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CN112004809A - 5-chloro-2, 4-pyrimidine derivatives as antitumor agents - Google Patents

5-chloro-2, 4-pyrimidine derivatives as antitumor agents Download PDF

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CN112004809A
CN112004809A CN201980023403.9A CN201980023403A CN112004809A CN 112004809 A CN112004809 A CN 112004809A CN 201980023403 A CN201980023403 A CN 201980023403A CN 112004809 A CN112004809 A CN 112004809A
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朱雷
陆柯潮
张四平
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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
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/48—Two nitrogen atoms
    • 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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Abstract

The present invention provides 5-chloro-2, 4-pyrimidine derivatives as ALK inhibitors. The compound is a compound shown as a formula I or a medicinal salt, a prodrug, a hydrate, a solvent compound and a metabolite of the compound shown as the formula I, wherein R is1，R2，R3，R4，R5As defined in the specification. The compound and the pharmaceutical composition can be used as an ALK inhibitor and can be used for preparing an anti-tumor therapeutic drug for inhibiting anaplastic lymphoma kinase.

Description

5-chloro-2, 4-pyrimidine derivatives as antitumor agents Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a 5-chloro-2, 4-pyrimidine derivative serving as an antitumor drug.
Background
Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been demonstrated to have a clear pathogenic role in lymphoma. Anaplastic Lymphoma Kinase (ALK) is the oncogene of most Anaplastic Large Cell Lymphomas (ALCLs) that is transformed and expressed by a variety of molecular mechanisms. Aberrant ALK translocation or expression leads to tumorigenesis. Activating mutations or translocations of the ALK gene have been identified in several types of cancer, including anaplastic large cell lymphoma, neuroblastoma, inflammatory myofibroblastoma, and non-small cell lung cancer. Some ALK inhibitors have been clinically proven effective in various cancers. In particular, a few ALK inhibitors, drugs that exist in the pharmaceutical market against NSCLC (non-small cell lung cancer), such as Crizotinib Ceritinib and Brigatinib.
Although a large number of compounds with protein kinase inhibitory activity have been researched, and some protein kinase inhibitors such as Crizotinib, Ceritinib and the like are marketed for treating NSCLC, but the compounds can generate drug resistance, have large adverse reaction and have certain defects, and in China, no ALK inhibitor drug with an independent intellectual property right is marketed at present, so that the development of a novel ALK inhibitor drug for treating cancer with higher safety and high efficiency has great social value and economic benefit.
Disclosure of Invention
The invention aims to provide a 5-chloro-2, 4-pyrimidine derivative serving as an anti-tumor medicament and application thereof.
In a first aspect of the present invention, there is provided a compound represented by formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, hydrate, or solvate thereof:
Figure PCTCN2019072915-APPB-000001
in formula (I):
x is- (S ═ O) -, or- (O ═ S ═ O) -;
y is N or CH;
l is selected from: hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C1-4A hydrocarbyl group;
R 1selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, and substituted or unsubstituted C1-8An alkoxy group;
R 2selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 3and R6Independently selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, and substituted or unsubstituted C1-8An alkoxy group;
R 4and R5Independently selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, R4And R 5Together with the atoms to which they are attached form a 3-to 8-membered ring, which 3-to 8-membered ring is optionally substituted with one or more substituents selected from: halogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy radical, C3-8Cycloalkyl radical, C1-4An alkyl substituted or unsubstituted 3-to 8-membered heterocyclyl.
In another preferred embodiment, the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally and independently substituted with 1 to 3 substituents each independently selected from the group consisting of: halogen, hydroxy, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, -CN, -NO2、C 1-4An alkoxy group; the above-mentioned aryl group is an aryl group having 6 to 12 carbon atoms unless otherwise specified; heteroaryl is 5-to 15-membered heteroaryl.
In another preferred embodiment, the compound has the structure of formula I':
Figure PCTCN2019072915-APPB-000002
in another preferred embodiment, R1Selected from: hydrogen, substituted or unsubstituted C1-4An alkyl group.
In another preferred embodiment, R2Is substituted or unsubstituted C1-4An alkyl group.
In another preferred embodiment, R3Is substituted or unsubstituted C1-4An alkoxy group.
In another preferred embodiment, R6Is hydrogen, or substituted or unsubstituted C1-4An alkyl group.
In another preferred example, X is- (S ═ O) -or- (O ═ S ═ O) -; preferably, X is- (S ═ O) -.
In another preferred embodiment, Y is N.
In another preferred embodiment, Y is CH, and R4And R5Together with the carbon atoms to which they are attached form a 3-to 8-membered ring (preferably a 6-membered ring) optionally containing 0-3 (e.g. 1,2, or 3) heteroatoms independently selected from N, O or S.
In another preferred embodiment, Y is N, and R is4And R5Together with the N atom to which they are attached form a 3-to 8-membered ring (preferably a 6-membered ring), optionally the 3-to 8-membered ring further contains 0-3 (e.g. 1,2, or 3) heteroatoms independently selected from N, O or S; optionally said 3-to 8-membered ring is substituted with one or more substituents selected from: halogen, C1-8Alkyl radical, C3-8Cycloalkyl radical, C1-4An alkyl substituted or unsubstituted 3-to 8-membered heterocyclyl.
In another preferred embodiment, when X is- (S ═ O) -, the compound is in the R configuration, S configuration, or R, S racemic form.
In another preferred embodiment, the compound has the structure shown in formula (II):
Figure PCTCN2019072915-APPB-000003
wherein J is N or C; k is N or C; r7Selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
X、L、R 1、R 2、R 3、R 6as described above respectively.
In another preferred embodiment, the compound has the structure of formula II':
Figure PCTCN2019072915-APPB-000004
wherein each substituent is as described above.
In another preferred embodiment, J is C; and K is N.
In another preferred embodiment, J is N; and K is C.
