their transfection, and design generates transgenic mice, specific expressed EML4-ALK in alveolar cell, generates many adenocarcinoma of lung tubercles thus.These transgenic mices of ALK inhibitor for treating are used to cause tumor load to reduce compared to untreated mouse.Major part mouse is very fast dead in 1 month.Identical ALK inhibitor for treating is used to cause lungs without EML4-ALK/3T3 cellular infiltration and life span extension.This research confirms that EML4-ALK is unique in nonsmall-cell lung cancer driving sudden change effectively, and suppresses EML4-ALK activity that lung cancer load can be caused to reduce (Soda, M., Choi, Y.L., Enomoto, M., etc., Nature, 2007:448) in vivo.EML4-ALK merges and appears in the nonsmall-cell lung cancer of about 3-5%, and specifically the difference to some extent because of the difference of the crowd of research and the ALK detection method of use, is the unique driving mutator gene in nonsmall-cell lung cancer.
Experimental data shows, the lymphoma cell suppressing ALK gene effectively to stop ALK to be positive and the growth of lung carcinoma cell, demonstrate ALK inhibitor in this kind of oncotherapy, have important value (Piva, R. etc., Blood, 2006,107,689-697; Galkin, A.V. etc., Proc.Natl.Acad.Sci.USA, 2007,104,270-275; Koivunen, J.P. etc., Clin.Cancer Res., 2008,14,4275-4238).
Summary of the invention
Contriver is in research process, and find the compound or pharmaceutically acceptable salt thereof of a class as shown in general formula (I), described compound has ALK inhibit activities, can be used for the associated cancer that treatment ALK is positive, has wide medication prospect.
One aspect of the present invention provides one to have the compound or pharmaceutically acceptable salt thereof of general formula (I):
Wherein:
Ring A is selected from 5-10 unit cycloalkyl, 5-10 unit heterocyclic radical, 5-10 unit's aryl or 5-10 unit heteroaryl;
R 1be selected from C 1-6the C of alkyl, halogen substiuted 1-6alkyl, C 3-6cycloalkyl or 4-tolyl;
R 2, R 3, R 4, R 5independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, C separately 1-6the C of alkyl, halogen substiuted 1-6alkyl, C 3-8cycloalkyl, C 1-6the C of alkoxyl group, halogen substiuted 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11;
R 6, R 7, R 8independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, C separately 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11,
Wherein said C 1-8alkyl, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, cyano group, nitro, C by one or more separately further 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced;
R 9, R 10, R 11be selected from hydrogen, C l-4alkyl;
M, n are 0,1,2,3,4;
L is 0,1,2,3,4,5;
P is 0,1 or 2.
Preferably, the structure that ring A and its substituting group are formed jointly is selected from following structure:
Preferred, the structure that ring A and its substituting group are formed jointly is selected from following structure:
Wherein, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p defined such as formula (I) compound.
Preferred further, R 2, R 5independently be selected from hydrogen, halogen, C separately 1-6the C of alkyl, halogen substiuted 1-6alkyl; R 3, R 4independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, C separately 1-6the C of alkyl, halogen substiuted 1-6alkyl, C 3-8cycloalkyl, C 1-6the C of alkoxyl group, halogen substiuted 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11; R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p defined such as formula (I) compound.
Most preferred, described formula (I) compound or pharmaceutically acceptable salt thereof is selected from:
Preferred, described compound or pharmaceutically acceptable salt thereof is selected from formula (II) compound:
Wherein:
R 3be selected from hydrogen, hydroxyl, cyano group, nitro, C 3-8cycloalkyl, C 1-6the C of alkoxyl group, halogen substiuted 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11;
R 2, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p defined such as formula (I) compound.
Preferred further, R 3be selected from the C of halogen substiuted 1-6alkoxyl group; R 2, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p defined such as formula (I) compound.
Most preferred, it is selected from following compound:
The present invention provides one to have the preparation method of the compound of general formula (I) on the other hand; this preparation method comprises the steps: that formula (III) compound and formula (IV) condensation obtain formula (I) compound; or formula (III) compound and formula (IV) condensation; then convert corresponding formula (I) compound to according to substituent different definition or Deprotection, its synthetic route is as follows:
Wherein, ring A, R 1, R 2, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p defined such as formula (I) compound.
Another aspect of the invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains the aforesaid compound or its pharmacologically acceptable salt and pharmaceutically useful carrier or vehicle for the treatment of effective dose.
Another aspect of the invention provides a kind of method of Function protein kinase catalytic activity, and it comprises described protein kinase and aforesaid compound or its pharmacologically acceptable salt, or foregoing pharmaceutical composition contacts, and described protein kinase is selected from Nucleophosmin-anaplastic lymphoma kinase.
Another aspect of the invention provides a kind of aforesaid compound or its pharmacologically acceptable salt, or the application of foregoing pharmaceutical composition in the medicine preparing Therapeutic cancer, the preferred nonsmall-cell lung cancer of wherein said cancer.
Embodiment
Describe in detail: unless stated to the contrary, following use term in the specification and in the claims has following implication.
" C 1-8alkyl " refer to the straight chained alkyl and the containg branched alkyl radical that comprise 1 to 8 carbon atom, alkyl refers to saturated aliphatic hydrocarbon group.Such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group or its various branched chain isomers etc.
Alkyl can be replacement or unsubstituted, and when substituted, substituting group can be substituted on any spendable tie point, is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, " C 3-8cycloalkyl " refer to the cycloalkyl comprising 3 to 8 carbon atoms, " 5-10 unit cycloalkyl " refers to the cycloalkyl comprising 5 to 10 carbon atoms, such as:
The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.
Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring." spiro cycloalkyl group " refers to the polycyclic moiety sharing a carbon atom (title spiro atom) between monocycle, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group by the number according to sharing spiro atom between ring and ring, and the non-limiting example of spiro cycloalkyl group comprises:
" cycloalkyl " refers to that each ring in system and other rings in system share the full carbon polycyclic moiety of a pair carbon atom adjoined, and wherein one or more rings can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl according to the number of makeup ring, the non-limiting example of cycloalkyl comprises:
" bridge ring alkyl " refers to that any two rings share the full carbon polycyclic moiety of two carbon atoms directly do not connected, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Can be divided into dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl according to the number of makeup ring, the non-limiting example of bridge ring alkyl comprises:
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linked together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.
Cycloalkyl can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O) p(wherein p be integer 0,1,2) heteroatoms, but do not comprise the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon." 5-10 unit heterocyclic radical " refers to the cyclic group comprising 5 to 10 annular atomses, and " 3-8 unit heterocyclic radical " refers to the cyclic group comprising 3 to 8 annular atomses.
The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.
Polycyclic naphthene base comprises the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to share the polycyclic heterocyclic group of an atom (title spiro atom) between monocycle, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O) p(wherein p be integer 0,1,2) heteroatoms, all the other annular atomses are carbon.These can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals by the number according to sharing spiro atom between ring and ring.The non-limiting example of spiro cycloalkyl group comprises:
" fused heterocycle base " refers to that each ring in system and other rings in system share the polycyclic heterocyclic group of a pair atom adjoined, one or more ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O) p(wherein p be integer 0 to 2) heteroatoms, all the other annular atomses are carbon.Can be divided into dicyclo, three rings, Fourth Ring or many rings fused heterocycloalkyl according to the number of makeup ring, the non-limiting example of fused heterocycle base comprises:
" bridge heterocyclic radical " refers to that any two rings share the polycyclic heterocyclic group of the atom that two directly do not connect, these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses be selected from nitrogen, oxygen or S (O) p(wherein p be integer 0,1,2) heteroatoms, all the other annular atomses are carbon.Can be divided into dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl according to the number of makeup ring, the non-limiting example of bridge ring alkyl comprises:
Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring wherein linked together with precursor structure is heterocyclic radical, and non-limiting example comprises:
Heterocyclic radical can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" aryl " refers to full carbon monocycle or fused polycycle (namely sharing the right ring of adjacent carbon atoms) group, has many rings (namely it is with the ring of the phase adjacency pair carbon atom) group of the π-electron system of conjugation, " C 5-10aryl " refer to containing 5-10 carbon full carbon aryl, " 5-10 unit aryl " refers to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
Aryl can be replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" heteroaryl " refers to comprise 1 to 4 heteroatomic heteroaromatic system, described heteroatoms comprises the heteroatoms of nitrogen, oxygen and S (O) p (wherein p is integer 0,1,2), 5-7 unit heteroaryl refers to the heteroaromatic system containing 5-7 annular atoms, 5-10 unit heteroaryl refers to the heteroaromatic system containing 5-10 annular atoms, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Heteroaryl can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond, C 2-8alkenyl refers to straight chain containing 2-8 carbon or containing branched-chain alkenyl.Such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.
Thiazolinyl can be replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" alkynyl " refers to the alkyl as defined above of at least two carbon atoms and at least one carbon-to-carbon triple bond composition, C 2-8alkynyl group refers to straight chain containing 2-8 carbon or containing branch alkynyl.Such as ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.
Alkynyl can be replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" alkoxyl group " refers to-O-(alkyl), and wherein the definition of alkyl is described above.C 1-6alkoxyl group refers to the alkyl oxy containing 1-6 carbon, and non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy etc.
Alkoxyl group can be optional replacement or unsubstituted, and when substituted, substituting group, is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced;
" cycloalkyloxy " refers to and-O-(unsubstituted cycloalkyl), and wherein the definition of cycloalkyl is described above.C 3-8cycloalkyloxy refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting example comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
Alkoxyl group can be optional replacement or unsubstituted, and when substituted, substituting group is preferably one or more following group, independent selected from halo, hydroxyl, cyano group, nitro, C 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced.
" the C of halogen substiuted 1-6alkyl " refer to 1-6 the carbon alkyl group replaced by fluorine, chlorine, bromine, atomic iodine that hydrogen on alkyl is optional, such as difluoromethyl, dichloromethyl, two brooethyls, trifluoromethyl, trichloromethyl, trisbromomethyl etc.
" the C of halogen substiuted 1-6alkoxyl group " optional 1-6 the carbon alkoxy base replaced by fluorine, chlorine, bromine, atomic iodine of hydrogen on alkyl.Such as difluoro-methoxy, dichloro methoxyl group, dibromo methoxyl group, trifluoromethoxy, trichloromethoxy, tribromo methoxyl group etc.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH group.
" nitro " refers to-NO 2group.
"-S (O) pR 9" refer to R 9the sulphur, sulfinyl, the sulfonyl that replace.
"-C (O) R 9" refer to R 9the carbonyl replaced.
"-C (O) OR 9" refer to R 9the oxygen base carbonyl replaced.
"-NR 10r 11" refer to R 10, R 11the amino replaced.
"-C (O) NR 11" refer to R 11the amide group replaced.
" optionally " or " optionally " mean subsequently described ground event or environment can but need not occur, this explanation comprises this event or environment occurs or not spot occasion.Such as, " optionally by heterocyclic group that alkyl replaces " mean alkyl can but must not exist, this explanation comprises situation that heterocyclic group replaced by alkyl and heterocyclic group not by situation that alkyl replaces.
" replacement " refers to the one or more hydrogen atoms in group, is preferably maximum 5, is more preferably 1 ~ 3 hydrogen atom and is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group is only in their possible chemical position, those skilled in the art can determine when not paying and too much making great efforts (by experiment or theoretical) may or impossible replacement.Such as, have the amino of free hydrogen or hydroxyl and the carbon atom with unsaturated (as olefinic) key in conjunction with time may be unstable.
