CN104672214B - Compound and its preparation and purposes with ALK inhibitory activity - Google Patents
Compound and its preparation and purposes with ALK inhibitory activity Download PDFInfo
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- CN104672214B CN104672214B CN201310641552.6A CN201310641552A CN104672214B CN 104672214 B CN104672214 B CN 104672214B CN 201310641552 A CN201310641552 A CN 201310641552A CN 104672214 B CN104672214 B CN 104672214B
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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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- C07D401/02—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
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- 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
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- 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 present invention relates to compounds and its preparation and purposes with ALK inhibitory activity.Specifically, the present invention relates to a kind of such as logical formula (I) compound represented or its officinal salt, Its Preparation Method And Use.The compound has ALK inhibitory activity, can be used for treating the associated cancer that ALK is positive, and has wide medication prospect.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to ALK inhibitory activity compound and its preparation with
Purposes.
Background technique
Anaplastic lymphoma kinase (ALK) is a kind of receptor tyrosine protein kinase, is drenched in Anaplastic large cell earliest
It is found, therefore is named as anaplastic lymphoma kinase (anaplastic lymphoma in one hypotype of bar tumor (ALCL)
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), 254 amino
Kinase domain is made of 1123 to 1376 amino acids residues, is the short cross-film being made of amino acid before this
Area.It is prompted to work in the development of maincenter and peripheral neverous system in the intracorporal expression-form of mouse；It is found in drosophila
ALK promotes intestinal tube musculature to be formed in the form of ligand binding, and mammalian ligands not yet determine；It is detected in human retina
To alk protein matter.ALK gene knock out the Bearing Mice Life period and vital movement show no obvious abnormalities (Webb, T.R. etc.,
Expert Rev.Anti-cancer Ther., 2009,9,331-356), imply that ALK inhibition will not cause body sternly
The injury of weight.
2007 Nian Liangge independent studies groups identify ALK gene rearrangement respectively in non-small cell lung cancer.Wherein one group
Researcher develops retrovirus cDNA expression library for screening new oncogene.They, which have transfected, extracts from a sieve in advance
The cDNA library of 62 years old negative Japanese male smoker's adenocarcinoma of lung of choosing display KRAS and EGFR mutation, and design to generate and turn base
Because of mouse, the specific expressed EML4-ALK in alveolar cell has thus generated many adenocarcinoma of lung tubercles.Use ALK inhibitor
Treating these transgenic mices causes tumor load to reduce compared to untreated mouse.Most of mouse is quickly in 1 month
It is dead.Cause lungs without EML4-ALK/3T3 cellular infiltration and life span extension using identical ALK inhibitor for treating.This research has
Power confirms that EML4-ALK is uniquely driving mutation in non-small cell lung cancer, and inhibits EML4-ALK activity that can lead in vivo
Lung cancer load is caused to reduce (Soda, M., Choi, Y.L., Enomoto, M., etc. Nature, 2007:448).EML4-ALK fusion
In the non-small cell lung cancer for appearing in about 3-5%, specifically have due to the difference of the crowd of research and the ALK detection method used
Institute's difference is unique driving mutated gene in non-small cell lung cancer.
Experimental data shows to inhibit the ALK gene lymphoma cell that can effectively prevent ALK from being positive and lung carcinoma cell
Growth, show 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.
Deng Clin.Cancer Res., 2008,14,4275-4238).
Summary of the invention
In the course of the research, discovery is a kind of such as logical formula (I) compound represented or its officinal salt, the chemical combination by inventor
Object has ALK inhibitory activity, can be used for treating the associated cancer that ALK is positive, and has wide medication prospect.
One aspect of the present invention provides a kind of compound or pharmaceutically acceptable salt thereof with logical formula (I):
Wherein:
Ring A is selected from 5-10 member naphthenic base, 5-10 circle heterocyclic ring base, 5-10 member aryl or 5-10 unit's heteroaryl；
R1Selected from C1-6The C that alkyl, halogen replace1-6Alkyl, C3-6Naphthenic base or 4- tolyl；
R2、R3、R4、R5It is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-6The C that alkyl, halogen replace1-6
Alkyl, C3-8Naphthenic base, C1-6The C that alkoxy, halogen replace1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C
(O)OR9、-NR10R11Or-C (O) NR11；
R6、R7、R8It is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkyne
Base, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O)
pR9、-C(O)R9、-C(O)OR9、-NR10R11Or-C (O) NR11,
The wherein C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl or 5-10 unit's heteroaryl are respectively only
It is vertical that halogen, hydroxyl, cyano, nitro, C are further optionally selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group,
C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C
(O)R9、-C(O)OR9、-NR10R11Or-C (O) NR11Substituent group replaced；
R9、R10、R11Selected from hydrogen, Cl-4Alkyl；
M, n is 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 substituent group are collectively formed is selected from such as flowering structure:
It is furthermore preferred that the structure that ring A and its substituent group are collectively formed is selected from such as flowering structure:
Wherein, R2、R3、R4、R5、R6、R7、R8、R9、R10、R11, m, n, L, p such as formula (I) compound defined.
It is further preferred that R2、R5It is independently selected from hydrogen, halogen, C1-6The C that alkyl, halogen replace1-6Alkyl；R3、
R4It is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-6The C that alkyl, halogen replace1-6Alkyl, C3-8Naphthenic base,
C1-6The C that alkoxy, halogen replace1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)OR9、-NR10R11Or-
C(O)NR11；R6、R7、R8、R9、R10、R11, m, n, L, p such as formula (I) compound defined.
Most preferably, formula (I) compound or pharmaceutically acceptable salt thereof is selected from:
It is furthermore preferred that the compound or pharmaceutically acceptable salt thereof is selected from formula (II) compound:
Wherein:
R3Selected from hydrogen, hydroxyl, cyano, nitro, C3-8Naphthenic base, C1-6The C that alkoxy, halogen replace1-6Alkoxy, C3-8Ring
Alkoxy ,-S (O) pR9、-C(O)R9、-C(O)OR9、-NR10R11Or-C (O) NR11；
R2、R4、R5、R6、R7、R8、R9、R10、R11, m, n, L, p such as formula (I) compound defined.
It is further preferred that R3The C replaced selected from halogen1-6Alkoxy；R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、
L, p such as formula (I) compound is defined.