In another preferred embodiment, J is N; and K is C; and R is7Is a substituted or unsubstituted 3-to 8-membered heterocyclic group optionally containing 0-3 (e.g., 1,2, or 3) heteroatoms independently selected from N, O or S.
In another preferred embodiment, R7Is C1-4Alkyl-substituted 3-to 8-membered heterocyclic groups containing 2N heteroatoms, preferably 5-to 8-membered heterocyclic groups.
In a second aspect of the invention, there is provided the use of a compound of formula (I) as described in the first aspect of the invention for:
(a) preparing a medicament for treating a disease associated with Anaplastic Lymphoma Kinase (ALK) activity or expression; and/or
(b) Preparing an Anaplastic Lymphoma Kinase (ALK) targeted inhibitor; and/or
(c) Non-therapeutically inhibiting Anaplastic Lymphoma Kinase (ALK) activity in vitro.
In another preferred embodiment, the "disease associated with Anaplastic Lymphoma Kinase (ALK) activity or expression" includes a tumor.
In another preferred embodiment, the tumor includes, but is not limited to: lymphoma, lung cancer, bladder cancer, breast cancer, kidney cancer, stomach cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, intestinal cancer, epithelial cell cancer, multiple myeloma, pancreatic cancer, leukemia, and the like.
In another preferred embodiment, the tumor comprises anaplastic large cell lymphoma, neuroblastoma, inflammatory myofibroblastoma, and non-small cell lung cancer.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:
(i) an effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, hydrate, or solvate thereof; and
(ii) a pharmaceutically acceptable carrier.
In a fourth aspect of the invention, there is provided a method of treating a tumour, the method comprising the steps of:
administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in the first aspect of the invention, or administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described in the third aspect of the invention.
In a fifth aspect of the invention, there is provided a process for the preparation of a compound according to the first aspect of the invention, the process comprising the steps of:
(a) reacting the compound A3 and the compound A4 in an inert solvent to obtain the compound shown in the formula I
Figure PCTCN2019072915-APPB-000005
In another preferred example, the method further comprises the steps of:
(b) reacting compound a1 and compound a2 in an inert solvent to give compound A3:
Figure PCTCN2019072915-APPB-000006
in another preferred embodiment, L is chloro.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies to obtain a class of compounds having a significant inhibitory effect on Anaplastic Lymphoma Kinase (ALK), and these compounds can be used for the preparation of pharmaceutical compositions for treating diseases associated with Anaplastic Lymphoma Kinase (ALK) activity or expression. On the basis of this, the present invention has been completed.
Before the present invention is described, it is to be understood that this invention is not limited to the particular methodology and experimental conditions described, as such methodologies and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now exemplified.
The present invention relates to novel 5-chloro-2, 4-substituted pyrimidine derivatives as ALK inhibitors and the use of these compounds in the preparation of medicaments for the treatment and prevention of cancer.
The present invention is directed to a compound of formula (I ') or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug of a compound of formula I':
Figure PCTCN2019072915-APPB-000007
in formula (I):
x is- (S ═ O) -, or- (O ═ S ═ O) -;
y is N or CH;
R 1selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, and substituted or unsubstituted C1-8An alkoxy group;
R 2selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R 3and R6Independently selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, and substituted or unsubstituted C1-8An alkoxy group;
R 4and R5Independently selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, R4And R5Together with the atoms to which they are attached form a 3-to 8-membered ring, which 3-to 8-membered ring is optionally substituted with one or more substituents selected from: halogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy radical, C3-8Cycloalkyl radical, C1-4An alkyl substituted or unsubstituted 3-to 8-membered heterocyclyl.
In a preferred embodiment of the invention, R1And R2May be independent substituents or may be linked to form a ring; r3And R6May be two substituents which may be the same or different；R 4And R5May be the same or different substituents and may be joined to form a five or six membered ring.
R 1，R 2，R 3，R 4，R 5，R 6May contain one or more heteroatoms such as, but not limited to, F, Cl, N, O, S.
Thus, throughout this specification, the skilled person will be able to refer to the R in the compounds of formula I1-R 6And substituents thereof are selected to provide stable compounds of formula I or pharmaceutically acceptable salts, hydrates, solvates, metabolites thereof, as described in the examples of the present invention.
Typical compounds of the invention include, but are not limited to:
Figure PCTCN2019072915-APPB-000008
Figure PCTCN2019072915-APPB-000009
wherein, the chiral atoms comprise R configuration, S configuration and R, S mixed rotation type compounds.
When X is- (S ═ O) -, the compound of the present invention has an R configuration, an S configuration, or an R, S racemic form, and the compound of the present invention exhibits an excellent tumor-inhibiting activity and has an unexpectedly excellent effect.
Term(s) for
Unless otherwise indicated, reference to "or" herein has the same meaning as "and/or" (meaning "or" and ").
Unless otherwise specified, each chiral carbon atom (chiral center) in all compounds of the invention may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
As used herein, the term "alkyl", alone or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched alkyl group having 1-8 carbon atoms, or a combination thereof. The alkyl groups may be saturated, monounsaturated or polyunsaturated, and may include divalent or polyvalent radicals. When the alkyl group is preceded by a carbon atom number limitation (e.g. C)1-8) When this is the case, it means that the alkyl group contains 1 to 8 carbon atoms, e.g. C1-8The alkyl group may include a straight or branched chain alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
As used herein, the term "alkenyl", alone or as part of another substituent, refers to a straight or branched carbon chain having at least 1 carbon-carbon double bond. The alkenyl group having one double bond may be represented as-CnH 2n- 1The alkenyl group having 2 double bonds may be represented as-CnH 2n-3. When the alkenyl radical is preceded by a carbon atom number limitation (e.g. C)2-8) When used, it means that the alkenyl group contains 2 to 8 carbon atoms, for example, a straight or branched chain alkenyl group having 2 to 8 carbon atoms, such as ethenyl, propenyl, 1, 2-butenyl, 2, 3-butenyl, butadienyl, or the like.