" pharmaceutical composition " represent containing on one or more compounds described herein or its physiology/mixture of pharmacologically acceptable salt or prodrug and other chemical compositions, and other components such as physiology/pharmaceutically useful carrier and vehicle.The object of pharmaceutical composition promotes the administration to organism, is beneficial to the absorption of activeconstituents and then plays biological activity.
Below in conjunction with embodiment, the present invention is described in further detail and completely, but limit the present invention by no means, and the present invention is also not only confined to the content of embodiment.
Embodiment 1:5-chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-(2-(sec.-propyl sulphonyl) pyridin-3-yl) pyrimidine-2,4-diamines
The preparation of the first step: 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl esters
By chloro-for compound 1-5-isopropoxy-2-methyl-4-oil of mirbane (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl--1,3,2-bis-Evil boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.7g, 11.97mmol), salt of wormwood (4.5g, 26.78mmol) and Pd (dppf) Cl 2(398mg, 0.55mmol) is dissolved in Isosorbide-5-Nitrae-dioxane.Nitrogen replacement is protected, and is heated to 150 DEG C of reactions.After 5 hours, revolve dereaction solvent, add water and methylene dichloride, separate aqueous layer and organic layer, aqueous phase dichloromethane extraction three times.Merge organic phase, anhydrous sodium sulfate drying.Steaming desolventizes, and column chromatographic isolation and purification obtains product.
LCMS:t=4.85min,347.1(M+H +).
The preparation of second step: 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester
Compound 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl esters (3.4g, 0.26mmol) are dissolved in methyl alcohol, add palladium/carbon (400mg).Hydrogen exchange, stirred overnight at room temperature under atmosphere of hydrogen.Filter, steam except methyl alcohol, obtain compound 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester (3.3g).
LCMS:t=4.16min,349.0(M+H +).
3rd step: the preparation of 2-sec.-propyl sulfydryl-3-nitropyridine
By fluoro-for 2-3-nitropyridine (500mg, 3.52mmol), salt of wormwood (973mg, 7.04mmol) is placed in 100mL round-bottomed bottle, adds 15 milliliters of DMF.Under agitation, add isopropyl mercaptan (0.36mL, 3.87mmol), mixture is at room temperature reacted 1 hour, revolves dereaction solvent after completion of the reaction, gained crude product is through washing, extraction into ethyl acetate, concentrated after dry, then column chromatography obtains product 2-sec.-propyl sulfydryl-3-nitropyridine (660mg, productive rate 95%).
1H NMR(400MHz,CDCl 3)δ8.61(dd,J=4.8，1.6Hz,1H),8.40(dd,J=8.4,1.6Hz,1H),7.10(dd,J=8.4,4.8Hz,1H),4.13-4.06(m,1H),1.35(d,J=6.8Hz,6H).
LCMS：t=4.31min,198.9(M+H +).
4th step: the preparation of 2-sec.-propyl sulfuryl-3-nitropyridine
2-sec.-propyl sulfydryl-3-nitropyridine (660mg, 3.33mmol) and mCPBA (85%, 2.2g, 9.99mmol) are placed in 100mL round-bottomed bottle, add 15 milliliters of DCM.Mixture is at room temperature stirred and spends the night, revolve dereaction solvent after completion of the reaction, gained crude product uses saturated sodium bisulfite solution successively, unsaturated carbonate potassium solution, saturated common salt is washed, dichloromethane extraction, dry, be spin-dried for, then obtain product 2-sec.-propyl sulfuryl-3-nitropyridine (700mg, productive rate 91%) through column chromatography.
1H NMR(400MHz,CDCl 3)δ8.84(dd,J=4.4,1.6Hz,1H),8.06(dd,J=8.4,1.6Hz,1H),7.68(dd,J=8.0,4.4Hz,1H),4.03-3.96(m,1H),1.36(d,J=6.8Hz,6H).
LCMS:t=3.39min,201.0(M+H +).
5th step: the preparation of 2-sec.-propyl sulfuryl-3-aminopyridine
By 2-sec.-propyl sulfuryl-3-nitropyridine (700mg, 2.18mmol) be placed in 100mL hydrogenation bottle, add 15 ml methanol, after nitrogen replacement, 100mg palladium/carbon is joined in bottle, spend the night with stirring after hydrogen balloon displacement, filtered by solution after completion of the reaction, filtrate decompression is spin-dried for and obtains product (600mg, productive rate 90%).
LCMS:t=2.85min,201.0(M+H +).
The preparation of the chloro-N-of the 6th step: 2,5-bis-(2-(isopropelsulfonyl) pyridin-3-yl) pyrimidine-4-amine
2-sec.-propyl sulfuryl-3-aminopyridine (200mg, 1.0mmol) is dissolved in DMF (6mL), at 0 DEG C, slowly adds NaH (44mg, 1.1mmol).After adding, reaction solution continues to stir half an hour at 0 DEG C, then 2,5,6-trichloropyrimidine (201mg, 1.1mmol) is instilled reaction solution at 0 DEG C.Drip and finish, mixture rises to stirred overnight at room temperature naturally.After, add 200mL water, and extract (30mL*3) with EA, dry after merging organic phase, revolve dereaction solvent, gained crude product obtains product (90mg, productive rate 26%) through column chromatography.
1H NMR(400MHz,CDCl 3)δ10.48(s,1H),9.17(dd,J=8.4,1.6Hz,1H),8.38(dd,J=4.4,2.8Hz,1H),8.26(s,1H),7.55(dd,J=8.8,3.2Hz,1H),3.90-3.87(m,1H),1.31(d,J=6.8Hz,6H).
