CN107043366B - 4-aminopyrimidine compound, preparation method and medical application thereof - Google Patents

4-aminopyrimidine compound, preparation method and medical application thereof Download PDF

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CN107043366B
CN107043366B CN201710277753.0A CN201710277753A CN107043366B CN 107043366 B CN107043366 B CN 107043366B CN 201710277753 A CN201710277753 A CN 201710277753A CN 107043366 B CN107043366 B CN 107043366B
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aminopyrimidin
acryloylpiperidin
carboxamide
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CN107043366A (en
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赖宜生
章颖溢
肖建虎
金双龙
李月珍
张奕华
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China Pharmaceutical University
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of medicines, and particularly relates to a 4-aminopyrimidine compound with structural characteristics of a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof, and application thereof as a Bruton's Tyrosine Kinase (BTK) inhibitor. The experimental result shows that the compound has a remarkable inhibiting effect on BTK, and can be used for treating diseases such as thromboembolism, inflammatory diseases, autoimmune diseases, Waldenstrom macroglobulinemia, B cell lymphoma and the like.

Description

4-aminopyrimidine compound, preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a 4-aminopyrimidine compound or pharmaceutically acceptable salt thereof, a preparation method thereof, and application thereof as a Bruton tyrosine kinase inhibitor.
Technical Field
Bruton's Tyrosine Kinase (BTK), a member of the Tec family of non-receptor tyrosine protein kinases, consists of 659 amino acids and contains multiple domains, such as the Pleckstrin Homology (PH) domain, the Tec Homology (TH) domain, the Src homology 3(SH3) domain, the SH2 and the SH1 domain (Future Med Chem,2014,6(6): 675) -695). BTK has been shown to play an extremely important role in a variety of physiological processes including development, maturation, differentiation and proliferation of B cells as an important component of the B Cell Receptor (BCR) signaling pathway (Nature,1993,361(6409): 226-233).
Precise regulation of BTK is critical to maintaining normal physiological function of B cells (Anticancer Agents MedChem,2007,7(6): 624-. Over-activation of BTK causes a slowing of B cell apoptosis and is prone to autoimmune reactions, thereby inducing the development and progression of diseases such as B cell lymphoma and inflammation (Int Rev Immunol,2012,31(2): 119-132).
BTK has been shown to be overexpressed in a variety of B-cell lymphomas (Blood,2011,117(23): 6287-. As in the mouse model of chronic lymphocytic leukemia, overexpression of BTK leads to increased tumor incidence and mortality (AmJBloodRes,2013,3(1): 71-83); in mantle cell lymphoma cells, BTK Tyr223 appears to undergo persistent autophosphorylation, resulting in over-activation of BTK (Blood,2013,122(14): 2412-2424). Over-activation by BTK gain-of-function mutations has also been confirmed in acute lymphoblastic leukemia (Leuk Lymphoma,2003,44(6): 1011-. The level of anti-apoptotic proteins Bcl-2, Bcl-xL and Mcl-1 can be reduced by inhibiting the activity of BTK, thereby promoting B cell lymphoma apoptosis (LeukRes,2013,37(10): 1271-.
BTK is also involved in regulating other signaling pathways in vivo in addition to BCR signaling pathway, such as Fc gamma receptor signaling pathway (Nat Chem Biol,2011,7(1):4-5) and Toll-like (TLR) signaling pathway (J Leukoc Biol,2014,95(2): 243-.
The literature also reports the association of BTK with heteroimmune diseases, thromboembolic diseases (Expert Opin TherPatents,2010,20(11): 1457-. In a mouse model of bone marrow transplantation, the addition of BTK inhibitors prescribed for the prevention of Graft Versus Host Disease (GVHD) can significantly improve the survival of allogeneic bone marrow transplantation. In patients with X-linked agammaglobulinemia (a congenital immunodeficiency disease caused by BTK mutation inactivation), the platelet aggregation and secretion ability in response to collagen or collagen-related peptides are obviously reduced.
In conclusion, BTK has become a valid target in the field of treatment of B-cell lymphoma and inflammatory diseases at present. A plurality of BTK inhibitors (such as BMS-986142, M-2951, CC-292 and GDC-0853) are currently used for treating B cell lymphoma, rheumatoid arthritis,
Figure BDA0001278762370000022
Syndrome (I),Clinical tests for diseases such as multiple sclerosis and systemic lupus erythematosus. Among them, Ibrutinib, developed by Pharmacyclics and qiangsheng corporation in combination, is currently the only BTK inhibitor that has obtained us FDA approval for marketing, and is used to treat relapsed or refractory mantle cell lymphoma, Chronic Lymphocytic Leukemia (CLL), CLL carrying 17p deletion mutations, Waldenstrom Macroglobulinemia (WM), Small Lymphocytic Lymphoma (SLL), Marginal Zone Lymphoma (MZL). However, the variety of BTK inhibitors with good drug properties is still few, and ibbrutinib has shown drug resistance in clinical application, so the development of new BTK inhibitors has important significance.
Disclosure of Invention
The invention aims to solve the technical problem of providing a 4-aminopyrimidine compound or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition and application thereof. The compound has good BTK inhibitory activity and can be used for treating and/or preventing related diseases caused by over-activation of BTK.
The invention discloses a 4-aminopyrimidine compound shown in a general formula (I) or pharmaceutically acceptable salt thereof:
Figure BDA0001278762370000021
wherein:
l represents C (O) or C (O) NH (CH)2)m；
m represents an integer of 0 to 5;
each R is1Each independently represents halogen, cyano, nitro, hydroxy, amino, trifluoromethyl, OR3、NHR3Or (C)1-C8) An alkyl group;
n represents an integer of 0 to 5;
R2is optionally selected from: NH (C)1-C8) Alkyl NHR4，
Figure BDA0001278762370000031
R3Is represented by (C)1-C8) Alkyl, (C)1-C8) Alkoxy (C)1-C8) Alkyl, (C)6-C10) Aryl or (C)1-C10) An aromatic heterocyclic group; wherein said heteroaromatic group may optionally contain one or more additional heteroatoms selected from O, S or N; the aryl and heteroaryl groups may be optionally substituted with one to five of the following groups: halogen, nitro, cyano, hydroxy, amino, (C)1-C8) Alkyl, (C)1-C8) Alkoxy or (C)3-C6) A cycloalkyl group;
R4represents propionyl, acryloyl or 2-chloroacetyl;
wherein, the compounds of the following formula (a-d) are excluded:
Figure BDA0001278762370000032
further, 4-aminopyrimidines having the general formula (I) or pharmaceutically acceptable salts thereof, wherein:
l represents C (O) or C (O) NH (CH)2)m；
m represents an integer of 0 to 2;
each R is1Each independently represents halogen, (C)1-C5) Alkyl, (C)1-C5) Alkoxy or phenoxy;
n is an integer of 0 to 2;
R2is optionally selected from: NH (C)1-C8) Alkyl NHR4，
Figure BDA0001278762370000033
R4Represents propionyl, acryloyl or 2-chloroacetyl.