As used herein, the term "alkynyl", alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be linear or branched, or a combination thereof. In some embodiments, the alkynyl group has 2 to 8 (e.g., 2 to 8, 2 to 6, or 2 to 4) carbon atoms. When alkynyl is preceded by a carbon atom number limitation (e.g. C)2-8Alkynyl) means that the alkynyl group contains 2 to 8 carbon atoms, e.g., the term "C2-8The alkynyl group "means a straight-chain or branched alkynyl group having 2 to 8 carbon atoms, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or the like.
As used herein, the term, alone or as part of another substituent"cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic (including fused, bridged, or spiro) ring system that is saturated or partially saturated. The cycloalkyl group can have 3 to 16 (e.g., 3 to 10, or 5 to 10) carbon atoms. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g. C)3-10) When used, means that the cycloalkyl group contains 3 to 10 carbon atoms. In some preferred embodiments, the term "C3-8Cycloalkyl "refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like.
As used herein, the term "alkoxy" or "alkyloxy" refers to an alkyl group (e.g., -O-alkyl) attached through an oxygen atom, wherein the alkyl group is as described above. Examples of specific alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. The alkoxy group may be substituted with 1 or more substituents such as halogen, amino, cyano, or hydroxy. The alkoxy group may be linear or branched. When alkoxy has a carbon atom number limitation (e.g. C)1-8) When used, it means that the cycloalkyl group has 1 to 8 carbon atoms.
As used herein, the term "halogen", alone or as part of another substituent, refers to F, Cl, Br, and I.
As used herein, the term "aryl", alone or as part of another substituent, refers to a monocyclic, bicyclic, or fused aromatic hydrocarbon group. The aryl group may be substituted or unsubstituted. When an aryl group is preceded by a carbon atom number limitation (e.g. C)6-12) When used, it means that the aryl group has 6 to 12 carbon atoms. Examples of aryl groups are, for example (but not limited to): phenyl, biphenyl, naphthyl, or the like (each carbon atom of which may be optionally substituted). The aryl group may be free of or contain one or more of the same or different (e.g., 2,3, 4) heteroatoms, which may be selected from N, O or S.
As used herein, the term "heteroaryl" alone or as part of another substituentThe group "means a monocyclic, bicyclic or fused aromatic group having a specific number of ring-forming carbon atoms (e.g., C)4-10I.e., having 4-10 ring-forming carbon atoms) and includes at least one identical or different heteroatom selected from N, O or S. Each ring atom may be optionally substituted. The heteroaryl group can be a 5-to 15-membered aromatic ring group having 1-5 heteroatoms each independently selected from N, O or S. Examples of heteroaryl groups are, for example (but not limited to): pyridine, pyrimidine, pyrrole, indazole, indole, furan, benzofuran, thiophene, or the like.
As used herein, the term "heterocyclyl", alone or as part of another substituent, refers to a saturated or partially saturated substituent of a single or fused ring, said group having the specified number of ring-forming carbon atoms (e.g., C)3-11I.e., having 3-11 ring-forming carbon atoms) and includes at least one identical or different heteroatom selected from N, O or S. The heterocyclyl group may be a 3-to 15-membered heterocyclyl group having 1-5 heteroatoms each independently selected from N, O or S. Examples of heterocyclyl groups are for example (but not limited to): nitrogen heterocyclic group, oxygen heterocyclic group, sulfur heterocyclic group, nitrogen oxygen heterocyclic group, nitrogen sulfur heterocyclic group, oxygen sulfur heterocyclic group and the like, and more preferred is a heterocyclic group as shown in each example of the present application. In the present invention, the heterocyclic group may be monocyclic, bicyclic or tricyclic (including bicyclic, bridged or spiro).
As used herein, the terms "optionally" or "optionally" (e.g., "optionally substituted") mean that the moiety in question is substituted or unsubstituted, and that the substitution occurs only at chemically realizable positions. For example, H, a covalent bond or a-C (═ O) -group may not be substituted by a substituent.
As used herein, the term "substituted" (with or without "optionally" modifying) means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. Particular substituents are those described correspondingly in the foregoing, or as appearing in the examples. Unless otherwise specified, an optionally substituted group may have a substituent selected from a specified group at any substitutable site of the groupThe substituents may be the same or different at each position. A cyclic substituent, such as heterocycloalkyl, may be attached to another ring, such as cycloalkyl, to form a spiro bicyclic ring system, e.g., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such substituents are for example (but not limited to): c1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), cyano, C1-8Aldehyde group, C2-10Acyl radical, C2-10Ester group and amino group.
For convenience and in accordance with conventional understanding, the terms "optionally substituted" or "optionally substituted" are only applicable to sites which can be substituted by substituents, and do not include those substitutions which are not chemically achievable.
General synthetic method of compound
The compound represented by the general formula I of the present invention can be prepared by the following method, however, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
In the preparation method of the present invention, each reaction is usually carried out in an inert solvent at a reaction temperature of-78 ℃ to 150 ℃ (preferably 20 ℃ to 120 ℃). The reaction time in each step is usually 0.5 to 48 hours, preferably 2 to 12 hours.
Equation a describes a general synthetic method for the compounds of the present invention:
reaction formula A:
Figure PCTCN2019072915-APPB-000010
as used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with pharmaceutically acceptable inorganic and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid, and the like; preferred organic acids include (but are not limited to): citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, sulfanilic acid, 2-acetoxybenzoic acid, isethionic acid and the like. As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without undue side effects. In some embodiments, pharmaceutically acceptable salts of a certain compound of the invention include salts of a compound of the invention having an acidic group (e.g., potassium, sodium, magnesium, calcium) or a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).
As used herein, the term "pharmaceutically acceptable solvate" refers to a solvate of a compound of the present invention with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, tetrahydrofuran and dichloromethane. Hydrates and solvates (such as methanolate, ethanolate and DMSO) of the compounds shown in the formula I are also in the scope of the invention. Methods of solvation are well known in the art.