LCMS:t=3.95min,346.9(M+H +).
The preparation of the 7th step: 4-(4-((the chloro-4-of 5-((2-(sec.-propyl sulphonyl) pyridin-3-yl) is amino) pyrimidine-2-base) is amino)-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester
By 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) pyridin-3-yl) pyrimidine-4-amine (90mg, 0.26mmol), 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester (100mg, 0.28mmol), palladium (6mg, 20 μm of ol), Xantphos (17mg, 22 μm of ol), cesium acetate (253mg, 0.78mmol) be placed in 10mL microwave tube, add 5 milliliters of dioxane, after nitrogen replacement, mixture microwave heating to 130 degree is reacted half an hour, revolve dereaction solvent after completion of the reaction, gained crude product obtains product (60mg through column chromatography, productive rate 35%).
LCMS:t=5.47min,658.9(M+H +).
The preparation of chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-(2-(isopropelsulfonyl) pyridin-3-yl) pyrimidine-2, the 4-diamines of the 8th step: 5-
By 4-(4-((the chloro-4-of 5-((2-(isopropelsulfonyl) pyridin-3-yl) is amino) pyrimidine-2-base) is amino)-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester (60mg; 91 μm of ol) be dissolved in 4 milliliters of DCM; at room temperature instill TFA (1mL) and stir half an hour; revolve dereaction solvent after completion of the reaction; gained crude product obtains product (30mg, productive rate 59%) through column chromatography and preparation TLC purifying.
1H NMR(400MHz,CDCl 3):δ10.01(s,1H),9.14(dd,J=8.8,1.2Hz,1H),8.31(dd,J=4.0,2.8Hz,1H),7.90(s,1H),7.43(s,1H),7.40-7.37(m,1H),6.76(s,1H),4.55-4.52(m,1H),3.89-3.85(m,1H),3.53-3.50(m,2H),2.96-2.85(m,3H),2.15(s,3H),2.05-2.02(m,2H),1.89-1.86(m,2H),1.33(d,J=7.2Hz,6H),1.30(d,J=6.4Hz,6H).
LCMS:t=3.69min,558.9(M+H +).
The preparation of embodiment 2:5-difluoro-methoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-sulphonyl)-phenyl]-pyrimidine-2,4-diamines
The preparation of the chloro-N-of the first step: 2-(2-(isopropelsulfonyl) phenyl)-5-methoxy pyrimidine-4-amine
By 2-sec.-propyl sulfuryl aniline (200mg, 0.99mmol) be dissolved in DMF (8mL), NaH (29mg is slowly added at 0 DEG C, 1.2mmol), add rear reaction solution and continue to stir half an hour at 0 DEG C, then by 2,6-dichloro-5-methoxy pyrimidine (197mg, 1.1mmol) at 0 DEG C, instill reaction solution, drip and finish, mixture rises to stirring at room temperature 4 hours naturally.After add 200mL water and with DCM extraction (30mL*3), merge after organic phase dry, revolve dereaction solvent, gained crude product obtains product (90mg, productive rate 26%) through column chromatography.
1H NMR(400MHz,CDCl 3):δ9.50(s,1H),9.87(s,1H),8.68(d,J=8.4,1.2Hz,1H),7.81(dd,J=8.0,1.6Hz,1H),7.76(s,1H),7.64-7.60(m,1H),7.17-7.15(m,1H),3.94(s,3H),3.17-3.10(m,1H),1.22(d,J=6.8Hz,6H).
LCMS:t=4.10min,341.8(M+H +).
The preparation of the chloro-4-of second step: 2-((2-(isopropelsulfonyl) phenyl) is amino) pyrimidine-5-phenol
Chloro-for compound 2-N-(2-(isopropelsulfonyl) phenyl)-5-methoxy pyrimidine-4-amine (50mg, 0.15mmol) is dissolved in anhydrous DCM (10mL), at 0 DEG C, slowly adds BBr 3(0.2mL, 4N in DCM, 0.75mmol), adds rear reaction solution and naturally rises to stirred overnight at room temperature.Methyl alcohol (3mL) cancellation reaction is slowly added after completion of the reaction at 0 DEG C, add 500mL washing again and extract (40mL*3) with DCM, dry after merging organic phase, revolve dereaction solvent, gained crude product obtains product faint yellow solid (30mg, productive rate 52%) through column chromatography.
LCMS:t=3.68min,327.9(M+H +).
The preparation of the 3rd step: 2-chloro-5-(difluoro-methoxy)-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
By chloro-for 2-4-((2-(isopropelsulfonyl) phenyl) is amino) pyrimidine-5-phenol (20mg; 61 μm of ol); difluoro sodium monochloracetate (28mg; 0.18mmol); salt of wormwood (25mg; 0.18mmol) be placed in 10mL microwave tube; add 3 milliliters of DMF and 3 ml waters; by mixture microwave heating to 120 degree reaction 1 hour after nitrogen replacement; revolve dereaction solvent after completion of the reaction; gained crude product obtains product (10mg, productive rate 43%) through column chromatography.
LCMS:t=4.29min,377.8(M+H +).
The preparation of the 4th step: 4-(4-((5-(difluoro-methoxy)-4-((2-(isopropelsulfonyl) phenyl) is amino) pyrimidine-2-base) is amino)-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester
By chloro-for compound 2-5-(difluoro-methoxy)-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (10mg, 26 μm of ol), 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester (14mg, 39 μm of ol), palladium (1mg, 2.08 μm of ol), Xantphos (2mg, 2.6 μm of ol), cesium acetate (25mg, 79 μm of ol) be placed in 10mL microwave tube, add 2 milliliters of dioxane, after nitrogen replacement, mixture microwave heating to 130 degree is reacted half an hour, revolve dereaction solvent after completion of the reaction, gained crude product obtains product (5mg through column chromatography, productive rate 27%).