Further, 4-aminopyrimidines having the general formula (I) or a pharmaceutically acceptable salt thereof, wherein:
l represents C (O) or C (O) NH (CH)2)m；
m represents an integer of 0 to 2;
each R is1Each independently represents halogen, (C)1-C3) Alkyl, (C)1-C3) Alkoxy or phenoxy;
n is an integer of 0 to 2;
R2is optionally selected from: NH (C)1-C5) Alkyl NHR4，
Figure BDA0001278762370000041
R4Represents propionyl, acryloyl or 2-chloroacetyl.
Specifically, the 4-aminopyrimidines of the formula (I) are preferably selected from the following compounds:
(S) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] piperidin-1-yl ] -2-propen-1-one (a-1);
(R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] piperidin-1-yl ] -2-propen-1-one (a-2);
1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] piperidin-1-yl ] -2-propen-1-one (a-3);
(R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] pyrrolidin-1-yl ] -2-propen-1-one (a-4);
(S) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] pyrrolidin-1-yl ] -2-propen-1-one (a-5);
(S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-propen-1-one (a-6);
(R) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-propen-1-one (a-7);
1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] azetidin-1-yl ] -2-propen-1-one (a-8);
(R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] piperidin-1-yl ] -2-chloroethan-1-one (a-9);
(S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-chloroethan-1-one (a-10);
n- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] ethyl ] acrylamide (A-11);
(S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] propan-1-one (a-12);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-1);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-bromophenyl) carboxamide (B-2);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-isopropylphenyl) carboxamide (B-3);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3-methoxy-4-methylphenyl) carboxamide (B-4);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3, 4-dimethoxyphenyl) carboxamide (B-5);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3, 5-dimethoxyphenyl) carboxamide (B-6);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (2-fluorophenyl) carboxamide (B-7);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3-fluorophenyl) carboxamide (B-8);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-fluorophenyl) carboxamide (B-9);
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-benzylcarboxamide (B-10);
(R) - [4- [ (1-acryloylpyrrolidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-11);
(S) - [4- [ [ (1-acryloylpyrrolidin-2-yl) methyl ] amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-12);
(R) - [4- [ (1-propionylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-13).
The compound numbers referred to in the following pharmacological experiments are equivalent to the compounds corresponding to the numbers here.
Another object of the present invention is to provide a process for producing a compound represented by the general formula (I), characterized in that:
a) when L is C (O), the preparation method of the compound shown in the general formula (I) comprises the following steps: 4, 6-dihydroxypyrimidine is used as a raw material, 4, 6-dichloro-5-pyrimidinecarbaldehyde 1 is prepared by Vilsmeier-Haack reaction and chlorination reaction, 4, 6-dichloro-5-pyrimidinecarboxylic acid 2 is prepared by oxidizing sodium chlorite, 2 is reacted with oxalyl chloride to prepare acyl chloride, then the acyl chloride is reacted with aromatic hydrocarbon to prepare (4, 6-dichloropyrimidin-5-yl) (4-phenoxyphenyl) methanone 3,3 is reacted with ammonia water to prepare (4-amino-6-chloropyrimidin-5-yl) (4-phenoxyphenyl) methanone 4, 4 and an amine compound (NH)2Y-Boc or NH2YH) to obtain 5-1 or 5-2, 5-1, removing Boc protecting group, and then reacting with acyl chloride, or directly reacting 5-2 with acyl chloride to obtain a compound of general formula (I):
Figure BDA0001278762370000051
wherein R is1And R2As defined above.
b) When L is C (O) NH (CH)2)mThe preparation method of the compound shown in the general formula (I) comprises the following steps: the intermediate 2 reacts with oxalyl chloride to prepare acyl chloride, then the acyl chloride is condensed with amine compounds to generate amide 6, the amide 6 reacts with ammonia water to prepare intermediates 7,7 and amine compounds (NH)2Y-Boc) to obtain 8, treating 8 with concentrated hydrochloric acid to remove Boc to obtain 9, and reacting 9 with acyl chloride to obtain a compound of general formula (I):
Figure BDA0001278762370000061
wherein, m, n, R1And R2As defined above.
The pharmaceutically acceptable salts of the compounds of general formula (I) can be synthesized by general chemical methods.
In general, salts can be prepared by reacting the free base or acid with a stoichiometric equivalent or excess of an acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.
The invention also provides a pharmaceutical composition, which consists of active components with effective therapeutic dose and pharmaceutically acceptable auxiliary materials; the active component comprises one or more of a compound shown in a general formula (I) and pharmaceutically acceptable salts thereof. In the pharmaceutical composition, the auxiliary materials comprise pharmaceutically acceptable carriers, diluents and/or excipients.
The pharmaceutical composition may be formulated into various types of administration unit dosage forms according to the therapeutic purpose, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably tablets, capsules, liquids, suspensions, and injections (solutions and suspensions).
For shaping the pharmaceutical composition in the form of tablets, pills or suppositories, any excipient known and widely used in the art can be used.
For preparing the pharmaceutical composition in the form of injection, the solution or suspension may be sterilized (preferably by adding appropriate amount of sodium chloride, glucose or glycerol) and made into injection with blood isotonic pressure. In the preparation of injection, any carrier commonly used in the art may also be used. For example: water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, usual dissolving agents, buffers and the like may be added.
The content of the composition in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, generally 5 to 95% by mass, preferably 30 to 85% by mass.
The method of administration of the pharmaceutical composition of the present invention is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient.
The invention further provides application of the compound with the general formula (I), the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing BTK inhibitors. The BTK inhibitors are useful for treating thromboembolism, fahrenheit macroglobulinemia, inflammatory disorders, autoimmune diseases, and B-cell lymphoma.
Such inflammatory or autoimmune diseases include, but are not limited to: one or more of a heteroimmune disease, asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, autoimmune-mediated hemolytic anemia, immune complex-mediated vasculitis, and psoriasis.
Such B cell lymphomas include, but are not limited to: one or more of chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, multiple myeloma, mucosa-associated lymphoid tissue lymphoma, hodgkin's lymphoma, and B-cell non-hodgkin's lymphoma.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1
Preparation of 4, 6-dichloro-5-pyrimidinecarbaldehyde (1)
DMF (5.50mL,71.34mmol) was slowly added dropwise to POCl in an ice bath3(17.00mL,185.71mmol), stirring for 1h, removing the ice bath, adding 4, 6-dihydroxypyrimidine (4.00g,35.68mmol), heating and refluxing for 3h, cooling to room temperature, pouring into ice water, extracting with dichloromethane, concentrating under reduced pressure, and recrystallizing with petroleum ether-ethyl acetate (P: E ═ 4:1(V: V)) to obtain a yellow solid (4.74 g, yield 75.4%, mp68-70 deg.C). ESI-MS:177[ M + H ]]+；1H NMR(300MHz,CDCl3)：δ(ppm):8.89(s,1H),10.43(s,1H)。
Preparation of 4, 6-dichloro-5-pyrimidinecarboxylic acid (2)
1(4.00g,22.72mmol) and NaH2PO4(9.55g,79.58mmol) was dissolved in a mixed solvent of 60mL of t-butanol and 10mL of water, and NaClO was added thereto under ice-cooling2(7.66g,84.69mmol), reacting for 1h, distilling off tert-butanol under reduced pressure, pouring into water, adjusting the pH to 5 with hydrochloric acid, extracting with ethyl acetate, and concentrating under reduced pressure to obtain yellow solid 3.12g, yield 71.5%, mp 131-. ESI-MS 190.9[ M-H ]]-；1HNMR(300MHz,DMSO-d6):δ(ppm):9.00(s,1H).