As used herein, the term "pharmaceutically acceptable stereoisomer" means that the chiral atom involved in the compounds of the present invention may be in the R configuration, or may be in the S configuration, or a combination thereof.
Pharmaceutical compositions and methods of administration
The compound has excellent inhibitory activity on ALK kinase, so the compound and various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving diseases related to ALK kinase activity or expression. The compounds of the invention may be used for the treatment or prevention of cancer and for inhibiting the proliferation of cancer cells.
According to the prior art, the compounds of the invention can be used for the treatment of the following diseases (but not limited to): various cancers, such as lung cancer, bladder cancer, breast cancer, kidney cancer, stomach cancer, liver cancer, ovarian cancer, prostate cancer, cervical cancer, intestinal cancer, epithelial cell cancer, multiple myeloma, pancreatic cancer, lymphoma, leukemia, and the like.
According to a particular embodiment of the invention, the medicament is for at least one of: useful as kinase inhibitors, inhibiting ALK kinase activity, treating or preventing cancer, and inhibiting cancer cell proliferation. According to the specific example of the invention, the activity (IC50) of the compound for inhibiting the proliferation activity of human anaplastic large cell lymphoma cell strains in vitro is tested, and the test result shows that the compounds shown in the formula I have good activity for inhibiting the proliferation of the human anaplastic large cell lymphoma cell strains.
Therefore, the medicine can be effectively used as an ALK inhibitor and is used for treating one or more tumor diseases related to ALK activity, particularly non-small cell lung cancer.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 5 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
In the specific examples described below, the compound structure was determined by Nuclear Magnetic Resonance (NMR) and liquid mass chromatography (LC-MS). Wherein NMR shifts () are given in parts per million (ppm) and NMR is determined using BA ruker AVANCE-400 nuclear magnetic instrument, wherein the determination solvent is deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated dimethyl sulfoxide (DMSO-d)6) Internal standard is Tetramethylsilane (TMS). An Agilent6120 mass spectrometer is used for measuring the LC-MS by the liquid chromatography-mass spectrometry, and the HPLC measurement model is as follows: agilent 1260(Poroshell 120 EC-C184.6X 50mm column)
The microwave reaction uses an XH-800A microwave high-pressure synthesizer.
Model number of the apparatus for determining the IC50 value of the compound of formula I by MTT method: flexstation 3 of MD corporation.
The progress of the reaction in the following examples was checked by Thin Layer Chromatography (TLC) using a system of developing reagents: n-hexane/ethyl acetate system, dichloromethane/methanol system, and volume ratio of the solvent is adjusted according to different polarities of the compounds. The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15-0.2mm, the specification of the thin layer chromatography separation and purification product is 0.4-0.5mm, and the column chromatography generally adopts the tobacco yellow sea silica gel 200-mesh and 300-mesh silica gel as a carrier.
The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying compounds comprise: a: dichloromethane and methanol system, B: the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
The starting materials used in the examples below may be synthesized by either methods known in the art or may be purchased from the companies such as Aladdin reagent, Shao Yuan chemical technology, Darrin Chemicals, and the like.
The main advantages of the invention are:
(1) the invention discloses a novel compound with obvious inhibition effect on Anaplastic Lymphoma Kinase (ALK) for the first time;
(2) the compound of the invention has remarkable and excellent inhibitory activity on ALK, and thus can be used for treating tumors.
(3) In the series of compounds, the activity of some compounds for inhibiting the proliferation of tumor cells (Karpas299) is obviously superior to that of a positive control (ceritinib), and the compounds have the potential of replacing positive control medicaments, so the development prospect is huge.
The present invention will be described in further detail with reference to the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures in the following examples, where no detailed conditions are indicated, are generally carried out according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. The test materials and reagents used in the following examples are commercially available without specific reference.
Example 1
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (3-methyl-2-methylsulfonyl) phenyl) pyrimidine-2, 4-diamine.
Figure PCTCN2019072915-APPB-000011
Figure PCTCN2019072915-APPB-000012
First step of
1-methyl-2-methylsulfonyl-3-nitrobenzene
3-Nitro-2-fluorotoluene (5.00g,32.2mmol) was dissolved in 15g of dimethyl sulfoxide, and sodium methanesulfinate (4.94g,48.4mmol) was added thereto, and the mixture was heated to 85 ℃ and stirred to react for 12 hours. The reaction was cooled to room temperature, 50g of water was added, the temperature was reduced to 0-10 deg.C, stirred for 40 minutes, filtered and dried under vacuum to give the title product 1-methyl-2-methanesulfonyl-3-nitrobenzene 1b (5.89g, off-white solid) in 85% yield.
Second step of
2-methanesulfonyl-3-methylaniline
1-methyl-2-methanesulfonyl-3-nitrobenzene (5.89g,27.4mmol) was dissolved in 25g of anhydrous ethanol, 5% palladium on carbon (0.6g) was added thereto, and the mixture was replaced with hydrogen three times under a hydrogen atmosphere (0.4MPa), followed by stirring for 48 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent n-hexane/ethyl acetate ═ 5:1) to give the title product 2-methanesulfonyl-3-methylaniline 1c (4.41g, white solid) in 87% yield.
The third step
2, 5-dichloro-N- ((3-methyl-2-methylsulfonyl) benzene) pyrimidin-4-amine
The mixed solvent of DMF/DMSO (50ml/5ml) is cooled to 0 ℃, NaH (1.37g) is added, stirring is carried out for half an hour, a DMF/DMSO (20ml/2ml) solution of 2-methanesulfonyl-3-methylaniline (4.41g,23.8mmol) is added, after dropping, stirring is carried out for half an hour at 0 ℃, a DMF/DMSO (15ml/1.5ml) solution of 2,4, 5-trichloropyrimidine (8.73g,47.6mmol) is slowly dropped, after dropping, the temperature is raised to room temperature, and stirring is carried out for 24 hours. 300ml of water was added, stirred for 1 hour and filtered to give a yellow solid which was purified by silica gel column chromatography (eluent N-hexane/ethyl acetate 5:1) to give the title product 2, 5-dichloro-N- ((3-methyl-2-methanesulfonyl) benzene) pyrimidin-4-amine 1e (4.35g, white solid) in 55% yield.