LCMS:t=5.36min,89.9(M+H +).
5th step: the preparation of 5-difluoro-methoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-24-diamines
By 4-(4-((5-(difluoro-methoxy)-4-((2-(isopropelsulfonyl) phenyl) is amino) pyrimidine-2-base) is amino)-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester (5mg; 7.2 μm of ol) be dissolved in 4 milliliters of DCM; at room temperature instill TFA(1mL) and stir half an hour; revolve dereaction solvent after completion of the reaction; gained crude product obtains product (2.8mg, productive rate 65%) through column chromatography and preparation TLC purifying.
1H NMR(400MHz,CDCl 3):δ9.50(s,1H),8.63(d,J=8.4Hz,1H),8.03(d,J=4.8Hz,2H),7.83(dd,J=8.0,2.8Hz,1H),7.55-7.45(m,2H),7.16-7.15(m,1H),6.92(s,0.2H),6.74(s,1H),6.71(s,0.2H),6.53(s,0.4H),6.35(s,0.2H),4.53-4.50(m,1H),3.48-3.42(m,2H),3.27-3.21(m,1H),2.92-2.78(m,3H),2.13(s,3H),1.99-1.77(m,4H),1.27(d,J=6Hz,6H).
LCMS：t=3.64min，590.0(M+H +).
The preparation of the chloro-2-of embodiment 3:5-[2-isopropoxy-5-methyl-4-(1-methyl-pi-4-base)-phenyl]-4-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamines
By chloro-for compound 5-(2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl)-(2-(isopropelsulfonyl) pyridin-3-yl) pyrimidine-2; 4-diamines (15mg; 26.8 μm of ol) be dissolved in dry anhydrous methanol; at room temperature add paraformaldehyde (4mg; 134 μm of ol); the acetic acid of sodium cyanoborohydride (3.37mg, 53.6 μm of ol) and catalytic amount.Mixture at room temperature stirs and spends the night, by TLC and LCMS detection reaction.1NNaOH aqueous solution cancellation reaction is dripped in reaction solution.Pressure reducing and steaming organic solvent; and residue is dispersed in methylene dichloride; and clean with water and salt solution; organic phase anhydrous magnesium sulfate drying; filtration is spin-dried for obtain thick product; the chloro-2-of target compound 5-[2-isopropoxy-5-methyl-4-(1-methyl-pi-4-base)-phenyl]-4-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamines (5mg, 30%) is separated to obtain through preparation TLC plate.
1H NMR(400MHz,CDCl 3):δ10.60(s,1H),10.06(s,1H),9.20(dd,J=8.7,1.3Hz,1H),8.93(dd,J=8.6,1.3Hz,1H),8.50(t,J=4.3,1.4Hz,2H),8.38(d,J=4.3,1.4Hz,1H),8.21(s,1H),8.19(s,1H),7.96(s,1H),7.58(s,1H),7.53(s,1H),7.48(dd,J=8.7,4.4Hz,1H),7.42(dd,J=8.6,4.4Hz,1H),6.95(s,1H),6.84(s,1H),4.76-4.55(m,2H),4.36(s,1H),4.10-3.87(m,2H),3.68(s,4H),3.12-2.79(m,11H),2.45-2.31(m,5H),2.22(s,3H),2.17(s,3H),2.07-1.99(m,6H),1.46-1.31(m,22H).
LCMS:t=3.60min,612.3(M+K +).
The preparation of embodiment 4:1-[4-(the chloro-4-of 4-{5-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl amino]-pyrimidine-2--amino }-5-isopropoxy-2-methylphenyl)-piperidin-1-yl]-ethyl ketone
The preparation of the first step: 1-[4-(4,4,5,5-tetramethyl--1,3,2-bis-Evil boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-Ji] ethyl ketone
4-(4,4,5,5-tetramethyl--1,3,2-bis-Evil boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl esters (1.0g, 3.2mmol) are dissolved in methylene dichloride, trifluoroacetic acid (4mL) adds rear stirring at room temperature 2 hours, directly steam solvent and obtain colorless oil, be dissolved under ice-water bath in methylene dichloride, add triethylamine (2mL, 14.3mmol), slow dropping Acetyl Chloride 98Min. (1.0mL, 8mmol), is freely raised to room temperature and continues stirring 2 hours.Add the water of 30mL and the methylene dichloride of 30mL toward system, divide phase of anhydrating, steam solvent and obtain orange/yellow solid (700mg, 86%).
Second step: 1-{4-[2-methyl-4-nitro-5-(propane-2-oxygen base) phenyl] piperidin-1-yl } preparation of-ethyl ketone
Under nitrogen protection; 1-[4-(4; 4,5,5-tetramethyl--1; 3; 2-bis-Evil boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-Ji] ethyl ketone (601.4mg, 2.3mmol) is dissolved in the dioxane/water (3:1) of 10mL; add 1-chloro-5-isopropoxy-2-methyl-4-oil of mirbane (500.0mg, 2.3mmol), Pd (dppf) Cl successively 2(80mg, 0.11mmol) with salt of wormwood (902mg, 6.5mmol), reaction system microwave under 150 degree stirs 1 hour, steam solvent, direct column chromatography obtains 1-{4-[2-methyl-4-nitro-5-(propane-2-oxygen base) phenyl] piperidin-1-yl }-ethyl ketone (600mg, 77%).
3rd step: 1-{4-[4-amino-2-methyl-5-(propane-2-oxygen base) phenyl] piperidin-1-yl } preparation of-ethyl ketone
By 1-{4-[2-methyl-4-nitro-5-(propane-2-oxygen base) phenyl] piperidin-1-yl }-ethyl ketone (600mg) is dissolved in the methyl alcohol of 10mL; palladium/carbon catalyst is added under nitrogen protection; stirred overnight at room temperature; solids removed by filtration; the direct evaporate to dryness of filtrate obtains colourless liquid (530mg, 95%).