Most preferably, it is selected from following compound:
Another aspect of the present invention provides a kind of preparation method of compound with logical formula (I), which includes such as
Lower step: formula (III) compound and formula (IV) are condensed to yield formula (I) compound or formula (III) compound and formula (IV) contracting
It closes, corresponding formula (I) compound is then converted into according to the different definition of substituent group or Deprotection, synthetic route is as follows:
Wherein, ring A, R1、R2、R4、R5、R6、R7、R8、R9、R10、R11, m, n, L, p such as formula (I) compound defined.
Another aspect of the invention provides a kind of pharmaceutical composition, and described pharmaceutical composition contains the aforementioned for the treatment of effective dose
Compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier or excipient.
Another aspect of the invention provides a kind of method of regulatory protein kinase catalytic activity comprising by the protein kinase
It is in contact with aforesaid compound or its officinal salt or foregoing pharmaceutical composition, the protein kinase is selected from anaplastic lymphoma
Kinases.
Another aspect of the invention provides a kind of aforesaid compound or its officinal salt or foregoing pharmaceutical composition is controlled in preparation
The application in the drug of cancer is treated, wherein the preferred non-small cell lung cancer of the cancer.
Specific embodiment
It is described in detail: unless stated to the contrary, following that there is following contain with term in the specification and in the claims
Justice.
“C1-8Alkyl " refers to that straight chained alkyl and containg branched alkyl radical including 1 to 8 carbon atom, alkyl refer to the aliphatic hydrocarbon of saturation
Group.Such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- diformazan
Base 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, 1,1,2- thmethylpropyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 2,2- dimethyl butyrate
Base, 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, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethylpentyl, 3- ethylpentyl, n-octyl, 2,3- dimethyl oneself
Base, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethylhexanyl, 3,3- dimethylhexanyl, 4,4- dimethyl oneself
Base, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- ethylpentyl, 2- methyl -3- ethylpentyl or it is each
Kind branched isomer etc..
Alkyl can be substituted or unsubstituted, and when substituted, substituent group can be in any workable tie point
It is upper to be substituted, preferably one or more following groups, independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Chain
Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkanes
Oxygroup ,-S (O) pR9、-C(O)R9、-C(O)OR9、-NR10R11Or-C (O) NR11Substituent group replaced.
" naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, " C3-8Naphthenic base " refer to including 3 to
The naphthenic base of 8 carbon atoms, " 5-10 member naphthenic base " refer to the naphthenic base including 5 to 10 carbon atoms, such as:
The non-limiting embodiment of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, ring
Hexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..
Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring." spiro cycloalkyl group ", which refers to, shares a carbon between monocycle
The polycyclic moiety of atom (claiming spiro-atom), these can be containing one or more double bonds, but none ring has total conjugated
Pi-electron system.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, double spiro cycloalkyl groups according to the number for sharing spiro-atom between ring and ring
Base or more spiro cycloalkyl groups, the non-limiting embodiment of spiro cycloalkyl group includes:
" cycloalkyl " refers to the full carbon of each ring in system and shared a pair of of the carbon atom adjoined of other rings in system
Polycyclic moiety, wherein one or more rings can be containing one or more double bonds, but none ring has the π electricity of total conjugated
Subsystem.Bicyclic, tricyclic, Fourth Ring or polycyclic fused ring alkyl can be divided into according to a group cyclic number, cycloalkyl it is unrestricted
Property embodiment includes:
" bridge ring alkyl " refers to that any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, these can
To contain one or more double bonds, but none ring has the pi-electron system of total conjugated.It can be with according to group cyclic number
It is divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl, the non-limiting embodiment of bridge ring alkyl includes:
The cycloalkyl ring can be condensed on aryl, heteroaryl or heterocycloalkyl ring, wherein being connected to precursor structure
Ring together is naphthenic base, and non-limiting embodiment includes indanyl, tetralyl, benzocyclohepta alkyl etc..
Naphthenic base can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-
8 circle heterocyclic ring bases, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)
OR9、-NR10R11Or-C (O) NR11Substituent group replaced.
" heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, wherein one or more annular atoms
Selected from nitrogen, oxygen or S (O) p(, wherein p is integer 0,1,2) hetero atom, but do not include the ring portion of-O-O- ,-O-S- or-S-S-
Point, remaining annular atom is carbon." 5-10 circle heterocyclic ring base " refers to the ring group comprising 5 to 10 annular atoms, and " 3-8 circle heterocyclic ring base ", which refers to, includes
The ring group of 3 to 8 annular atoms.
The non-limiting embodiment of monocyclic cycloalkyl includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholine
Base, high piperazine base etc..
Polycyclic naphthene base includes the heterocycle of loop coil, condensed ring and bridged ring." spiro heterocyclic radical ", which refers to, shares an original between monocycle
The polycyclic heterocyclic group of son (claim spiro-atom), wherein one or more annular atoms be selected from nitrogen, oxygen or S (O) p(wherein p be integer 0,
1,2) hetero atom, remaining annular atom are carbon.These can be containing one or more double bonds, but none ring is with completely total
The pi-electron system of yoke.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, double spiroheterocyclics according to the number for sharing spiro-atom between ring and ring
Base or more spiro heterocyclic radicals.The non-limiting embodiment of spiro cycloalkyl group includes:
" condensed hetero ring base " refers to that each ring and other rings in system in system share the polycyclic miscellaneous of a pair of of the atom adjoined
Cyclic group, one or more rings can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated
System, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O) p(, and wherein p is integer 0 to 2) hetero atom, remaining annular atom is
Carbon.Bicyclic, tricyclic, Fourth Ring or polycyclic fused heterocycloalkyl can be divided into according to a group cyclic number, condensed hetero ring base it is non-limiting
Embodiment includes:
" bridge heterocycle " refers to that any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, these can be with
Containing one or more double bonds, but none ring has the pi-electron system of total conjugated, the choosing of wherein one or more annular atoms
From nitrogen, oxygen or S (O) p(, wherein p is integer 0,1,2) hetero atom, remaining annular atom be carbon.It can be with according to group cyclic number
It is divided into bicyclic, tricyclic, Fourth Ring or polycyclic bridge ring alkyl, the non-limiting embodiment of bridge ring alkyl includes:
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein being connected to one with precursor structure
The ring risen is heterocycle, and non-limiting embodiment includes:
Heterocycle can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-
8 circle heterocyclic ring bases, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)
OR9、-NR10R11Or-C (O) NR11Substituent group replaced.