The fourth step
4- (4- (5-chloro-4- (3-methyl-2-methanesulfonyl) aniline) pyrimidine-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butyl alcohol ether
4- (4-amino-5-isopropoxy-2-methylphenyl) piperidine-1-carboxylic acid tert-butyl alcohol ether (2.28g,6.26mmol),2, 5-dichloro-N- ((3-methyl-2-methanesulfonyl) benzene) pyrimidin-4-amine (2.18g,6.26mmol),4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (0.376g,0.626mmol), palladium acetate (73.76mg,0.313mmol), cesium carbonate (6.4g,19.64mmol) and 40ml tetrahydrofuran were charged into a reaction flask and reacted at 150 ℃ for 20 minutes by microwave. The reaction solution was cooled to room temperature, distilled under reduced pressure, and evaporated to dryness, and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane/ethyl acetate ═ 5:1) to give the title product, 4- (4- (5-chloro-4- (3-methyl-2-methanesulfonyl) aniline) pyrimidin-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butanol ether 1g (1.78g, white solid) in 42% yield.
The fifth step
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-methyl-2-methanesulfonyl) phenyl) pyrimidine-2, 4-diamine
Dissolving tert-butyl alcohol ether (1.78g,2.76mmol) of 4- (4- (5-chloro-4- (3-methyl-2-methanesulfonyl) aniline) pyrimidine-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid in 50ml dichloromethane, adding trifluoroacetic acid (20g), stirring at room temperature for 1 hour, concentrating under reduced pressure, adding 20ml aqueous sodium hydroxide solution (20%), 70ml ethyl acetate, stirring for half an hour, separating the liquid, extracting the aqueous phase with 70ml ethyl acetate, combining the organic phases, washing the organic phase with water (30 ml. times.1) and saturated sodium chloride solution (30 ml. times.2), drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and crystallizing with n-hexane/ethyl acetate (10/1), the title product was obtained as 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-methyl-2-methanesulfonyl) phenyl) pyrimidine-2, 4-diamine 1(1.28g, white solid) in 85% yield.
LCMS:544
1H-NMR(400MHz,CDCl3):＝1.38(d,J＝6.1Hz,6H),1.59-1.78(m,5H),2.18(s,3H),2.35(s,3H),2.84(s,3H),2.75-2.82(m,3H),3.20-3.24(M,2H),4.56(sept,J＝6.1Hz),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 2
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-methyl-2-ethanesulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000013
The synthesis of example 2 is as in example 1.
LC-MS:558
1H-NMR(400MHz,CDCl3):＝1.24(m,J＝6.5Hz,3H),1.38(d,J＝6.1Hz,6H),1.59-1.78(m,5H),2.18(s,3H),2.35(s,3H),3.45(m,2H),2.75-2.82(m,3H),3.20-3.24(M,2H),4.56(sept,J＝6.1Hz),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 3
(R, S) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine.
Figure PCTCN2019072915-APPB-000014
First step of
2, 5-dichloro-N- (2- (isopropylsulfide) phenyl) pyrimidin-4-amine
2-Isoprothionaniline hydrochloride (5g,24.4mmol) and 2,4, 5-trichloropyrimidine (4.48g,24.4mmol) were dissolved in a mixed solvent of 50ml of toluene and 5ml of N-butanol, N-diisopropylethylamine (6.3g,48.8mmol) was added, and the mixture was heated under reflux for 24 hours, cooled to room temperature, 20ml of water was added, stirred for 10 minutes, and allowed to stand for separation to obtain an organic phase, which was washed successively with water (20 ml. times.1) and a saturated sodium chloride solution (20 ml. times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and crystallized with ethanol to obtain the title product 2, 5-dichloro-N- (2- (isopropylsulfide) phenyl) pyrimidin-4-amine 3b (6.2g, white solid) in a yield of 81%.
Second step of
(R, S) -2, 5-dichloro-N- (2- (isopropylsulfinyl) phenyl) pyrimidin-4-amine
Dissolving 2, 5-dichloro-N- (2- (isopropylsulfinyl) phenyl) pyrimidin-4-amine (6.2g,20mmol) in 100ml of dichloromethane, cooling to 0-5 ℃, slowly adding a dichloromethane solution of m-chloroperoxybenzoic acid (3.14g of 85% mCPBA/100ml of dichloromethane) dropwise over about 1 hour, after completion of the dropwise addition, heating to room temperature, stirring for 5 hours, cooling to-5 ℃ -10 ℃, stirring for 1 hour, filtering, removing insoluble matter, concentrating the filtrate under reduced pressure, adding N-hexane to the residue, crystallizing ethyl acetate (N-hexane/ethyl acetate ═ 5:1), to obtain the title product (R, S) -2, 5-dichloro-N- (2- (isopropylsulfinyl) phenyl) pyrimidin-4-amine 3c (5.2g, white solid), yield 80%.
The third step
(R, S) -4- (4- (5-chloro-4- (2-isopropylsulfinyl) aniline) pyrimidine-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butyl alcohol ether
Synthesis method referring to the synthesis method of the fourth step of example 1, the title product, (R, S) -4- (4- (5-chloro-4- (2-isopropylsulfinyl) aniline) pyrimidin-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butyl alcohol ether (white solid) was obtained in a yield of 40%
The fourth step
(R, S) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine.
Synthetic methods the title product (R, S) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine (white solid) was obtained in 83% yield with reference to the synthetic method of the fifth step of example 1.