The preparation of the 4th step: 1-[4-(the chloro-4-of 4-{5-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl amino]-pyrimidine-2--amino }-5-isopropoxy-2-methylphenyl)-piperidin-1-yl]-ethyl ketone
By chloro-for compound 2-5-(difluoro-methoxy)-N-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (60mg, 0.173mmol) be dissolved in dry DMF (2mL), N is added under room temperature, N-dimethylisopropylamine (89.59mg, 693 μm of ol), TBTU (58mg, 181.9 μm ol), and room temperature for overnight, thin up reaction solution, be extracted with ethyl acetate, merge organic phase and wash 3 ~ 4 times with salt, use anhydrous sodium sulfate drying organic phase, filter, be spin-dried for, the residue obtained is dissolved in dry dioxane (5mL), and add 1-{4-[4-amino-2-methyl-5-(propane-2-oxygen base) phenyl] piperidin-1-yl wherein }-ethyl ketone (62.5mg, 215 μm of ol), tosic acid (46.3mg, 269 μm of ol), be heated to 150 DEG C of reactions to spend the night, use LCMS detection reaction.By reaction solution diluted ethyl acetate; wash with saturated sodium bicarbonate aqueous solution; and wash with salt; by organic phase anhydrous sodium sulfate drying; filter; steam solvent and obtain thick product, obtain 1-[4-(the chloro-4-of 4-{5-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl amino]-pyrimidine-2--amino }-5-isopropoxy-2-methylphenyl)-piperidin-1-yl]-ethyl ketone (23mg, 21.3%) through column chromatography for separation.
1H NMR(400MHz,CDCl 3):δ10.11(s,1H),9.22(dd,J=8.7,1.2Hz,1H),8.39(dd,J=4.3,1.3Hz,1H),8.18(s,1H),7.92(s,1H),7.57(s,1H),7.45(dd,J=8.7,4.4Hz,1H),6.71(s,1H),4.83(d,J=13.3Hz,1H),4.58-4.53(m,1H),3.98-3.93(m2H),3.23-3.20(m,1H),2.93-2.92(m1H),2.68-2.62(m,1H),2.24(s,3H),2.16(s,3H),1.87-1.80(m,2H),1.63-1.56(m,2H),1.41-1.36(m,12H).
LCMS:t=4.43min,601.2(M +).
The chloro-2-{2-isopropoxy of embodiment 5:5--5-methyl-4-[1-(2-morpholine-4-base-ethyl)-piperidin-4-yl]-phenyl } preparation of-4-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamines
1-[4-(the chloro-4-of 4-{5-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl amino]-pyrimidine-2--amino }-5-isopropoxy-2-methylphenyl)-piperidin-1-yl]-ethyl ketone (20mg) is dissolved in 2mL ethanol; and add the 1mL6N NaOH aqueous solution wherein; be heated to 80 DEG C of stirrings spend the night; reaction solution is cooled to room temperature; solvent evaporated, obtains thick product.This thick product is dissolved in the DMF of 2mL drying, and adds sodium carbonate (8mg, 75 μm of ol) and 2-(4-morpholine) monobromoethane hydrobromate (14.58mg, 75 μm of ol) wherein, be heated to 60 DEG C of stirrings and spend the night.Thin up reaction solution; be extracted with ethyl acetate; merge organic phase and wash 3 ~ 4 times with salt; use anhydrous sodium sulfate drying organic phase; filter, steam solvent and obtain thick product, be separated to obtain the chloro-2-{2-isopropoxy of target compound 5--5-methyl-4-[1-(2-morpholine-4-base-ethyl)-piperidin-4-yl]-phenyl through preparation TLC-4-[2-(propane-2-alkylsulfonyl)-pyridin-3-yl]-pyrimidine-2; 4-diamines (12mg, 71%).
1H NMR(400MHz,CDCl 3):δ10.07(s,1H),9.22(d,J=8.6Hz,1H),8.38(dd,J=4.3,1.2Hz,1H),8.18(d,J=3.5Hz,1H),7.86(s,1H),7.57(s,1H),7.45(dd,J=8.6,4.3Hz,1H),6.96(s,1H),4.77-4.58(m,1H),4.15(t,J=11.6Hz,2H),3.93-3.89(m,3H),3.85-3.66(m,1H),3.58(d,J=6.6Hz,2H),3.37(d,J=11.4Hz,2H),2.86(d,J=3.1Hz,5H),2.68-2.34(m,6H),2.20(s,3H),1.88(br,2H),1.49-1.29(m,12H).
LCMS:t=3.79min,672.2(M +).
The preparation of the chloro-2-of embodiment 6:5-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-4-[2-(propane-2-alkylsulfonyl)-thiene-3-yl-]-pyrimidine-2,4-diamines
The first step: the preparation of 3-nitro-2-(propane-2-base sulfanyl) thiophene
The chloro-3-nitrothiophene (500mg, 3.05mmol) of 2-and isopropyl mercaptan (697mg, 9.16mmol) are blended in N, in dinethylformamide, add potash solid (843mg, 9.16mmol), then at room temperature stir 2 hours.Add water and the extraction of ethyl acetate separatory, merge organic phase and use anhydrous sodium sulfate drying, filter, filtrate evaporate to dryness obtains yellow solid, is directly used in next step reaction.
Second step: the preparation of 3-nitro-2-(propane-2-base alkylsulfonyl) thiophene
3-nitro-2-(propane-2-base sulfanyl) thiophene is dissolved in methylene dichloride, adds m-chloro-benzoic acid peroxide (3.1g, 15.2mmol) in batches, adds stirred overnight at room temperature.Add the saturated sodium sulfite aqueous solution of 30mL, be adjusted to about pH=9 with sodium carbonate, with dichloromethane extraction, organic phase dried over sodium sulfate, filter, filtrate is spin-dried for obtain white solid (1.0g, 80%).