Preparation of (4, 6-dichloropyrimidin-5-yl) (4-phenoxyphenyl) methanone (3)
2(3.00g,15.63mmol) in 20mL of anhydrous THF, oxalyl chloride (4.00mL,46.87mmol) and 2 drops of DMF were added dropwise, reacted at room temperature for 4h, the solvent and the remaining oxalyl chloride, anhydrous CH, were evaporated under reduced pressure2Cl2Dissolving, transferring to a constant pressure dropping funnel, and dropwise adding to diphenyl ether (12.40mL,8.31mmol) and AlCl under ice bath3(3.12g,23.46mmol) of anhydrous CH2Cl2After the dripping is finished, reflux reaction is carried out for 3 hours, ice water is poured in, and concentrated hydrochloric acid is used for adjusting the pH value to 2, CH2Cl2Extracting, drying over anhydrous magnesium sulfate, and purifying by column chromatography [ petroleum ether: ethyl acetate (P: E) ═ 5:1(V: V) ]]3.82g of white solid is obtained, with a yield of 71.1% and mp 91-93 ℃. ESI-MS:345[ M + H ]]+；1HNMR(300MHz,CDCl3):δ(ppm):7.07(d,J＝8.97Hz,2H),7.13(d,J＝9.72Hz,2H),7.26(t,J＝6.27Hz,1H),7.44(t,J＝7.53Hz,2H),7.80(d,J＝9.72Hz,2H),8.91(s,1H).
Preparation of (4-amino-6-chloropyrimidin-5-yl) (4-phenoxyphenyl) methanone (4)
3(1.0g,2.91mmol) is added with 25mL ethanol and ammonia water (8mL,52.0mmol), reacted for 24h at room temperature, cooled in ice bath, filtered, dried to obtain white solid 0.51g, yield 53.9%, mp 264 and 266 ℃. ESI-MS:324[ M-H ]]-；1H NMR(300MHz,DMSO-d6):δ(ppm):7.07(d,J＝8.82Hz,2H),7.16(d,J＝7.68Hz,2H),7.28(t,J＝7.35Hz,1H),7.35(s,2H),7.49(t,J＝7.86Hz,2H),7.84(d,J＝8.79Hz,2H),8.32(s,1H).
Preparation of (S) -3- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] aminomethyl ] piperidine-1-carboxylic acid tert-butyl ester (5a)
4(0.30g,0.92mmol) was dissolved in 20mL of ethanol was added with (S) -1-Boc-3-aminomethylpiperidine (0.26g,1.20mmol) and DIPEA (0.18mL,1.01mmol), and the mixture was refluxed for 48 hours, dissolved in ethyl acetate, filtered with suction, and purified by column chromatography [ P: E ═ 1:1(V: V)]To obtain a pale yellow solid 0.24g with a yield of 51.8%. ESI-MS 504[ M + H ]]+.
Preparation of (S) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] piperidin-1-yl ] -2-propen-1-one (A-1)
Figure BDA0001278762370000081
5a (0.20g,0.40mmol) in 20mL CH2Cl2Adding concentrated hydrochloric acid (0.33mL,4.0mmol) under ice bath, reacting at room temperature for 12H, concentrating under reduced pressure, and dissolving in tetrahydrofuran-water (THF: H)2O ═ 5:1(V: V)) mixed system, NaHCO was added3(0.10g,1.20mmol), acryloyl chloride (0.04mL,0.46mmol) was added dropwise under ice-bath conditions, the reaction was allowed to proceed overnight at room temperature, THF was removed by distillation under reduced pressure, and the appropriate amount of water, CH, was added to the remaining reaction mixture2Cl2Extracting, drying with anhydrous magnesium sulfate, and purifying by column chromatography [ Ethyl Acetate (EA)]To obtain 0.04g of yellow solid with the yield of 17.6%. ESI-MS 458[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.01(s,1H),7.69(d,J＝8.2Hz,2H),7.44(t,J＝7.7Hz,2H),7.22(t,J＝7.4Hz,1H),7.10-6.99(m,4H),6.79-6.52(m,3H),6.02(d,J＝17.0Hz,1H),5.59(t,J＝13.1Hz,1H),4.20-3.69(m,3H),3.23(s,2H),3.08-2.95(m,1H),2.79(s,1H),1.61(s,3H),1.20(d,J＝31.9Hz,2H).
Example 2
Preparation of (R) -3- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] aminomethyl ] piperidine-1-carboxylic acid tert-butyl ester (5b)
Referring to the preparation of 5a, 4 and (R) -1-Boc-3-aminomethylpiperidine were reacted to give a pale yellow solid in 56.2% yield. ESI-MS 504[ M + H ]]+.
Preparation of (R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] piperidin-1-yl ] -2-propen-1-one (A-2)
Figure BDA0001278762370000091
Referring to the preparation of A-1, 5b was deprotected and reacted with acryloyl chloride to give a yellow solid in 17.2% yield. ESI-MS 458[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):7.97(s,1H),7.65(d,J＝8.2Hz,2H),7.39(d,J＝8.7Hz,2H),7.19(s,1H),7.09-6.94(m,4H),6.64(s,3H),5.99(d,J＝16.7Hz,1H),5.57(s,1H),4.20-3.62(m,3H),3.18(s,2H),2.98(s,1H),2.74(s,1H),1.57(s,3H),1.16(d,J＝24.2Hz,2H).
Example 3
Preparation of [ 4-amino-6- [ (piperidin-2-methyl) amino ] pyrimidin-5-yl ] (4-phenoxyphenyl) methanone (5c)
Referring to the preparation of 5a, 4 and 2-aminomethylpiperidine were reacted to give a pale yellow solid in a yield of 45.8%. ESI-MS:404[ M + H ]]+.
Preparation of 1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] piperidin-1-yl ] -2-propen-1-one (A-3)
Figure BDA0001278762370000092
5c (0.23g,0.57mmol) was dissolved in 18mL tetrahydrofuran-water (THF: H)2O ═ 5:1(V: V)) mixed system, NaHCO was added3(0.14g,1.71mmol), acryloyl chloride (0.06mL,0.68mmol) was added dropwise under ice-bath conditions, the reaction was allowed to proceed overnight at room temperature, THF was removed by distillation under reduced pressure, and the appropriate amount of water, CH, was added to the remaining reaction mixture2Cl2Extracting, drying with anhydrous magnesium sulfate, and purifying by column chromatography [ Ethyl Acetate (EA)]To obtain 0.04g of yellow solid with the yield of 16.0%. ESI-MS 458[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.04(s,1H),7.65(d,J＝8.3Hz,2H),7.45(t,J＝7.9Hz,2H),7.25(q,J＝8.6,7.4Hz,2H),7.11(d,J＝8.0Hz,2H),7.00(d,J＝8.4Hz,2H),6.65(dd,J＝16.4,10.6Hz,1H),6.50(s,2H),5.92(d,J＝16.3Hz,1H),5.46(d,J＝11.0Hz,1H),4.33(s,1H),3.62(s,2H),2.72(t,J＝13.1Hz,1H),1.64-1.47(m,5H),1.23(s,2H).