LC-MS:542
1H-NMR(400MHz,DMSO-d 6):＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45-3.51(m,1H),4.51-4.57(m,2H),6.82(s,1H),7.32-7.36(t,J＝7.6Hz,1H),7.51(s,1H),7.59-7.63(t,J＝7.2Hz,1H),7.85(dd,1H),8.05(s,1H),8.23(s,1H),8.45-8.47(m,1H)ppm.
By chiral preparative column resolution, (R) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine and (S) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine were obtained.
Example 4
5-chloro-N2- (2-methoxy-4- (4- (4-methyl-1-piperazinyl) -1-piperidinyl) phenyl) -N4- ((3-methyl-2-methanesulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000015
Dissolving 2, 5-dichloro-N- ((3-methyl-2-methylsulfonyl) phenyl) pyrimidin-4-amine (1.56g,4.70mmol) and 2-methoxy-4- (4- (4-methylpiperazinyl) piperidinyl) aniline (2g,6.59mmol) in 2-methoxyethanol (25ml), adding 2.5M ethanol hydrochloride (5ml), pouring the mixture into a thick-walled glass bottle, heating to 120 ℃, reacting for 6 hours, cooling to room temperature, concentrating under reduced pressure, adding 50ml water and 50ml ethyl acetate to the residue, stirring for layering, removing the ethyl acetate layer, collecting the water layer, and adding 20% aqueous sodium hydroxide solution dropwise to the water layer to adjust the pH value to 12. The aqueous phase was extracted with dichloromethane (50ml × 3), the organic phase was washed successively with water (30ml × 1) and saturated sodium chloride solution (30ml × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent, dichloromethane/methanol ═ 10:1) to give the title product 5-chloro-N2- (2-methoxy-4- (4- (4-methyl-1-piperazinyl) -1-piperidinyl) phenyl) -N4- ((3-methyl-2-methanesulfonyl) phenyl) pyrimidine-2, 4-diamine 4(1.41g, off-white solid) in 50% yield.
LC-MS:600
1H-NMR(400MHz,CD 3OD):＝1.66(dq,J＝3.89,12.09Hz,2H),1.97-2.08(m,2H),2.29(s,3H),2.35(s,3H),2.89(s,3H),2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,6H),3.69(d,J＝12.30Hz,2H),3.84(s,3H),6.65(d,J＝2.51Hz,1H),7.25(ddt,J＝1.00,2.26,7.53Hz,1H),7.47-7.54(m,1H),7.60(m,1H),7.66(d,J＝8.78Hz,1H),8.02(s,1H),8.33(dd,J＝4.52,8.03Hz,1H)ppm.
Example 5
(R, S) -5-chloro-N2- (2-methoxy-4- (4- (4-methyl-1-piperazinyl) -1-piperidinyl) phenyl) -N4- ((2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000016
The synthesis of example 5 is as in example 4.
LC-MS:598
1H-NMR(400MHz,CD 3OD):＝1.30(d,J＝7.0Hz,6H),1.66(dq,J＝3.89,12.09Hz,2H),1.97-2.08(m,2H),2.29(s,3H),2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,6H),3.18(m,J＝6.7Hz,1H)3.69(d,J＝12.30Hz,2H),3.84(s,3H),6.45(dd,J＝2.51,8.78Hz,1H),6.65(d,J＝2.51Hz,1H),7.25(ddt,J＝1.00,2.26,7.53Hz,1H),7.47-7.54(m,1H),7.60(m,1H),7.66(d,J＝8.78Hz,1H),8.02(s,1H),8.33(dd,J＝4.52,8.03Hz,1H)ppm.
By chiral preparative column resolution, (R) -5-chloro-N2- (2-methoxy-4- (4- (4-methyl-1-piperazinyl) -1-piperidinyl) phenyl) -N4- ((2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine and (S) -5-chloro-N2- (2-methoxy-4- (4- (4-methyl-1-piperazinyl) -1-piperidinyl) phenyl) -N4- ((2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine can be prepared.
One of the R, S counterparts is more active, so that one of the homochiral isomers is more active.
Example 6
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-methyl-2-isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000017
First step 3-Nitro-2-Isopropylmercaptotoluene
3-Nitro-2-fluorotoluene (5.00g,32.2mmol) and isopropylmercaptan (2.7g,35.5mmol) were dissolved in 30g of DMF and K was added2CO 3(6.7g,48.5mmol), heated to 85 ℃ and stirred for 12 hours. The reaction mixture was cooled to room temperature, 50g of water and 100ml of ethyl acetate were added, stirring was carried out for half an hour, liquid separation was carried out, the aqueous phase was extracted with 100ml of ethyl acetate again, the organic phases were combined, the organic phase was washed successively with water (50ml × 1) and a saturated sodium chloride solution (50ml × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent, n-hexane/ethyl acetate ═ 5:1) after evaporation to dryness to give the title product 3-nitro-2-isopropylmercaptotoluene 6b (4.90g, yellow liquid) in a yield of 72%.
Second step 2-isopropylmercapto-3-methylaniline hydrochloride
3-Nitro-2-isopropylmercaptotoluene (4.90g,23.2mmol) was dissolved in 25g of anhydrous ethanol, and 5% palladium on carbon (0.49g) was added thereto, and the mixture was replaced with hydrogen three times under a hydrogen atmosphere (0.4MPa), followed by stirring and reacting for 48 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, evaporated to dryness, 50ml of ethyl acetate and 2ml of isopropanol hydrochloride were added, the temperature was reduced to 0-5 ℃, and filtered to obtain the title product 2-isopropylmercapto-3-methylaniline hydrochloride 6c (4.65g, white solid) with a yield of 92%.