The preparation of the 3rd step: 2-(propane-2-base alkylsulfonyl) thiophene-3-amine
3-nitro-2-(propane-2-base alkylsulfonyl) thiophene (200mg, 0.85mmol) is dissolved in the methyl alcohol of 5mL, adds the palladium/carbon (10%) of 20mg, normal pressure hydrogenation 2 hours.TLC (PE:EA=3:1) shows raw material and disappears, and crosses and filters palladium/carbon, be spin-dried for methyl alcohol and obtain colorless oil (202mg, 100%).
The preparation of the chloro-N-of the 4th step: 2,5-bis-[2-(propane-2-base alkylsulfonyl) thiene-3-yl-] pyrimidine-4-amine
By 2-(propane-2-base alkylsulfonyl) thiophene-3-amine (870mg; 4.2mmol) be dissolved in 40mL trifluoroethanol; add 2 successively; 4; 5-trichloropyrimidine (3.0g; 12.6mmol) with saturated hydrochloric acid dioxane solution (4.3mL), then stir under 45 degree and spend the night.Reaction solution is directly spin-dried for column chromatography and obtains light yellow solid (220mg, 14%).
LC-MS:t R=4.40min,[M+H] +=351.9.
The preparation of the 5th step: 1-(4-{4-[(the chloro-4-{ of 5-[2-(propane-2-base alkylsulfonyl) thiene-3-yl-] amino } pyrimidine-2-base) is amino]-2-methyl-5-(propane-2-oxygen base) phenyl } piperidin-1-yl) ethyl ketone
By 2; the chloro-N-of 5-bis-[2-(propane-2-base alkylsulfonyl) thiene-3-yl-] pyrimidine-4-amine (200mg; 0.62mmol) be dissolved in N; in dinethylformamide; add DIPEA (0.44mL successively; 2.48mmol) with O-benzotriazole-N; N, N', N'-tetramethyl-urea Tetrafluoroboric acid (200mg; 0.62mmol); then in stirred overnight at room temperature, TLC (PE:EA=3:1) shows raw material 6 and disappears, and adds the water of 20mL and the ethyl acetate of 20mL in system; divide phase of anhydrating, be directly spin-dried for for next step after organic phase dried over sodium sulfate.
LC-MS:t R=4.34min,[M+H] +=451.0.
The preparation of the chloro-N-2-of the 6th step: 5-[5-methyl-4-(piperidines-4-ethanoyl)-2-(propane-2-oxygen base) phenyl]-N-4-[2-(propane-2-base alkylsulfonyl) thiene-3-yl-] pyrimidine-2,4-diamines
White solid (the 130mg that previous step is obtained by reacting, 0.28mmol) with 1-{4-[4-amino-2-methyl-5-(propane-2-oxygen base) phenyl] piperidin-1-yl }-ethyl ketone (110mg, 0.42mmol) be dissolved in the dioxane of 2mL, add single hydrate (90mg of p-methyl benzenesulfonic acid, 0.42mmol), system is heated to 150 degree of stirrings to spend the night.Directly be spin-dried for solvent column chromatography and obtain yellow solid (50mg, 28%).
LC-MS:t R=4.64min,[M+H] +=606.1。
The preparation of the chloro-N-2-of the 7th step: 5-[5-methyl-4-(piperidin-4-yl)-2-(propane-2-oxygen base) phenyl]-N-4-[2-(propane-2-base alkylsulfonyl) thiene-3-yl-] pyrimidine-2,4-diamines
By 1-(4-{4-[(the chloro-4-{ of 5-[2-(propane-2-base alkylsulfonyl) thiene-3-yl-] amino } pyrimidine-2-base) is amino]-2-methyl-5-(propane-2-oxygen base) phenyl } piperidin-1-yl) ethyl ketone (10mg; 0.016mmol) be dissolved in the ethanol of 0.1mL; add 30% aqueous sodium hydroxide solution; then stir 3 hours under 100 degree; LC-MS detects without raw material; revolve desolventizing; add the water of 5mL and the ethyl acetate of 10mL; after organic phase drying, column chromatography must change white solid (1.7mg, 17%).
1H NMR(400MHz,CDCl 3):δ9.44(s,1H),8.33(d,J=5.4Hz,1H),8.15(s,1H),8.05(s,1H),7.65(d,J=5.4Hz,1H),7.53(s,1H),6.83(s,1H),4.62(dt,J=11.8,6.0Hz,1H),3.69(d,J=11.8Hz,2H),3.34(dt,J=13.7,6.8Hz,1H),3.06(t,J=12.0Hz,2H),2.96(t,J=11.8Hz,1H),2.28(s,3H),2.08-1.93(m,8H),1.48-1.31(m,25H).
LC-MS:t R=3.90min,[M+H] +=564.1.
biological assessment
Experimental example 1:ALK gene fusion cell inhibitory effect is tested
In vitro tests below can be used to measure the human lymphoma cell Karpas299 of high expression level of proliferation inhibition activity the compounds of this invention merges to(for) ALK gene.
The cell assay in vitro of the following stated can measure the proliferation inhibition activity to human lymphoma cell Karpas299 of test-compound, its active available IC 50value represents.The general approach of this type of test is as follows: first select human lymphoma cell Karpas299, with suitable cell concn (such as, 100 μ L substratum in 6000 cells/well) be seeded on 96 well culture plates, the test-compound solution of a series of gradient concentrations (general 6 to 10 concentration) with substratum dilution is added, cultured continuously 72 hours subsequently to each hole.After 72 hours, available luminescent Cell Viability Assay kit(is purchased from Promega).Method measures the activity of compound antiproliferative effect.IC 50value is by under measuring a series of different concns, and the suppression numerical value of test-compound on cell proliferation calculates.