Example 4
Preparation of (R) -3- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (5d)
Referring to the preparation of 5a, 4 and (R) -1-Boc-3-aminopyrrolidine were reacted to give a pale yellow solid in 57.1% yield. ESI-MS 476[ M + H ]]+.
Preparation of (R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] pyrrolidin-1-yl ] -2-propen-1-one (A-4)
Figure BDA0001278762370000101
Referring to the preparation of A-1, 5d was deprotected and reacted with acryloyl chloride to give a yellow solid with a yield of 19.5%. ESI-MS of 430[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.06(s,1H),7.64(dd,J＝8.8,2.5Hz,2H),7.45(t,J＝7.8Hz,2H),7.27-7.19(m,1H),7.11(td,J＝7.3,1.3Hz,2H),6.99-6.79(m,5H),6.49(ddd,J＝16.8,10.3,3.6Hz,1H),6.11(dt,J＝16.8,2.5Hz,1H),5.63(ddd,J＝10.3,4.4,2.5Hz,1H),4.57(dq,J＝37.8,5.8Hz,1H),3.66(ddd,J＝67.6,11.7,6.4Hz,2H),3.21(dq,J＝9.5,5.9,5.4Hz,1H),2.15-1.91(m,1H),1.75(ddt,J＝33.0,12.9,6.0Hz,1H),1.31-1.12(m,1H).
Example 5
Preparation of (S) -3- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (5e)
Referring to the preparation of 5a, 4 and (S) -1-Boc-3-aminopyrrolidine were reacted to give a pale yellow solid with a yield of 52.8%. ESI-MS 476[ M + H ]]+.
Preparation of (S) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] pyrrolidin-1-yl ] -2-propen-1-one (A-5)
Figure BDA0001278762370000111
Referring to the preparation of A-1, 5e was deprotected from Boc and reacted with acryloyl chloride to give a yellow solid with a yield of 13.0%. ESI-MS of 430[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.59(s,1H),7.82-7.71(m,2H),7.41-7.27(m,2H),7.22-7.05(m,3H),7.05-6.93(m,2H),6.62(dd,J＝10.0,16.8Hz,1H),6.28(dd,J＝10.1,13.8Hz,1H),5.67(dd,J＝13.8,16.7Hz,1H),4.09(s,2H),3.88(dd,J＝6.9,9.4Hz,1H),3.62-3.37(m,3H),3.30(p,J＝6.9Hz,1H),2.24-2.06(m,1H),1.92-1.74(m,1H),0.93(s,1H).
Example 6
Preparation of (S) -2- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] aminomethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester (5f)
Referring to the preparation of 5a, 4 and (S) -1-Boc-2-aminomethylpyrrolidine were reacted to give a pale yellow solid with a yield of 47.9%. ESI-MS 490[ M + H ]]+.
Preparation of (S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-propen-1-one (A-6)
Figure BDA0001278762370000112
Referring to the preparation of A-1, 5f was deprotected from Boc and reacted with acryloyl chloride to give a yellow solid with 18.6% yield. ESI-MS 444[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.08(s,1H),7.69(dd,J＝8.7,11.5Hz,3H),7.49-7.42(m,3H),7.24(dd,J＝1.5,7.5Hz,2H),7.09(dq,J＝1.1,7.5Hz,3H),7.05-6.99(m,3H),6.66-6.47(m,3H),6.11(ddd,J＝2.6,16.7,19.1Hz,1H),5.65(dt,J＝3.1,10.2Hz,1H),4.15(s,1H),1.76(d,J＝13.6Hz,2H),1.69(s,2H).
Example 7
Preparation of (R) -tert-butyl 2- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] aminomethyl ] pyrrolidine-1-carboxylate (5g)
Referring to the preparation of 5a, 4 and (R) -1-Boc-2-aminomethylpyrrolidine were reacted to give a pale yellow solid with a yield of 56.1%. ESI-MS 490[ M + H ]]+.
Preparation of (R) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-propen-1-one (A-7)
Figure BDA0001278762370000121
Referring to the preparation of A-1, 5g of a yellow solid was prepared in 18.9% yield by removing the Boc protecting group and reacting with acryloyl chloride. ESI-MS 444[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.08(s,1H),7.69(dd,J＝8.5,11.3Hz,3H),7.48-7.42(m,3H),7.24(d,J＝6.8Hz,2H),7.12-7.08(m,3H),7.02(dd,J＝5.3,8.6Hz,3H),6.64-6.47(m,3H),6.18-6.04(m,1H),5.67-5.62(m,1H),4.16(s,1H),1.77(d,J＝14.2Hz,2H),1.70(s,2H).
Example 8
Preparation of 3- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] aminomethyl ] azetidine-1-carboxylic acid tert-butyl ester (5h)
Referring to the preparation of 5a, 4 and 1-Boc-3-aminomethylazetidine reacted to give a pale yellow solid with 59.7% yield. ESI-MS 476[ M + H ]]+.
Preparation of 1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] azetidin-1-yl ] -2-propen-1-one (A-8)
Figure BDA0001278762370000122
Referring to the preparation of A-1, a yellow solid was prepared in 16.9% yield by 5h removal of Boc protecting group and reaction with acryloyl chloride. ESI-MS of 430[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.41(s,1H),7.84-7.73(m,2H),7.41-7.27(m,2H),7.22-7.05(m,3H),7.05-6.93(m,2H),6.62(dd,J＝10.0,16.8Hz,1H),6.27(dd,J＝10.1,13.8Hz,1H),5.69(dd,J＝13.8,16.8Hz,1H),5.07(s,1H),4.53(s,2H),3.99(dd,J＝7.0,11.2Hz,2H),3.61(dd,J＝7.0,11.2Hz,2H),3.24(d,J＝7.0Hz,2H),2.88(hept,J＝6.9Hz,1H).
Example 9
Preparation of (R) -3- [ [ 6-amino-5- (4-phenoxybenzoyl) pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (5i)
Referring to the preparation of 5a, 4 and (R) -1-Boc-3-aminopiperidine were reacted to give a pale yellow solid in 67.5% yield, mp68-70 ℃. ESI-MS 512[ M + Na ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):1.16(t,J＝6.96Hz,2H),1.22～1.24(m,2H),1.32(s,9H),1.49～1.51(m,1H),1.70～1.72(m,1H),2.24～2.26(m,1H),4.00～4.02(m,1H),6.76(s,2H),7.01(d,J＝8.70Hz,2H),7.16(d,J＝7.68Hz,3H),7.22(t,J＝7.41Hz,1H),7.44(t,J＝8.19Hz,2H),7.65(d,J＝8.64Hz,2H),8.02(s,1H).