The third step is 2, 5-dichloro-N- (3-methyl-2- (isopropyl sulfide) phenyl) pyrimidin-4-amine
Synthetic method the title product 2, 5-dichloro-N- (3-methyl 2- (isopropylthioether) phenyl) pyrimidin-4-amine 6d (5.96g, white solid) was obtained in 85% yield according to the synthetic method of the first step 3b of example 3.
Fourthly, 2, 5-dichloro-N- (3-methyl-2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine 2, 5-dichloro-N- (3-methyl-2- (isopropylsulfide) phenyl) pyrimidin-4-amine (5.96g,20mmol) is dissolved in 100ml of dichloromethane, the temperature is reduced to 0-5 ℃, a dichloromethane solution of m-chloroperoxybenzoic acid (6.1g of 85% mCPBA/200ml of dichloromethane) is slowly dropped, the dropping is finished for about 1 hour, the temperature is raised to room temperature after the dropping is finished, the stirring is carried out for 5 hours, the temperature is reduced to-5 ℃ to-10 ℃, the stirring is carried out for 1 hour, filtering out is carried out, insoluble matters are filtered out, the filtrate is concentrated under reduced pressure, N-hexane is added to the residue, ethyl acetate crystals (N-hexane/ethyl acetate are 5:1), the title product, 2, 5-dichloro-N- (3-methyl-2- (isopropylsulfonyl) phenyl) pyrimidin-4-amine 6e (5.6g, white solid) was obtained in 84% yield.
The fifth step was 4- (4- (5-chloro-4- (3-methyl-2-isopropylsulfonyl) aniline) pyrimidine-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butyl alcohol ether
Synthetic method referring to the synthetic method of the fourth step 1g of example 1, the title product 4- (4- (5-chloro-4- (3-methyl-2-isopropylsulfonyl) aniline) pyrimidin-2-amino) -5-isopropoxy-2-methylphenylpiperidine-1-carboxylic acid tert-butyl alcohol ether 6f (white solid) was obtained in 40% yield.
Sixth step 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-methyl-2-isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine
Synthesis method referring to the synthesis method of compound 1 in the fifth step of example 1, the target product 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-methyl-2-isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine is obtained
LC-MS:572
1H-NMR(400MHz,CDCl3):＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.18(s,3H),2.35(s,3H)2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45-3.51(m,1H),4.51-4.57(m,1H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 7
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-hydroxymethyl-2-isopropylsulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000018
Figure PCTCN2019072915-APPB-000019
Synthesis method of example 7 reference is made to example 6
LC-MS:588
1H-NMR(400MHz,CDCl3,):＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45-3.51(m,1H),4.51-4.57(m,2H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 8
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-hydroxymethyl-2-ethanesulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000020
Figure PCTCN2019072915-APPB-000021
Synthesis method of example 8 reference is made to example 1
LC-MS:574
1H-NMR(400MHz,CDCl3,):＝1.28(m,J＝6.8Hz,3H),1.38(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),3.45(m,2H),4.51-4.57(m,2H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 9
5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-hydroxymethyl-2-methanesulfonyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000022
Synthesis method of example 9 reference is made to example 1
LC-MS:560
1H-NMR(400MHz,CDCl3,):＝1.38(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),2.84(s,3H)3.03-3.06(d,2H),4.51-4.57(m,2H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 10
(R, S) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- (3-methyl-2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine.
Figure PCTCN2019072915-APPB-000023
Synthesis method of example 10 reference is made to example 3
LC-MS:556
1H-NMR(400MHz,CDCl3):＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.18(s,3H),2.35(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),2.89(m,1H),3.03-3.06(d,2H),,4.51-4.57(m,1H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 11
(R, S) -5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- ((3-hydroxymethyl-2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000024
Synthesis method of example 11 reference is made to example 3
LC-MS:572
1H-NMR(400MHz,CDCl3,):＝1.18(d,J＝6.8Hz,6H),1.24(d,J＝6.1Hz,6H),1.46-1.62(m,4H),2.0(s,1H),2.18(s,3H),2.59-2.65(m,2H),2.69-2.75(m,1H),3.03-3.06(d,2H),2.89(m,1H),4.51-4.57(m,1H),4.79(S,2H),6.82(s,1H),7.25-7.29(m,1H),7.56(br,s,1H),7.64(m,1H),7.94(m,1H),8.01(br.s,1H),8.16(br.s,1H),8.60(m,1H),9.51(br.s,1H)ppm.
Example 12
(R, S) -5-chloro-N2- (2-methoxy-4- (4- (4-methyl-1-piperazinyl) -1-piperidinyl) phenyl) -N4- ((3-methyl 2-isopropylsulfinyl) phenyl) pyrimidine-2, 4-diamine
Figure PCTCN2019072915-APPB-000025
Figure PCTCN2019072915-APPB-000026
The synthesis of example 12 refers to example 3 and example 4.
LC-MS:612
1H-NMR(400MHz,CD 3OD):＝1.30(d,J＝7.0Hz,6H),1.66(dq,J＝3.89,12.09Hz,2H),1.97-2.08(m,2H),2.29(s,3H),2.30(s,3H)2.33-2.42(m,1H),2.43-2.62(m,4H),2.62-2.86(m,6H),3.18(m,J＝6.7Hz,1H)3.69(d,J＝12.30Hz,2H),3.84(s,3H),6.65(d,J＝2.51Hz,1H),7.25(ddt,J＝1.00,2.26,7.53Hz,1H),7.47-7.54(m,1H),7.60(m,1H),7.66(d,J＝8.78Hz,1H),8.02(s,1H),8.33(dd,J＝4.52,8.03Hz,1H)ppm.
Test example:
biological evaluation
Test example 1, evaluation of proliferation inhibition of the compound of the present invention against human anaplastic large cell lymphoma cell line Karpas 299.
The cell lines used in this experiment were derived from: karpas299 (Kebai Biotechnology Nanjing Co., Ltd.)