" aryl " refers to full carbon monocycle or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, has conjugation
Polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of pi-electron system, " C5-10Aryl " refers to the full carbon containing 5-10 carbon
Aryl, " 5-10 member aryl " refer to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthalene.The aryl rings can condense in
On heteroaryl, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limiting embodiment with the ring that precursor structure links together
Include:
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups,
Independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring
Base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)OR9、-
NR10R11Or-C (O) NR11Substituent group replaced.
" heteroaryl " refers to comprising 1 to 4 heteroatomic heteroaromatic system, and the hetero atom includes nitrogen, oxygen and S (O) p (its
Middle p is integer 0,1,2) hetero atom, and 5-7 unit's heteroaryl refers to the heteroaromatic system containing 5-7 annular atom, 5-10 unit's heteroaryl
Refer to the heteroaromatic system containing 5-10 annular atom, such as furyl, thienyl, pyridyl group, pyrrole radicals, N- alkyl pyrrole radicals,
Pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical etc..The heteroaryl ring can be condensed on aryl, heterocycle or cycloalkyl ring,
The ring wherein to link together with precursor structure is heteroaryl ring, and non-limiting embodiment includes:
Heteroaryl can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-
8 circle heterocyclic ring bases, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)
OR9、-NR10R11Or-C (O) NR11Substituent group replaced.
" alkenyl " refers to the alkyl as defined above being made of at least two carbon atoms and at least one carbon-to-carbon double bond, C2-8
Alkenyl refers to the straight chain containing 2-8 carbon or containing branched-chain alkenyl.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3-
Cyclobutenyl etc..
Alkenyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups,
Independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring
Base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)OR9、-
NR10R11Or-C (O) NR11Substituent group replaced.
" alkynyl " refers to the alkyl as defined above of at least two carbon atoms and at least one carbon-carbon triple bond composition, C2-8Chain
Alkynyl refers to the straight chain containing 2-8 carbon or containing branch alkynyl.Such as acetenyl, 1- propinyl, 2-propynyl, 1-, 2- or 3- fourth
Alkynyl etc..
Alkynyl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups,
Independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring
Base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)OR9、-
NR10R11Or-C (O) NR11Substituent group replaced.
" alkoxy " refers to-O- (alkyl), and wherein alkyl is as defined above.C1-6Alkoxy refers to the alkyl containing 1-6 carbon
Oxygroup, non-limiting embodiment include methoxyl group, ethyoxyl, propoxyl group, butoxy etc..
Alkoxy can be it is optionally substituted or unsubstituted, when substituted, substituent group, it is preferably one or more with
Lower group, independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-
8 circle heterocyclic ring bases, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)
OR9、-NR10R11Or-C (O) NR11Substituent group replaced;
" cycloalkyloxy " refers to and-O- (unsubstituted naphthenic base), and wherein naphthenic base is as defined above.C3-8Cycloalkanes oxygen
Base refers to the cycloalkyl oxy containing 3-8 carbon, and non-limiting embodiment includes cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, hexamethylene oxygen
Base etc..
Alkoxy can be it is optionally substituted or unsubstituted, when substituted, substituent group be preferably it is one or more with
Lower group, independently selected from halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-
8 circle heterocyclic ring bases, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)
OR9、-NR10R11Or-C (O) NR11Substituent group replaced.
" the C that halogen replaces1-6Alkyl " refers to the optional 1-6 carbon alkane replaced by fluorine, chlorine, bromine, iodine atom of the hydrogen on alkyl
Base group, such as difluoromethyl, dichloromethyl, two bromomethyls, trifluoromethyl, trichloromethyl, trisbromomethyl etc..
" the C that halogen replaces1-6The 1-6 carbon alkane replaced by fluorine, chlorine, bromine, iodine atom of hydrogen optionally on alkoxy " alkyl
Oxygroup group.Such as difluoro-methoxy, dichloro methoxyl group, dibromo methoxyl group, trifluoromethoxy, trichloromethoxy, tribromo methoxy
Base etc..
" halogen " refers to fluorine, chlorine, bromine or iodine.
" hydroxyl " refers to-OH group.
" nitro " refers to-NO2Group.
“-S(O)pR9" refer to R9Substituted sulphur, sulfinyl, sulfonyl.
“-C(O)R9" refer to R9Substituted carbonyl.
“-C(O)OR9" refer to R9Substituted Epoxide carbonyl.
“-NR10R11" refer to R10、R11Substituted amino.
“-C(O)NR11" refer to R11Substituted amide groups.
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes
The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group "
But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom
Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this
Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take
Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key
Fixed.
" pharmaceutical composition " indicates to contain one or more compounds described herein or its physiologically/officinal salt or preceding
The mixture and other components such as physiology/pharmaceutical carrier and excipient of body drug and other chemical constituents.Drug
The purpose of composition is the administration promoted to organism, plays bioactivity in turn conducive to the absorption of active constituent.
Below with reference to embodiment, the present invention is described in further detail and completely, but the limitation present invention by no means, the present invention
Also it is not intended to be limited to the content of embodiment.
Chloro- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-(2- (isopropyl sulphonyl) pyrrole of embodiment 1:5-
Pyridine -3- base) pyrimidine -2,4- diamines
Step 1: 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester
Preparation
By the chloro- 5- isopropoxy -2- methyl -4- nitrobenzene (2.5g, 10.89mmol) of compound 1-, 4- (4,4,5,5- tetra-
Methyl-1,3,2- bis- dislike penta ring -2- base of boron) -3,6- dihydropyridine -1 (2H)-carboxylic acid tert-butyl ester (3.7g, 11.97mmol), carbon
Sour potassium (4.5g, 26.78mmol) and Pd (dppf) Cl2(398mg, 0.55mmol) is dissolved in 1,4- dioxane.Nitrogen displacement
Protection is heated to 150 DEG C of reactions.After 5 hours, dereaction solvent is revolved, adds water and methylene chloride, separates water layer and organic layer, water
It is mutually extracted with dichloromethane three times.Merge organic phase, anhydrous sodium sulfate is dry.Solvent is evaporated off, column chromatographic isolation and purification is produced
Product.