Preparation of (R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] piperidin-1-yl ] -2-chloroethan-1-one (A-9)
Figure BDA0001278762370000131
Referring to the preparation of A-1, 5i was deprotected from Boc and reacted with chloroacetyl chloride to give a yellow solid with a yield of 19.7%. ESI-MS 466[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.58(s,1H),7.82-7.72(m,2H),7.41-7.27(m,2H),7.18-7.04(m,3H),7.05-6.93(m,2H),4.51(d,J＝12.3Hz,1H),4.43-4.23(m,2H),4.05(s,2H),3.86(dd,J＝6.8,12.3Hz,1H),3.34-3.08(m,2H),2.89(dt,J＝7.0,12.5Hz,1H),2.13-1.95(m,1H),1.80-1.47(m,3H),1.07(s,1H).
Example 10
Preparation of (S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-chloroethan-1-one (A-10)
Figure BDA0001278762370000141
Referring to the preparation of A-1, 5f was deprotected from Boc and reacted with chloroacetyl chloride to give a yellow solid with 20.2% yield. ESI-MS 466[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.54(s,1H),7.82-7.71(m,2H),7.41-7.27(m,2H),7.19-7.05(m,3H),7.05-6.93(m,2H),5.07(s,1H),4.74(d,J＝12.4Hz,1H),4.17(d,J＝12.4Hz,1H),4.16-3.97(m,1H),3.93(s,2H),3.90-3.66(m,3H),3.35(dt,J＝6.8,9.4Hz,1H),2.20-1.85(m,3H),1.90-1.69(m,1H).
Example 11
Preparation of [ 4-amino-6- [ (2-aminoethyl) amino ] pyrimidin-5-yl ] (4-phenoxyphenyl) methanone (5j)
Referring to the preparation of 5a, 4 was reacted with ethylenediamine to give a pale yellow solid with a yield of 49.7%. ESI-MS 350[ M + H ]]+N- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl]Amino group]Ethyl radical]Preparation of acrylamide (A-11)
Figure BDA0001278762370000142
Referring to the preparation method of A-3, a yellow solid was obtained in a yield of 18.2% by reacting 5j with acryloyl chloride. ESI-MS:404[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.57(s,1H),7.74-7.63(m,2H),7.41-7.27(m,2H),7.12(ddt,J＝2.1,6.3,8.3Hz,3H),7.05-6.93(m,2H),6.62(s,1H),6.48(dd,J＝10.1,16.7Hz,1H),6.07(dd,J＝10.1,13.8Hz,1H),5.79(dd,J＝13.8,16.6Hz,1H),5.07(s,1H),3.96-3.82(m,4H),3.51(t,J＝4.9Hz,2H).
Example 12
Preparation of (S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] propan-1-one (A-12)
Figure BDA0001278762370000151
Referring to the preparation of A-1, 5f was deprotected from Boc and reacted with propionyl chloride to give a yellow solid with a yield of 19.8%. ESI-MS 446[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.01(d,J＝8.8Hz,1H),7.69(dd,J＝8.7,10.2Hz,2H),7.50-7.41(m,2H),7.23(t,J＝7.6Hz,1H),7.17-7.08(m,2H),7.02(dd,J＝4.3,8.7Hz,2H),6.66(s,1H),6.59(s,1H),4.01(d,J＝8.7Hz,1H),3.45(dq,J＝6.0,7.0,12.7Hz,4H),2.43(dd,J＝5.3,7.5Hz,1H),2.23-2.13(m,1H),1.77(s,1H),1.66(s,1H),1.25-1.15(m,2H),1.02-0.88(m,4H).
Example 13
Preparation of (4, 6-dichloropyrimidin-5-yl) -N-phenylcarboxamide (6a)
2(2.0g,10.36mmol) in 20mL dry THF, oxalyl chloride (2.65mL,31.09mmol) and 2 drops DMF were added dropwise, reacted at room temperature for 4h, the solvent and remaining oxalyl chloride, dry CH, were evaporated under reduced pressure2Cl2Dissolve, move to a constant pressure dropping funnel, and add aniline (1.04mL,11.39mmol) and triethylamine (3.14g,31.07mmol) in anhydrous CH dropwise under ice bath2Cl2After the dripping is finished, the reaction solution is poured into a proper amount of water and CH after the reaction solution reacts at room temperature overnight2Cl2Extracting, drying with anhydrous magnesium sulfate, concentrating under reduced pressure, filtering, and adding small amount of CH2Cl2Washing, and drying the filter cake to obtain 1.47g of white solid with the yield of 52.9%. ESI-MS 268[ M + H ]]+Preparation of (4-amino-6-chloropyrimidin-5-yl) -N-phenylcarboxamide (7a)
6a (1.0g,3.72mmol), 25mL of ethyl acetate and ammonia (10mL,67.1mmol) are added, the mixture is reacted for 24h at room temperature, cooled in an ice bath, filtered by suction, and dried to obtain 0.74g of white solid with yield of 79.8%. ESI-MS:249[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- (phenylcarbamoyl) pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8a)
Referring to the preparation of 5a, 7a was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid in 57.9% yield. ESI-MS:413[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-1)
Figure BDA0001278762370000152
Referring to the preparation method of A-1, after removing Boc protecting group from 8a, it was reacted with acryloyl chloride to obtain a yellow solid with a yield of 18.9%. ESI-MS 367[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):9.93(s,1H),7.98(s,1H),7.70–7.62(m,2H),7.31(t,J＝7.8Hz,2H),7.06(t,J＝7.4Hz,1H),6.62(s,3H),6.05(dd,J＝2.4,16.8Hz,1H),5.62(dd,J＝2.4,10.4Hz,1H),4.31–3.75(m,2H),3.15(s,3H),1.91(s,1H),1.75-1.37(m,3H),1.24(s,1H).
Example 14
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (4-bromophenyl) carboxamide (6b)
Referring to the preparation of 6a, 2 and 4-bromoaniline reacted to give a white solid in 53.8% yield. ESI-MS 346[ M + H ]]+(4-amino-Preparation of 6-chloropyrimidin-5-yl) -N- (4-bromophenyl) carboxamide (7b)
Referring to the preparation of 7a, 6b reacted to give a white solid in 80.1% yield. ESI-MS:327[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (4-bromophenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8b)
Referring to the preparation of 5a, 7b was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid in 53.3% yield. ESI-MS 491[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-bromophenyl) carboxamide (B-2)
Figure BDA0001278762370000161
Referring to the preparation method of A-1, 8b was deprotected from Boc-protecting group and reacted with acryloyl chloride to give a yellow solid with a yield of 17.5%. ESI-MS 445[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.50(s,1H),8.07(s,1H),7.72-7.61(m,2H),7.55-7.45(m,2H),6.62(dd,J＝10.1,16.8Hz,1H),6.17(dd,J＝10.1,13.8Hz,1H),5.66(dd,J＝13.8,16.8Hz,1H),4.50(s,2H),4.28(dt,J＝7.0,12.5Hz,1H),3.69(dd,J＝6.9,12.4Hz,1H),3.32(dd,J＝7.0,12.4Hz,1H),3.16(p,J＝6.9Hz,1H),2.94(dt,J＝7.0,12.5Hz,1H),2.15-1.96(m,1H),1.81-1.46(m,3H),1.23(s,1H).