The in vitro cell assay described below measures proliferation inhibitory activity of test compounds against human anaplastic large cell lymphoma cell lines, and the activity can be expressed as IC50 value. The general protocol for such tests is as follows: firstly, a cell strain to be tested (Kebai Biotechnology Nanjing Co., Ltd.) is inoculated on a 96-well culture plate by a medium with a cell concentration of 5000 cells/ml, 80 mu L of cell suspension is inoculated in each well, the cells were then incubated in a 5% carbon dioxide incubator at 37 ℃ and allowed to grow overnight, the medium was changed to one containing a series of test compound solutions with a concentration gradient (3. mu.M, 1. mu.M, 0.3. mu.M, 0.1. mu.M, 30nM, 10nM,3nM, 1nM,0.3nM), the culture substrate was returned to the incubator and incubated continuously for 72 hours, after the incubation was completed, 13.5. mu.l of CCK-8 solution was added to the cell plate, incubated at 37 ℃ for about 2 to 4 hours in an incubator, gently shaken, the absorbance at a wavelength of 450nm was measured on a SpectraMax M5 Microplate Reader, and the inhibition was calculated with the absorbance at 650nm as a reference.
The inhibition rate of the drug on the growth of tumor cells was calculated according to the following formula: tumor cell growth inhibition rate ═ Ac-As)/(Ac-Ab) ] × 100%
As OA of sample (cell + CCK-8+ test Compound)
Ac negative control OA (cell + CCK-8+ DMSO)
Ab: OA of Positive control (Medium + CCK-8+ DMSO)
IC50 curve fitting was performed using software Graphpad Prism 6 and using the calculation formula log (inhibitor) vs. normalized response-variable slope and the IC50 values were calculated.
The biological activity of the compounds of the invention is determined by the above analysis and the calculated IC50The values are given in Table 2:
table 2: inhibition rate of target compound on tumor cells Karpas299
Example numbering IC 50/(nM)
1 52.3
2 35.4
3(R, S racemic compound) 3.51
4 38.7
5(R, S racemic compound) 1.34
6 104.1
7 64.5
8 42.3
9 50.2
10(R, S racemic compound) 16.04
11(R, S racemic compound) 5.12
12(R, S racemic compound) 7.84
Positive control (Ceritinib) 23.7
And (4) conclusion: the preferred compounds of the invention all have obvious proliferation inhibition activity on Karpas299 cells. Wherein, the compounds 3,5,10,11 and 12 show significantly better inhibitory activity, and the activity of the compound 3 reaches about 7 times of the activity of a positive control; the activity of compound 5 was more than 17 times that of the positive control.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (15)

  1. A compound of formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, hydrate, or solvate thereof:
    Figure PCTCN2019072915-APPB-100001
    wherein, in formula (I):
    x is- (S ═ O) -, or- (O ═ S ═ O) -;
    y is N or CH;
    l is selected from: hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C1-4A hydrocarbyl group;
    R 1selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, and substituted or unsubstituted C1-8An alkoxy group;
    R 2selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
    R 3and R6Independently selected from: hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, and substituted or unsubstituted C1-8An alkoxy group;
    R 4and R5Independently selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted aryl, and substituted or unsubstitutedA substituted heteroaryl group; or, R4And R5Together with the atoms to which they are attached form a 3-to 8-membered ring, which 3-to 8-membered ring is optionally substituted with one or more substituents selected from: halogen, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy radical, C3-8Cycloalkyl radical, C1-4An alkyl substituted or unsubstituted 3-to 8-membered heterocyclyl.
  2. The compound of claim 1, wherein R is1Selected from: hydrogen, and substituted or unsubstituted C1-4And (4) a base.
  3. The compound of claim 1, wherein R is2Is substituted or unsubstituted C1-4And (4) a base.
  4. The compound of claim 1, wherein R is3Is substituted or unsubstituted C1-4An alkoxy group.
  5. The compound of claim 1, wherein R is6Is hydrogen, or substituted or unsubstituted C1-4An alkyl group.
  6. A compound according to claim 1, wherein X is- (S ═ O) -.
  7. The compound of claim 1, having the structure of formula (II):
    Figure PCTCN2019072915-APPB-100002
    wherein J is N or C; k is N or C; r7Selected from: hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkenyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
    X、L、R 1、R 2、R 3、R 6as described in claim 1, respectively.
  8. A compound according to claim 1, wherein L is halogen, preferably chlorine.
  9. A compound according to claim 1, wherein when X is- (S ═ O) -, the compound is in the R configuration, S configuration, or R, S racemic form.
  10. The compound of claim 1, wherein R is7Is C1-4Alkyl-substituted 3-to 8-membered heterocyclic groups containing 2N heteroatoms.
  11. The compound of claim 1, wherein the compound of formula (I) has a structure selected from the group consisting of:
    Figure PCTCN2019072915-APPB-100003
    Figure PCTCN2019072915-APPB-100004
    wherein is a chiral atom.
  12. Use of a compound of formula (I) according to claim 1, for:
    (a) preparing a medicament for treating a disease associated with Anaplastic Lymphoma Kinase (ALK) activity or expression; and/or
    (b) Preparing an Anaplastic Lymphoma Kinase (ALK) targeted inhibitor; and/or
    (c) Non-therapeutically inhibiting Anaplastic Lymphoma Kinase (ALK) activity in vitro.
  13. A pharmaceutical composition, comprising:
    (i) an effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, hydrate, or solvate thereof; and
    (ii) a pharmaceutically acceptable carrier.
  14. A process for the preparation of a compound according to claim 1, comprising the steps of:
    (a) reacting compound A3 with compound A4 in an inert solvent to obtain a compound of formula I:
    Figure PCTCN2019072915-APPB-100005
    wherein, X, Y, R1、R 2、R 3、R 4、R 5、R 6Respectively as claimed in claim 1.
  15. A method of treating a tumor, the method comprising the steps of:
    administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, or administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as claimed in claim 8.
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CN103641816A (en) * 2006-12-08 2014-03-19 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
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