LCMS:t=4.85min,347.1(M+H+).
Step 2: the preparation of 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl ester
By compound 4- (5- isopropoxy -2- methyl -4- nitrobenzophenone) -3,6- dihydropyridine -1 (the 2H)-tertiary fourth of carboxylic acid
Ester (3.4g, 0.26mmol) is dissolved in methanol, is added palladium/carbon (400mg).Hydrogen is replaced, and is stirred overnight at room temperature under atmosphere of hydrogen.
Filtering, is evaporated off methanol, obtains 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+).
Step 3: the preparation of 2- isopropyl sulfydryl -3- nitropyridine
By the fluoro- 3- nitropyridine (500mg, 3.52mmol) of 2-, potassium carbonate (973mg, 7.04mmol) is placed in 100mL round bottom
In bottle, 15 milliliters of DMF are added.Under stiring, isopropyl mercaptan (0.36mL, 3.87mmol) is added, mixture is anti-at room temperature
It answers 1 hour, end of reaction back spin dereaction solvent, through washing, ethyl acetate extraction is concentrated, then column layer gained crude product after dry
Analyse to obtain product 2- isopropyl sulfydryl -3- nitropyridine (660mg, yield 95%).
1H NMR(400MHz,CDCl3) δ 8.61 (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+).
Step 4: the preparation of 2- isopropyl sulfuryl -3- nitropyridine
2- isopropyl sulfydryl -3- nitropyridine (660mg, 3.33mmol) and mCPBA (85%, 2.2g, 9.99mmol) are set
In 100mL round-bottomed bottle, 15 milliliters of DCM are added.Mixture is stirred at room temperature overnight, end of reaction back spin dereaction is molten
Agent, gained crude product successively use saturated sodium bisulfite solution, and unsaturated carbonate potassium solution, saturated common salt washing, methylene chloride extracts, dry
It is dry, it is spin-dried for, then chromatograph to obtain product 2- isopropyl sulfuryl -3- nitropyridine (700mg, yield 91%) through column.
1H NMR(400MHz,CDCl3)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+).
Step 5: the preparation of 2- isopropyl sulfuryl -3- aminopyridine
2- isopropyl sulfuryl -3- nitropyridine (700mg, 2.18mmol) is placed in 100mL hydrogenation bottle, is added 15 milliliters
100mg palladium/carbon is added in bottle after nitrogen displacement, is stirred overnight after being replaced with hydrogen balloon, after completion of the reaction by solution by methanol
Filtering, filtrate decompression are spin-dried for up to product (600mg, yield 90%).
LCMS:t=2.85min,201.0(M+H+).
Step 6: the preparation of the chloro- N- of 2,5- bis- (2- (isopropelsulfonyl) pyridin-3-yl) pyrimidine -4- amine
2- isopropyl sulfuryl -3- aminopyridine (200mg, 1.0mmol) is dissolved in DMF (6mL), is slowly added at 0 DEG C
Enter NaH (44mg, 1.1mmol).After adding, reaction solution continuation is stirred half an hour at 0 DEG C, then by 2,5,6- trichloropyrimidines
(201mg, 1.1mmol) instills reaction solution at 0 DEG C.Drop finishes, and mixture is warmed to room temperature naturally and is stirred overnight.After, it is added
200mL water, and (30mL*3) is extracted with EA, merge drying after organic phase, revolve dereaction solvent, gained crude product is chromatographed to obtain through column and be produced
Object (90mg, yield 26%).
1H NMR(400MHz,CDCl3)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+).
Step 7: 4- (4- ((the chloro- 4- of 5- ((2- (isopropyl sulphonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino)-
5- isopropoxy -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl ester preparation
By the chloro- N- of 2,5- 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), and palladium acetate (6mg, 20
μm ol), Xantphos (17mg, 22 μm of ol), cesium acetate (253mg, 0.78mmol) is placed in 10mL microwave tube, is added 5 milliliters
Dioxane, by mixture microwave heating to 130 degree of reaction half an hour after nitrogen displacement, end of reaction back spin dereaction solvent,
Gained crude product chromatographs to obtain product (60mg, yield 35%) through column.
LCMS:t=5.47min,658.9(M+H+).
Step 8: chloro- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-(2- (isopropelsulfonyl) pyrrole of 5-
Pyridine -3- base) pyrimidine -2,4- diamines preparation
By 4-, (4- ((the chloro- 4- of 5- ((2- (isopropelsulfonyl) pyridin-3-yl) amino) pyrimidine -2-base) amino) -5- is different
Propoxyl group -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl ester (60mg, 91 μm of ol) is dissolved in 4 milliliters of DCM, instills at room temperature
TFA (1mL) is simultaneously stirred half an hour, end of reaction back spin dereaction solvent, and gained crude product chromatographs and prepares TLC through column and purifies to produce
Object (30mg, yield 59%)
1H NMR(400MHz,CDCl3):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+).
Embodiment 2:5- difluoro-methoxy-(2- isopropoxy -5- methyl -4- piperidin-4-yl-phenyl)-[2- (propane -2-
Sulphonyl)-phenyl]-pyrimidine -2,4- diamines preparation
Step 1: the preparation of the chloro- N- of 2- (2- (isopropelsulfonyl) phenyl) -5- methoxy pyrimidine -4- amine
2- isopropyl sulfuryl aniline (200mg, 0.99mmol) is dissolved in DMF (8mL), is slowly added into NaH at 0 DEG C
(29mg, 1.2mmol) adds the continuation of rear reaction solution and stirs half an hour at 0 DEG C, then by 2,6- dichloro-5-methoxy pyrimidine
(197mg, 1.1mmol) instills reaction solution at 0 DEG C, and drop finishes, and mixture is warmed to room temperature stirring 4 hours naturally.After be added
200mL water simultaneously extracts (30mL*3) with DCM, merges drying after organic phase, revolves dereaction solvent, and gained crude product is chromatographed to obtain through column and be produced
Object (90mg, yield 26%).
1H NMR(400MHz,CDCl3):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+).