Example 15
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (4-isopropylphenyl) carboxamide (6c)
Referring to the preparation of 6a, white solid was obtained in 62.3% yield from 2 and 4-isopropylaniline. ESI-MS 310[ M + H ]]+.
Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (4-isopropylphenyl) carboxamide (7c)
Referring to the preparation of 7a, the reaction from 6c gave a white solid in 83.1% yield. ESI-MS:291[ M + H ]]+.
Preparation of tert-butyl (R) -3- [ [ 6-amino-5- [ (4-isopropylphenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylate (8c)
Referring to the preparation of 5a, 7c was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid with a yield of 66.5%. ESI-MS:455[ M + H]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-isopropylphenyl) carboxamide (B-3)
Figure BDA0001278762370000171
Referring to the preparation method of A-1, 8c was deprotected from Boc-protecting group and reacted with acryloyl chloride to give a yellow solid with a yield of 19.2%. ESI-MS 409[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):9.88(d,J＝14.8Hz,1H),7.97(s,1H),7.56(d,J＝8.5Hz,2H),7.17(d,J＝8.5Hz,2H),6.96(d,J＝30.9Hz,1H),6.80-6.53(m,3H),6.04(dd,J＝2.4,16.8Hz,1H),5.62(dd,J＝2.5,10.5Hz,1H),3.91(d,J＝37.9Hz,3H),3.14(dt,J＝8.1,19.1Hz,2H),2.89-2.80(m,1H),1.91(s,1H),1.59(dd,J＝10.3,18.0Hz,2H),1.50-1.40(m,1H),1.18(d,J＝6.9Hz,6H).
Example 16
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (3-methoxy-4-methylphenyl) carboxamide (6d)
Referring to the preparation of 6a, 2 and 3-methoxy-4-methylaniline reacted to give a white solid in 49.9% yield. ESI-MS 312[ M + H ]]+.
Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (3-methoxy-4-methylphenyl) carboxamide (7d)
Referring to the preparation of 7a, the reaction from 6d gave a white solid with a yield of 81.8%. ESI-MS 293[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (3-methoxy-4-methylphenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8d)
Referring to the preparation of 5a, 7d was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid in 53.9% yield. ESI-MS 457[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3-methoxy-4-methylphenyl) carboxamide (B-4)
Figure BDA0001278762370000181
Referring to the preparation method of A-1, 8d was subjected to removal of Boc protecting group and then reacted with acryloyl chloride to obtain a yellow solid with a yield of 20.1%. ESI-MS:411[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.11(s,1H),8.01(s,1H),7.50(d,J＝9.4Hz,1H),7.41(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),6.55(dd,J＝10.6,17.0Hz,1H),6.16(dd,J＝16.7,43.1Hz,1H),5.60(d,J＝10.2Hz,1H),5.45(d,J＝12.7Hz,2H),4.00(d,J＝14.0Hz,1H),3.30-3.13(m,2H),2.88(p,J＝6.9Hz,1H),2.02(s,1H),1.61(dq,J＝7.3,8.1,16.6Hz,3H),1.23(s,3H),1.21(s,3H).
Example 17
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (3, 4-dimethoxyphenyl) carboxamide (6e)
Referring to the preparation of 6a, 2 and 3, 4-dimethoxyaniline reacted to give a white solid in 57.4% yield. ESI-MS:328[ M + H ]]+.
Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (3, 4-dimethoxyphenyl) carboxamide (7e)
Referring to the preparation of 7a, a white solid was obtained from 6e in 81.0% yield. ESI-MS 309[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (3, 4-dimethoxyphenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8e)
Referring to the preparation of 5a, 7e was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid in 64.2% yield. ESI-MS 473[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3, 4-dimethoxyphenyl) carboxamide (B-5)
Figure BDA0001278762370000182
Referring to the preparation method of A-1, 8e was subjected to removal of Boc protecting group and then reacted with acryloyl chloride to obtain a yellow solid with a yield of 17.9%. ESI-MS 427[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):9.80(d,J＝18.6Hz,1H),7.98(s,1H),7.40(s,1H),7.18-7.13(m,1H),7.04-6.87(m,2H),6.58(s,3H),6.05(dd,J＝2.5,16.7Hz,1H),5.63(d,J＝10.3Hz,1H),3.90(d,J＝43.9Hz,3H),3.73(d,J＝2.0Hz,6H),3.18(d,J＝36.3Hz,1H),1.95(d,J＝23.7Hz,1H),1.66(s,2H),1.46(s,1H),1.21(d,J＝18.8Hz,1H).
Example 18
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (3, 5-dimethoxyphenyl) carboxamide (6f)
Referring to the preparation of 6a, 2 and 3, 5-dimethoxyaniline reacted to give a white solid in 63.0% yield. ESI-MS:328[ M + H ]]+.
Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (3, 5-dimethoxyphenyl) carboxamide (7f)
Referring to the preparation of 7a, the reaction from 6f gave a white solid in 78.4% yield. ESI-MS 309[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (3, 5-dimethoxyphenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8f)
Referring to the preparation of 5a, 7f was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid in 52.3% yield. ESI-MS 473[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3, 5-dimethoxyphenyl) carboxamide (B-6)
Figure BDA0001278762370000191
Referring to the preparation method of A-1, 8f was deprotected from Boc-protecting group and reacted with acryloyl chloride to give a yellow solid with a yield of 19.3%. ESI-MS 427[ M + H ]]+；1H NMR(300MHz,Chloroform-d):δ(ppm):8.43(s,1H),8.22(s,1H),6.82(d,J＝2.0Hz,2H),6.62(dd,J＝10.0,16.7Hz,1H),6.19(dd,J＝10.0,13.8Hz,1H),6.02(t,J＝2.0Hz,1H),5.67(dd,J＝13.8,16.7Hz,1H),4.84(s,2H),4.39(dt,J＝7.0,12.6Hz,1H),3.80(s,6H),3.75(dd,J＝7.0,12.5Hz,1H),3.45(dd,J＝7.0,12.5Hz,1H),3.16(p,J＝6.9Hz,1H),2.90(dt,J＝7.0,12.5Hz,1H),2.15-1.97(m,1H),1.81-1.46(m,3H),1.26(s,1H).
Example 19
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (2-fluorophenyl) carboxamide (6g)
Referring to the preparation method of 6a, 2 and 2-fluoroaniline were reacted to obtain a white solid with a yield of 68.6%. ESI-MS 286M + H]+Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (2-fluorophenyl) carboxamide (7g)
Referring to the preparation of 7a, a white solid was obtained from 6g of the reaction in 82.3% yield. ESI-MS 267[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (2-fluorophenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8g)
Referring to the preparation of 5a, 7g was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid with a yield of 52.2%. ESI-MS 431[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (2-fluorophenyl) carboxamide (B-7)
Figure BDA0001278762370000201
Referring to the preparation method of A-1, 8g of a yellow solid was obtained in 16.9% yield by removing the Boc protecting group and reacting with acryloyl chloride. ESI-MS:385[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):9.69(s,1H),7.95(d,J＝23.4Hz,3H),7.69(s,1H),7.18(s,3H),6.73(s,2H),6.03(d,J＝16.5Hz,1H),5.62(s,1H),4.25-4.16(m,1H),3.98(s,1H),3.79(s,1H),1.91(s,1H),1.62(s,2H),1.43(s,1H),1.21(s,1H),0.93-0.85(m,1H).