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded 50value sees the following form.
Conclusion: embodiment of the present invention compound all has obvious proliferation inhibition activity to Karpas299 cell.
Experimental example 2:ALK kinase inhibition is tested
In vitro tests below can be used to measure the compounds of this invention for ALK kinases and the ALKL1196M kinase inhibiting activity producing variation, its active available IC 50value represents.The half-inhibition concentration IC of compound 50(compound concentration by required during certain density inhibition of enzyme activity to 50%) is by being gone out by measure and calculation after the testing compound hybrid reaction of a certain amount of kinases and specific substrate and different concns.This tests ALK kinases behaviour source recombinant protein used, and this enzyme is containing 50mM HEPES(pH7.5), 10mMMgCl 22M DTT(1000x) buffered soln and 30 μMs of ATP reaction system in jointly carry out reacting (25 DEG C with the test-compound of peptide substrate and different concns, 45min), FAM traget antibody marks substrate subsequently, carries out quantitative assay finally by the Mobility shift technology based on microfluidic chip technology to ALK kinase activity.
The biochemical activity of the compounds of this invention is measured by above test, the IC recorded 50value sees the following form.
Conclusion: embodiment of the present invention compound all has obvious restraining effect to ALK and ALKL1196M kinase activity.

Claims (12)

1. one kind has the compound or pharmaceutically acceptable salt thereof of general formula (I):
Wherein:
Ring A is selected from 5-10 unit cycloalkyl, 5-10 unit heterocyclic radical, 5-10 unit's aryl or 5-10 unit heteroaryl;
R 1be selected from C 1-6the C of alkyl, halogen substiuted 1-6alkyl, C 3-6cycloalkyl or 4-tolyl;
R 2, R 3, R 4, R 5independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, C separately 1-6the C of alkyl, halogen substiuted 1-6alkyl, C 3-8cycloalkyl, C 1-6the C of alkoxyl group, halogen substiuted 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11;
R 6, R 7, R 8independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, C separately 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11,
Wherein said C 1-8alkyl, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl or 5-10 unit heteroaryl are independently optionally selected from halogen, hydroxyl, cyano group, nitro, C by one or more separately further 1-8alkyl, C 2-8alkenyl, C 2-8alkynyl group, C 3-8cycloalkyl, 3-8 unit heterocyclic radical, C 5-10aryl, 5-10 unit heteroaryl, C 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11substituting group replaced;
R 9, R 10, R 11be selected from hydrogen, C l-4alkyl;
M, n are 0,1,2,3,4;
L is 0,1,2,3,4,5;
P is 0,1 or 2.
2. compound or pharmaceutically acceptable salt thereof according to claim 1, is characterized in that: the structure that ring A and its substituting group are formed jointly is selected from following structure:
3. compound or pharmaceutically acceptable salt thereof according to claim 1, is characterized in that: the structure that ring A and its substituting group are formed jointly is selected from following structure:
Wherein, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p as claim 1 define.
4. compound or pharmaceutically acceptable salt thereof according to claim 1, is characterized in that:
R 2, R 5independently be selected from hydrogen, halogen, C separately 1-6the C of alkyl, halogen substiuted 1-6alkyl;
R 3, R 4independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, C separately 1-6the C of alkyl, halogen substiuted 1-6alkyl, C 3-8cycloalkyl, C 1-6the C of alkoxyl group, halogen substiuted 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11;
R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p as claim 1 define.
5. the compound or pharmaceutically acceptable salt thereof according to any one of claim 1-4, wherein this compound is selected from:
6. compound or pharmaceutically acceptable salt thereof according to claim 1, is characterized in that: it is selected from formula (II) compound:
Wherein:
R 3be selected from hydrogen, hydroxyl, cyano group, nitro, C 3-8cycloalkyl, C 1-6the C of alkoxyl group, halogen substiuted 1-6alkoxyl group, C 3-8cycloalkyloxy ,-S (O) pR 9,-C (O) R 9,-C (O) OR 9,-NR 10r 11or-C (O) NR 11;
R 2, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p as claim 1 define.
7. compound or pharmaceutically acceptable salt thereof according to claim 6, is characterized in that:
R 3be selected from the C of halogen substiuted 1-6alkoxyl group;
R 2, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p as claim 1 define.
8. compound or pharmaceutically acceptable salt thereof according to claim 7, is characterized in that: it is selected from following compound:
9. a preparation method with the compound of general formula (I) according to claim 1; this preparation method comprises the steps: that formula (III) compound and formula (IV) condensation obtain formula (I) compound; or formula (III) compound and formula (IV) condensation; then convert corresponding formula (I) compound to according to substituent different definition or Deprotection, its synthetic route is as follows:
Wherein, ring A, R 1, R 2, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, m, n, L, p as claim 1 define.
10. a pharmaceutical composition, described pharmaceutical composition contains the compound or pharmaceutically acceptable salt thereof according to any one of claim 1-8 and pharmaceutically useful carrier or vehicle for the treatment of effective dose.
The method of 11. 1 kinds of Function protein kinase catalytic activity, it comprises described protein kinase and the compound or pharmaceutically acceptable salt thereof according to any one of claim 1-8, or pharmaceutical composition according to claim 10 contacts, described protein kinase is selected from Nucleophosmin-anaplastic lymphoma kinase.
12. compound or pharmaceutically acceptable salt thereofs according to any one of claim 1-8, or the application of pharmaceutical composition according to claim 10 in the medicine preparing Therapeutic cancer, the preferred nonsmall-cell lung cancer of wherein said cancer.
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