Step 2: the preparation of the chloro- 4- of 2- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -5- phenol
By the chloro- N- of compound 2- (2- (isopropelsulfonyl) phenyl) -5- methoxy pyrimidine -4- amine (50mg,
It 0.15mmol) is dissolved in anhydrous DCM (10mL), is slowly added into BBr at 0 DEG C3(0.2mL, 4N in DCM, 0.75mmol), adds
Reaction solution is warmed to room temperature naturally after complete is stirred overnight.Methanol (3mL) quenching reaction is slowly added at 0 DEG C after completion of the reaction, then
500mL washing is added and extracts (40mL*3) with DCM, merges drying after organic phase, revolves dereaction solvent, gained crude product is through column layer
Analyse to obtain product faint yellow solid (30mg, yield 52%).
LCMS:t=3.68min,327.9(M+H+).
Step 3: the preparation of 2- chloro- 5- (difluoro-methoxy)-N- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine
By the chloro- 4- of 2- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -5- phenol (20mg, 61 μm of ol), one chlorine of difluoro
Sodium acetate (28mg, 0.18mmol), potassium carbonate (25mg, 0.18mmol) are placed in 10mL microwave tube, and the milli of 3 milliliters of DMF and 3 is added
Rise water, after nitrogen displacement by mixture microwave heating to 120 degree reaction 1 hour, end of reaction back spin dereaction solvent, gained is thick
Product chromatograph to obtain product (10mg, yield 43%) through column.
LCMS:t=4.29min,377.8(M+H+).
Step 4: 4- (4- ((5- (difluoro-methoxy) -4- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base)
Amino) -5- isopropoxy -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl ester preparation
By compound 2- chloro- 5- (difluoro-methoxy)-N- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine (10mg, 26
μm ol), 4- (4- amino -5- isopropoxy -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl ester (14mg, 39 μm of ol), palladium acetate
(1mg, 2.08 μm of ol), Xantphos (2mg, 2.6 μm of ol), cesium acetate (25mg, 79 μm of ol) are placed in 10mL microwave tube, are added
2 milliliters of dioxane, by mixture microwave heating to 130 degree of reaction half an hour, end of reaction back spin dereaction after nitrogen displacement
Solvent, gained crude product chromatograph to obtain product (5mg, yield 27%) through column.
LCMS:t=5.36min,89.9(M+H+).
Step 5: 5- difluoro-methoxy-(2- isopropoxy -5- methyl -4- piperidin-4-yl-phenyl)-[2- (propane -2-
Sulfonyl)-phenyl]-pyrimidine -24- diamines preparation
By 4- (4- ((5- (difluoro-methoxy) -4- ((2- (isopropelsulfonyl) phenyl) amino) pyrimidine -2-base) ammonia
Base) -5- isopropoxy -2- aminomethyl phenyl) piperidines -1- carboxylic acid tert-butyl ester (5mg, 7.2 μm of ol) is dissolved in 4 milliliters of DCM, in room temperature
Lower instillation TFA(1mL) and stir half an hour, end of reaction back spin dereaction solvent, gained crude product is chromatographed through column and preparation TLC is pure
Change to obtain product (2.8mg, yield 65%).
1H NMR(400MHz,CDCl3):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 chloro- 2- of embodiment 3:5- [2- isopropoxy -5- methyl -4- (1- methyl-pi -4- base)-phenyl] -4- [2- (third
Alkane -2- sulfonyl)-pyridin-3-yl]-pyrimidine -2,4- diamines preparation
By chloro- (2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl)-(2- (isopropelsulfonyl) of compound 5-
Pyridin-3-yl) pyrimidine -2,4- diamines (15mg, 26.8 μm of ol) is dissolved in dry anhydrous methanol, poly is added at room temperature
Formaldehyde (4mg, 134 μm of ol), the acetic acid of sodium cyanoborohydride (3.37mg, 53.6 μm of ol) and catalytic amount.Mixture is at room temperature
It is stirred overnight, with TLC and LCMS detection reaction.1NNaOH aqueous solution quenching reaction is added dropwise into reaction solution.Decompression boils off organic
Solvent, and in methylene chloride by residue dispersion, and cleaned with water and saline solution, organic phase is dry with anhydrous magnesium sulfate, mistake
Filter is spin-dried for obtaining crude product, is prepared TLC plate and separates to obtain the chloro- 2- of target compound 5- [2- isopropoxy -5- methyl -4- (1- first
Base-piperidin-4-yl)-phenyl] -4- [2- (propane -2- sulfonyl)-pyridin-3-yl]-pyrimidine -2,4- diamines (5mg, 30%).
1H NMR(400MHz,CDCl3):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+).
Embodiment 4:1- [4- (4- { the chloro- 4- of 5- [2- (propane -2- sulfonyl)-pyridin-3-yl amino]-pyrimidine -2-base ammonia
Base } -5- isopropoxy -2- methylphenyl)-piperidin-1-yl] and-ethyl ketone preparation
Step 1: 1- [4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -3,6- dihydropyridine -1
(2H)-yl] ethyl ketone preparation
4- (4,4,5,5- tetramethyl -1,3,2- two dislikes penta ring -2- base of boron) -3,6- dihydropyridine -1 (the 2H)-tertiary fourth of carboxylic acid
Ester (1.0g, 3.2mmol) is dissolved in methylene chloride, and trifluoroacetic acid (4mL) is stirred at room temperature 2 hours after being added, and directly steams solvent
Colorless oil is obtained, is dissolved in methylene chloride under ice-water bath, is added triethylamine (2mL, 14.3mmol), chloroacetic chloride is slowly added dropwise
(1.0mL, 8mmol) is freely raised to room temperature and continues stirring 2 hours.The water of 30mL and the methylene chloride of 30mL are added toward system,
Divide and go water phase, steams solvent and obtain orange/yellow solid (700mg, 86%).