Example 20
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (3-fluorophenyl) carboxamide (6h)
Referring to the preparation method of 6a, 2 and 3-fluoroaniline were reacted to give a white solid in 66.4% yield. ESI-MS 286M + H]+Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (3-fluorophenyl) carboxamide (7h)
Referring to the preparation method of 7a, a white solid was obtained in 80.2% yield from 6h reaction. ESI-MS 267[ M ]+H]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (3-fluorophenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8h)
Referring to the preparation of 5a, 7h was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid with a yield of 50.7%. ESI-MS 431[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3-fluorophenyl) carboxamide (B-8)
Figure BDA0001278762370000202
Referring to the preparation method of A-1, after removing Boc protecting group for 8h, it was reacted with acryloyl chloride to obtain a yellow solid with a yield of 18.4%. ESI-MS:385[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):7.97(s,1H),7.65(dd,J＝4.8,9.4Hz,3H),7.14(t,J＝8.7Hz,2H),6.62(d,J＝15.9Hz,2H),6.03(d,J＝16.6Hz,1H),5.61(d,J＝10.4Hz,1H),4.21(t,J＝6.6Hz,1H),3.89(d,J＝42.3Hz,3H),1.90(s,1H),1.67-1.58(m,2H),1.37(dt,J＝8.6,14.7Hz,2H),1.19(d,J＝21.8Hz,1H),0.90(t,J＝7.5Hz,1H).
Example 21
Preparation of (4, 6-dichloropyrimidin-5-yl) -N- (4-fluorophenyl) carboxamide (6i)
Referring to the preparation method of 6a, 2 and 4-fluoroaniline were reacted to give a white solid in 67.5% yield. ESI-MS 286M + H]+Preparation of (4-amino-6-chloropyrimidin-5-yl) -N- (4-fluorophenyl) carboxamide (7i)
Referring to the preparation of 7a, a white solid was obtained from 6i with a yield of 79.6%. ESI-MS 267[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- [ (4-fluorophenyl) carbamoyl ] pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8i)
Referring to the preparation of 5a, 7i was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid with a yield of 60.4%. ESI-MS 431[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-fluorophenyl) carboxamide (B-9)
Figure BDA0001278762370000211
Referring to the preparation method of A-1, 8i was deprotected from Boc-protecting group and reacted with acryloyl chloride to give a yellow solid with a yield of 19.0%. ESI-MS:385[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):1H NMR(300MHz,DMSO-d6)δ7.98(s,1H),7.75-7.57(m,2H),7.40-7.26(m,2H),6.87(t,J＝8.3Hz,1H),6.65(d,J＝17.0Hz,2H),6.04(dd,J＝2.4,16.7Hz,1H),5.62(d,J＝10.3Hz,1H),4.21(t,J＝6.5Hz,1H),4.06-3.75(m,3H),1.90(s,1H),1.64(q,J＝7.1,7.6Hz,2H),1.41-1.32(m,1H),1.15(d,J＝7.1Hz,2H),0.90(t,J＝7.4Hz,1H).
Example 22
Preparation of (4, 6-dichloropyrimidin-5-yl) -N-benzylcarboxamide (6j)
Referring to the preparation of 6a, a white solid was obtained in 54.4% yield from the reaction of 2 with benzylamine. ESI-MS 282[ M + H ]]+Preparation of (4-amino-6-chloropyrimidin-5-yl) -N-benzylcarboxamide (7j)
Referring to the preparation of 7a, a white solid was obtained from 6j with a yield of 80.9%. ESI-MS:263[ M + H ]]+.
Preparation of (R) -3- [ [ 6-amino-5- (benzylcarbamoyl) pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester (8j)
Referring to the preparation of 5a, 7j was reacted with (R) -1-Boc-3-aminopiperidine to give a pale yellow solid in 55.6% yield. ESI-MS 427[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-benzylcarboxamide (B-10)
Figure BDA0001278762370000221
Referring to the preparation method of A-1, 8j was deprotected and reacted with acryloyl chloride to give a yellow solid with a yield of 17.7%. ESI-MS 381[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.51(s,1H),7.95(s,1H),7.70(d,J＝8.6Hz,1H),7.32(d,J＝4.7Hz,4H),7.25(s,1H),7.08-6.57(m,2H),6.48(s,1H),6.06(d,J＝16.7Hz,1H),5.63(s,1H),4.41-4.38(m,1H),4.23(t,J＝6.5Hz,1H),3.94(s,1H),3.75(d,J＝12.9Hz,1H),3.24(d,J＝10.6Hz,1H),1.89(s,1H),1.65(t,J＝7.4Hz,2H),1.43-1.34(m,1H),1.21(d,J＝21.3Hz,1H),0.92(t,J＝7.4Hz,1H)
Example 23
Preparation of (R) -3- [ [ 6-amino-5- (phenylcarbamoyl) pyrimidin-4-yl ] amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (8k)
Referring to the preparation of 5a, 7a was reacted with (R) -1-Boc-3-aminopyrrolidine to give a pale yellow solid with 59.8% yield. ESI-MS of 399[ M + H ]]+.
Preparation of (R) - [4- [ (1-acryloylpyrrolidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-11)
Figure BDA0001278762370000222
Referring to the preparation method of A-1, 8k was subjected to removal of Boc protecting group and then reacted with acryloyl chloride to obtain a yellow solid with a yield of 18.6%. ESI-MS:353[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):10.00(s,1H),8.00(s,1H),7.69-7.64(m,2H),7.30(t,J＝7.8Hz,2H),7.07(d,J＝7.8Hz,1H),6.64(s,2H),6.60-6.47(m,1H),6.12(dt,J＝2.7,16.9Hz,1H),4.69-4.51(m,1H),4.23(t,J＝6.5Hz,1H),3.68(td,J＝6.4,13.7,15.0Hz,1H),2.14(dq,J＝6.7,18.7Hz,1H),1.68-1.62(m,1H),1.44-1.33(m,2H),0.91(d,J＝7.4Hz,2H).
Example 24
Preparation of (S) -2- [ [ 6-amino-5- (phenylcarbamoyl) pyrimidin-4-yl ] aminomethyl ] pyrrolidine-1-carboxylic acid tert-butyl ester (8l)
Referring to the preparation of 5a, 7a was reacted with (S) -1-Boc-2-aminomethylpyrrolidine to obtain a pale yellow solid with a yield of 54.1%. ESI-MS:413[ M + H ]]+.
Preparation of (S) - [4- [ [ (1-acryloylpyrrolidin-2-yl) methyl ] amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-12)
Figure BDA0001278762370000231
Referring to the preparation method of A-1, 8l of the product was subjected to removal of Boc protecting group and then reacted with acryloyl chloride to obtain a yellow solid with a yield of 19.4%. ESI-MS 367[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.04(d,J＝6.1Hz,1H),7.70(d,J＝7.7Hz,2H),7.32(t,J＝7.9Hz,3H),7.20(t,J＝5.6Hz,1H),7.07(t,J＝7.4Hz,1H),6.53(d,J＝5.3Hz,2H),6.20-5.99(m,1H),5.71-5.59(m,1H),4.23(t,J＝6.5Hz,2H),1.83(s,2H),1.68-1.61(m,1H),1.38(q,J＝6.5,7.4Hz,1H),1.21(d,J＝20.9Hz,2H),0.92(t,J＝7.4Hz,2H).