Step 2: the preparation of 1- { 4- [2- methyl -4- nitro -5- (propane -2- oxygroup) phenyl] piperidin-1-yl }-ethyl ketone
Under nitrogen protection, 1- [4- (4,4,5,5- tetramethyls -1,3,2- bis- dislike penta ring -2- base of boron) -3,6- dihydro pyrrole
Pyridine -1 (2H)-yl] ethyl ketone (601.4mg, 2.3mmol) is dissolved in dioxane/water (3:1) of 10mL, sequentially add the chloro- 5- of 1-
Isopropoxy -2- methyl -4- nitrobenzene (500.0mg, 2.3mmol), Pd (dppf) Cl2(80mg, 0.11mmol) and potassium carbonate
(902mg, 6.5mmol), reaction system microwave under 150 degree stir 1 hour, steam solvent, direct column chromatographs to obtain 1- { 4- [2-
Methyl -4- nitro -5- (propane -2- oxygroup) phenyl] piperidin-1-yl }-ethyl ketone (600mg, 77%).
Step 3: the preparation of 1- { 4- [4- amino-2-methyl -5- (propane -2- oxygroup) phenyl] piperidin-1-yl }-ethyl ketone
1- { 4- [2- methyl -4- nitro -5- (propane -2- oxygroup) phenyl] piperidin-1-yl }-ethyl ketone (600mg) is dissolved in
In the methanol of 10mL, palladium/carbon catalyst is added under nitrogen protection, is stirred overnight at room temperature, be filtered to remove solid, filtrate is directly evaporated
It obtains colourless liquid (530mg, 95%).
Step 4: 1- [4- (4- { the chloro- 4- of 5- [2- (propane -2- sulfonyl)-pyridin-3-yl amino]-pyrimidine -2-base ammonia
Base } -5- isopropoxy -2- methylphenyl)-piperidin-1-yl] and-ethyl ketone preparation
By compound 2- chloro- 5- (difluoro-methoxy)-N- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine (60mg,
It 0.173mmol) is dissolved in dry DMF (2mL), is added N at room temperature, N- dimethylisopropylamine (89.59mg, 693 μm of ol),
TBTU (58mg, 181.9 μm of ol), and be stirred overnight at room temperature, it is diluted with water reaction solution, is extracted with ethyl acetate, is merged organic
Xiang Bingyong salt is washed 3~4 times, and with the dry organic phase of anhydrous sodium sulfate, filtering is spin-dried for, obtained residue is dissolved in dry
Dry dioxane (5mL), and 1- { 4- [4- amino-2-methyl -5- (propane -2- oxygroup) phenyl] piperidines -1- is added thereto
Base }-ethyl ketone (62.5mg, 215 μm of ol), p-methyl benzenesulfonic acid (46.3mg, 269 μm of ol), be heated to 150 DEG C reaction overnight, use
LCMS detection reaction.Reaction solution is diluted with ethyl acetate, is washed with saturated sodium bicarbonate aqueous solution, and washed with salt, will be had
Machine is mutually dried, filtered with anhydrous sodium sulfate, is steamed solvent and is obtained crude product, obtains 1- [4- (4- { the chloro- 4- of 5- through column chromatography for separation
[2- (propane-2- sulfonyl)-pyridin-3-yl amino]-pyrimidine -2 --amino }-5- isopropoxy-2- methylphenyl)-piperazine
Pyridine -1- base]-ethyl ketone (23mg, 21.3%).
1H NMR(400MHz,CDCl3):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- of embodiment 5:5- { 2- isopropoxy -5- methyl -4- [1- (2- morpholine -4- base-ethyl)-piperidin-4-yl] -
Phenyl } -4- [2- (propane -2- sulfonyl)-pyridin-3-yl]-pyrimidine -2,4- diamines preparation
By 1- [4- (4- { the chloro- 4- of 5- [2- (propane-2- sulfonyl)-pyridin-3-yl amino]-pyrimidine -2 --amino }-5-
Isopropoxy -2- methylphenyl)-piperidin-1-yl]-ethyl ketone (20mg) is dissolved in 2mL ethyl alcohol, and 1mL6N is added thereto
NaOH aqueous solution is heated to 80 DEG C and is stirred overnight, and reaction solution is cooled to room temperature, and solvent evaporated obtains crude product.By the crude product
It is dissolved in the dry DMF of 2mL, and sodium carbonate (8mg, 75 μm of ol) and 2- (4- morpholine) bromic ether hydrobromate is added thereto
(14.58mg, 75 μm of ol), are heated to 60 DEG C and are stirred overnight.It is diluted with water reaction solution, is extracted with ethyl acetate, organic phase is merged
And washed 3~4 times with salt, with the dry organic phase of anhydrous sodium sulfate, filtering steams solvent and obtains crude product, through preparation TLC separation
Obtain the chloro- 2- of target compound 5- { 2- isopropoxy -5- methyl -4- [1- (2- morpholine -4- base-ethyl)-piperidin-4-yl]-benzene
Base } -4- [2- (propane -2- sulfonyl)-pyridin-3-yl]-pyrimidine -2,4- diamines (12mg, 71%).
1H NMR(400MHz,CDCl3):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 chloro- 2- of embodiment 6:5- (2- isopropoxy -5- methyl -4- piperidin-4-yl-phenyl) -4- [2- (propane -2- sulphonyl
Base)-thiene-3-yl]-pyrimidine -2,4- diamines preparation
Step 1: 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, N- bis-
In methylformamide, it is added potash solid (843mg, 9.16mmol), is then stirred at room temperature 2 hours.Add water and acetic acid
Ethyl ester liquid separation extraction merges organic phase and is dried, filtered with anhydrous sodium sulfate, and filtrate is evaporated to obtain yellow solid, is directly used in
It reacts in next step.
Step 2: the preparation of 3- nitro -2- (propane -2- base sulfonyl) thiophene
3- nitro -2- (propane -2- base sulfanyl) thiophene is dissolved in methylene chloride, and m-chloro-benzoic acid peroxide is added portionwise
(3.1g, 15.2mmol), adds and is stirred overnight at room temperature.The saturated aqueous sodium sulfite of 30mL is added, is adjusted to sodium carbonate
PH=9 or so are extracted with methylene chloride, and organic phase sodium sulphate dries, filters, and filtrate is spin-dried for obtaining white solid (1.0g, 80%).
Step 3: the preparation of 2- (propane -2- base sulfonyl) thiophene -3- amine
3- nitro -2- (propane -2- base sulfonyl) thiophene (200mg, 0.85mmol) is dissolved in the methanol of 5mL, is added
Palladium/carbon (10%) of 20mg, normal pressure hydrogenation 2 hours.TLC (PE:EA=3:1) shows that raw material disappears, and is filtered to remove palladium/carbon, is spin-dried for
Methanol obtains colorless oil (202mg, 100%).
Step 4: the preparation of the chloro- N- of 2,5- bis- [2- (propane -2- base sulfonyl) thiene-3-yl] pyrimidine -4- amine
2- (propane -2- base sulfonyl) thiophene -3- amine (870mg, 4.2mmol) is dissolved in 40mL trifluoroethanol, successively
2,4,5- trichloropyrimidine (3.0g, 12.6mmol) and saturation hydrochloric acid dioxane solution (4.3mL) is added, is then stirred under 45 degree
It mixes overnight.Reaction solution directly revolves dry chromatography and obtains light yellow solid (220mg, 14%).
LC-MS:tR=4.40min,[M+H]+=351.9.
Step 5: 1- (4- { 4- [(the chloro- 4- of 5- { [2- (propane -2- base sulfonyl) thiene-3-yl] amino } pyrimidine -2-
Base) amino] -2- methyl -5- (propane -2- oxygroup) phenyl piperidin-1-yl) ethyl ketone preparation
By the chloro- N- of 2,5- bis- [2- (propane -2- base sulfonyl) thiene-3-yl] pyrimidine -4- amine (200mg, 0.62mmol)
It is dissolved in n,N-Dimethylformamide, sequentially adds DIPEA (0.44mL, 2.48mmol) and O- benzotriazole-N, N, N',
N'- tetramethylurea tetrafluoro boric acid (200mg, 0.62mmol), is then stirred at room temperature overnight, and TLC (PE:EA=3:1) shows raw material
6 disappear, and the water of 20mL and the ethyl acetate of 20mL are added into system, divide and go water phase, directly revolve after organic phase sodium sulphate is dry
It does in next step.
LC-MS:tR=4.34min,[M+H]+=451.0.
Step 6: the chloro- N-2- of 5- [5- methyl -4- (piperidines -4- acetyl group) -2- (propane -2- oxygroup) phenyl]-N-4-
The preparation of [2- (propane -2- base sulfonyl) thiene-3-yl] pyrimidine -2,4- diamines
White solid (130mg, 0.28mmol) and the 1- { 4- [4- amino-2-methyl -5- (third that previous step is reacted
Alkane -2- oxygroup) phenyl] piperidin-1-yl }-ethyl ketone (110mg, 0.42mmol) is dissolved in the dioxane of 2mL, it is added to methyl
The single carbohydrate (90mg, 0.42mmol) of benzene sulfonic acid, is heated to 150 degree for system and is stirred overnight.Directly it is spin-dried for solvent column layer
Analysis obtains yellow solid (50mg, 28%).
LC-MS:tR=4.64min,[M+H]+=606.1。
Step 7: the chloro- N-2- of 5- [5- methyl -4- (piperidin-4-yl) -2- (propane -2- oxygroup) phenyl]-N-4- [2- (third
Alkane -2- base sulfonyl) thiene-3-yl] pyrimidine -2,4- diamines preparation
By 1- (4- { 4- [(the chloro- 4- of 5- { [2- (propane -2- base sulfonyl) thiene-3-yl] amino } pyrimidine -2-base) ammonia
Base] -2- methyl -5- (propane -2- oxygroup) phenyl } piperidin-1-yl) ethyl ketone (10mg, 0.016mmol) is dissolved in the ethyl alcohol of 0.1mL
In, 30% sodium hydrate aqueous solution is added, is then stirred 3 hours under 100 degree, LC-MS detection is removed solvent, added without raw material, rotation
The water of 5mL and the ethyl acetate of 10mL, the dry rear pillar of organic phase chromatograph to change white solid (1.7mg, 17%).
1H NMR(400MHz,CDCl3):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:tR=3.90min,[M+H]+=564.1.
Biological assessment
The test of experimental example 1:ALK Gene Fusion cell inhibitory effect
Following in vitro test can be used to measure the compounds of this invention, and to merge highly expressed human lymphoma for ALK gene thin
The proliferation inhibition activity of born of the same parents Karpas299.
Cell assay in vitro as described below can measure the proliferation to human lymphoma cell Karpas299 of test-compound
Inhibitory activity, activity can use IC50Value indicates.The general approach of such test is as follows: selection human lymphoma cell first
Karpas299 is seeded in 96 well culture plates with suitable cell concentration (for example, 100 μ L culture mediums in 6000 cells/wells)
On, it is molten then to a series of test-compound of the diluted gradient concentrations (general 6 to 10 concentration) of each hole addition culture medium
Liquid continuously cultivates 72 hours.After 72 hours, it can useLuminescent Cell Viability
Assay kit(is purchased from Promega).Method measures the activity that compound inhibits cell Proliferation.IC50Value can be a series of by measuring
Under various concentration, the inhibition numerical value of test-compound cell proliferation is calculated.
The biochemical activity of the compounds of this invention is measured by test above, the IC measured50Value see the table below.
Conclusion: compound of the embodiment of the present invention has apparent proliferation inhibition activity to Karpas299 cell.
The test of experimental example 2:ALK kinase inhibition
Following in vitro test can be used to measure the compounds of this invention for ALK kinases and generate the ALKL1196M to make a variation
Kinase inhibiting activity, activity can use IC50Value indicates.The half-inhibitory concentration IC of compound50(by certain density enzyme activity
Property compound concentration required when inhibiting to 50%) be by by a certain amount of kinases and specific substrate and various concentration to
Tester calculates after survey compound hybrid reaction.This experiment ALK kinases used is source of people recombinant protein, which is containing
50mM HEPES(pH7.5), 10mMMgCl2, 2M DTT(1000x) buffer solution and 30 μM of ATP reaction system in it is more
The test-compound of peptide substrates and various concentration is reacted (25 DEG C, 45min) jointly, and subsequent FAM labelled antibody is to substrate
It is marked, ALK kinase activity is quantified finally by the Mobility shift technology based on microfluidic chip technology
Measurement.
The biochemical activity of the compounds of this invention is measured by test above, the IC measured50Value see the table below.
Conclusion: compound of the embodiment of the present invention has apparent inhibiting effect to ALK and ALKL1196M kinase activity.