Example 25
Preparation of (R) - [4- [ (1-propionylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide (B-13)
Figure BDA0001278762370000232
Referring to the preparation of A-1, a yellow solid was prepared in 21.1% yield by removing the Boc protecting group from 8a and reacting with propionyl chloride. ESI-MS 369[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):9.99(d,J＝3.7Hz,1H),7.98(d,J＝9.1Hz,1H),7.66(d,J＝8.0Hz,2H),7.31(t,J＝7.8Hz,2H),7.05(d,J＝7.1Hz,1H),6.63(d,J＝19.9Hz,2H),4.26-3.54(m,4H),2.86(dt,J＝11.3,48.2Hz,1H),2.35-2.24(m,2H),1.90(d,J＝11.2Hz,1H),1.68-1.55(m,2H),1.42-1.33(m,1H),1.18(t,J＝7.1Hz,1H),1.00-0.94(m,3H).
Example 26
Preparation of (R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] piperidin-1-yl ] -2-propen-1-one (b)
Figure BDA0001278762370000233
Referring to the preparation of A-1, 5i was deprotected from Boc and reacted with acryloyl chloride to give a yellow solid with a yield of 23.7%. ESI-MS 444[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ(ppm):8.04(s,1H),7.64(d,J＝6.21Hz,2H),7.45(t,J＝6.48Hz,2H),7.22(t,J＝7.08Hz,1H),7.09(d,J＝6.75Hz,2H),7.00(d,J＝8.34Hz,2H),6.76(s,2H),6.55(dd,J＝6.96,15.38Hz,1H),6.03(d,J＝16.32Hz,1H),5.62(d,J＝9.23Hz,1H),4.14-4.15(m,2H),3.74-3.76(m,1H),3.67-3.69(m,1H),1.77-1.79(m,1H),1.43-1.46(m,3H),1.23-1.25(m,2H).
Example 27
Assay for BTK kinase Activity
Using radioactive isotopes P33Detection of the Compound of the present invention and (R) -1- [3- [ [5- (4-Phenoxybenzoyl) -6-aminopyrimidin-4-yl ] by ATP-labeling]Amino group]Piperidin-1-yl radical]-inhibitory activity of 2-propen-1-one (compound b) on BTK kinase. The radioactive isotope detection method has high sensitivity and accurate test result, and is considered as a 'gold standard' for detecting the biochemical activity of the protein kinase.
In particular by the HotSpot method, by Reaction Biology Corp (Malverm PA). 8nM recombinant human BTK kinase (Invitrogen, Cat # PV3363) and 0.2mg/mL substrate pEY in buffer (20mM hepespH7.5,10mM MgCl)2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO42mM DTT, 1% DMSO) was mixed at room temperature, then the compound was dissolved in the indicated dose of 100% DMSO (3-fold dilution from 10 μ M) and purified by Acoustic technique (Echo 550; nanoliter range) was delivered to the mixture of kinase reactions followed by 20min at room temperature. Followed by addition of 10. mu.M33P-ATP (specific activity 10. mu. Ci/. mu.L), reaction start, reaction was monitored for 120 min. Kinase Activity determined by the Filter-binding method, IC50Values and curve fits were achieved by prism (graphpad software). The results of the experiment are shown in table 1.
TABLE 1 inhibitory Activity of the Compounds of the present invention on BTK
Figure BDA0001278762370000241
Figure BDA0001278762370000251
Figure BDA0001278762370000261
Figure BDA0001278762370000271
Figure BDA0001278762370000281
The experimental result shows that part of the compounds have obvious inhibition effect on the activity of BTK kinase. Wherein, the inhibitory activity of the compounds A-1, A-2, A-8, A-9, A-10, B-2 and B-9 on BTK is equivalent to that of the compound B, while the activity of the compounds A-4, A-6, B-1, B-7, B-8 and B-11 is better than that of the compound B, especially the activity of the compounds A-6 and B-1 is more obviously stronger than that of the compound B. In addition, different stereoisomers of the compounds of the present invention show different activities from each other. For example, compounds A-1 and A-2 are in S configuration and R configuration, respectively, the former (S configuration) has slightly stronger inhibitory activity against BTK than the latter (R configuration); for compounds A-4(R configuration) and A-5(S configuration), the activity of the R configuration is 235 times stronger than that of the S configuration; whereas for compounds A-6(S configuration) and A-7(R configuration), the S configuration is 1800 times more active than the R configuration. In addition, the activity of compound B-1 was 150 times stronger than that of compound B, whereas the activity of compound B-12 was unexpectedly decreased 2600 times lower than that of compound A-6.

Claims (6)

1. A 4-aminopyrimidine compound or a pharmaceutically acceptable salt thereof, wherein the compound is preferably selected from:
(R) -1- [3- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] amino ] pyrrolidin-1-yl ] -2-propen-1-one;
(S) -1- [2- [ [5- (4-phenoxybenzoyl) -6-aminopyrimidin-4-yl ] aminomethyl ] pyrrolidin-1-yl ] -2-propen-1-one;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-bromophenyl) carboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-isopropylphenyl) carboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3-methoxy-4-methylphenyl) carboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (2-fluorophenyl) carboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (3-fluorophenyl) carboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N- (4-fluorophenyl) carboxamide;
(R) - [4- [ (1-acryloylpiperidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-benzylcarboxamide;
(R) - [4- [ (1-acryloylpyrrolidin-3-yl) amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide;
(S) - [4- [ [ (1-acryloylpyrrolidin-2-yl) methyl ] amino ] -6-aminopyrimidin-5-yl ] -N-phenylcarboxamide.
2. A pharmaceutical composition, which consists of a therapeutically effective amount of an active ingredient and pharmaceutically acceptable excipients; the active ingredient comprises a 4-aminopyrimidine compound according to claim 1 or a pharmaceutically acceptable salt thereof; the pharmaceutically acceptable auxiliary materials comprise pharmaceutically acceptable carriers, diluents and/or excipients.
3. Use of a compound according to any one of claims 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of bruton's tyrosine kinase.
4. The use of a compound according to any one of claims 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of thromboembolism, an inflammatory disorder, an autoimmune disease, B-cell lymphoma, or fahrenheit macroglobulinemia, as a bruton's tyrosine kinase inhibitor.
5. The use according to claim 4, wherein the inflammatory or autoimmune disease is a heteroimmune disease, asthma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, idiopathic thrombocytopenic purpura, autoimmune-mediated hemolytic anemia, immune complex-mediated vasculitis, or psoriasis.
6. The use of claim 4, wherein the B-cell lymphoma is chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, multiple myeloma, mucosa-associated lymphoid tissue lymphoma, Hodgkin's lymphoma, or B-cell non-Hodgkin's lymphoma.
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