Claims (9)
1. a kind of logical formula (I) compound or its pharmaceutical salt:
Wherein:
Ring A and R1The structure that substituent group is collectively formed is selected from such as flowering structure,
R2、R3、R4、R5It is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-6The C that alkyl, halogen replace1-6Alkyl,
C3-8Naphthenic base, C1-6The C that alkoxy, halogen replace1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)
OR9、-NR10R11Or-C (O) NR11；
R6、R7、R8It is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group,
C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C
(O)R9、-C(O)OR9、-NR10R11Or-C (O) NR11,
The wherein C1-8Alkyl, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl or 5-10 unit's heteroaryl are respectively individually optional
Halogen, hydroxyl, cyano, nitro, C are further selected from by one or more1-8Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Cycloalkanes
Base, 3-8 circle heterocyclic ring base, C5-10Aryl, 5-10 unit's heteroaryl, C1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C
(O)OR9、-NR10R11Or-C (O) NR11Substituent group replaced；R9、R10、R11Selected from hydrogen, Cl-4Alkyl；
M, n is 0,1,2,3,4；
L is 0,1,2,3,4,5；
P is 0,1 or 2.
2. compound according to claim 1 or its pharmaceutical salt, it is characterised in that:
R2、R5It is independently selected from hydrogen, halogen, C1-6The C that alkyl, halogen replace1-6Alkyl；
R3、R4It is independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-6The C that alkyl, halogen replace1-6Alkyl, C3-8Ring
Alkyl, C1-6The C that alkoxy, halogen replace1-6Alkoxy, C3-8Cycloalkyloxy ,-S (O) pR9、-C(O)R9、-C(O)OR9、-
NR10R11Or-C (O) NR11；
R6、R7、R8、R9、R10、R11, m, n, L, p it is as defined in claim 1.
3. according to claim 1 or the 2 any compounds or its pharmaceutical salt, wherein the compound is selected from:
4. a kind of logical formula (II) compound or its pharmaceutical salt:
Wherein:
R3The C replaced selected from halogen1-6Alkoxy；
R2、R4、R5、R6、R7、R8, m, n, L it is as defined in claim 1.
5. compound according to claim 4 or its pharmaceutical salt, it is characterised in that: be selected from following compound:
6. a kind of preparation method of compound shown in logical formula (I) described in claim 1, the preparation method include the following steps:
Formula (III) compound and formula (IV) are condensed to yield formula (I) compound or formula (III) compound and formula (IV) is condensed, then basis
The different definition or Deprotection of substituent group are converted into corresponding formula (I) compound, and synthetic route is as follows:
Wherein, ring A, R1、R2、R4、R5、R6、R7、R8, m, n, L it is as defined in claim 1.
7. a kind of pharmaceutical composition, described pharmaceutical composition contains the -5 any described according to claim 1 for the treatment of effective dose
Compound or its pharmaceutical salt and pharmaceutical carrier or excipient.
8.-the 5 any compound or its pharmaceutical salt or pharmaceutical composition as claimed in claim 7 according to claim 1
Application of the object in preparation regulatory protein kinase catalytic activity drug, wherein the protein kinase swashs selected from anaplastic lymphoma
Enzyme.
9. any compound or its pharmaceutical salt of claim 1-5 or pharmaceutical composition as claimed in claim 7 exist
The application in the drug for the treatment of cancer is prepared, wherein the cancer is non-small cell lung cancer.
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| TW103141352A TW201609699A (en) | 2013-12-03 | 2014-11-28 | Compounds with ALK inhibitory activities, process for preparing and their use thereof |
| PCT/CN2014/092492 WO2015081813A1 (en) | 2013-12-03 | 2014-11-28 | Compound with alk inhibitory activity and preparation and use thereof |
| CN201480055111.0A CN105612151B (en) | 2013-12-03 | 2014-11-28 | Compound and its preparation and purposes with ALK inhibitory activity |
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| JP7219511B2 (en) | 2018-12-26 | 2023-02-08 | 上海▲テツ▼▲ギョウ▼生物科技有限公司 | 2,4-diaminopyrimidine derivative and its application |
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| EP3150592B1 (en) * | 2014-05-30 | 2023-08-30 | Shanghai Emerald Wellcares Pharmaceutical Co., LTD | Alk kinase inhibitor, and preparation method and use thereof |
| CN105461616A (en) * | 2015-02-27 | 2016-04-06 | 上海麦步医药科技有限公司 | New synthesis technology of ceritinib intermediate |
| BR112017017887A2 (en) * | 2015-03-04 | 2018-04-10 | Novartis Ag | chemical process for preparing pyrimidine derivatives and intermediates |
| CN106146387A (en) * | 2015-03-30 | 2016-11-23 | 湖北生物医药产业技术研究院有限公司 | The preparation method of ALK inhibitor |
| GB201514021D0 (en) | 2015-08-07 | 2015-09-23 | Arner Elias Set Jeno | Novel Pyridines and their use in the treatment of cancer |
| CN106699743B (en) | 2015-11-05 | 2020-06-12 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| EP3504203B1 (en) * | 2016-08-29 | 2022-09-28 | The Regents of The University of Michigan | Aminopyrimidines as alk inhibitors |
| MX2019009356A (en) | 2017-02-07 | 2019-09-19 | Oblique Therapeutics Ab | Sulfinylpyridines and their use in the treatment of cancer. |
| KR20190115012A (en) | 2017-02-07 | 2019-10-10 | 오블리크 세러퓨틱스 에이비 | Heterocyclylsulfonyl-substituted pyridine and its use in the treatment of cancer |
| JP2020507625A (en) | 2017-02-07 | 2020-03-12 | オブリーク セラピューティクス アーベー | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| MX2019009266A (en) | 2017-02-07 | 2019-11-05 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer. |
| CN109422733A (en) * | 2017-09-03 | 2019-03-05 | 上海美志医药科技有限公司 | One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades |
| CN110563656A (en) * | 2018-06-06 | 2019-12-13 | 四川大学 | Pyrimidine small molecule compound and application thereof in preparing anti-mycobacteria drugs |
| TWI726363B (en) * | 2018-07-31 | 2021-05-01 | 大陸商蘇州亞盛藥業有限公司 | Combination of FAK/ALK/ROS1 inhibitor and EGFR inhibitor to treat cancer |
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| CN105612151B (en) | 2017-08-15 |
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