CN113527298A - Macrocyclic lactam derivative, preparation method and application thereof - Google Patents

Macrocyclic lactam derivative, preparation method and application thereof Download PDF

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CN113527298A
CN113527298A CN202010302699.2A CN202010302699A CN113527298A CN 113527298 A CN113527298 A CN 113527298A CN 202010302699 A CN202010302699 A CN 202010302699A CN 113527298 A CN113527298 A CN 113527298A
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cycloalkyl
heterocyclyl
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heteroaryl
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陈友喜
龚亮
朱行武
向清
毛文涛
赵雯雯
叶成
胡泰山
陈磊
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Shanghai Aryl Pharmtech Co Ltd
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    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract

The invention relates to the interior of large ringsAmide derivatives, preparation method and medical application thereof. Specifically, the invention relates to a macrocyclic lactam derivative shown in a general formula (I), a preparation method thereof, a pharmaceutically acceptable salt thereof, and application thereof as a therapeutic agent, in particular to an ALK, TRK and ROS1 family protein tyrosine kinase inhibitor, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Macrocyclic lactam derivative, preparation method and application thereof
Technical Field
The invention relates to a novel macrocyclic lactam derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular as a TRK inhibitor.
Background
Protein Kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins, and play a very important role in signal transduction, where tyrosine phosphorylation mechanisms are ubiquitous in signal transduction and regulate a variety of cellular functions such as mitosis, cell cycle progression, and differentiation. Normal cells can be transformed into a tumor phenotype when protein tyrosine kinases are expressed under variant, uncontrolled conditions, or at abnormally high levels. In addition, abnormal PK activity is associated with host disease, ranging from relatively non-life threatening diseases such as psoriasis to extremely fatal diseases such as glioblastoma (brain cancer). PKs can be conveniently broken down into two classes, Protein Tyrosine Kinases (PTKs) and Serine Threonine Kinases (STKs).
Tropomyosin-related receptor tyrosine kinases (TRKs) are high affinity receptors for Neurotrophins (NTs), the neurotrophic factor (NGF) family of proteins. The neurotrophic factor receptor tyrosine kinase genes NTRK1, NTRK2 and NTRK3 encode the TRKA, TRKB and TRKC proteins, respectively, which are tyrosine kinases collectively referred to as TRK family proteins. All TRK proteins have similar extracellular domain structures, but each has a different ligand: NGF binds to TRKA, brain-derived neurotrophic factor (BDNF) and neurotrophic factor 4(NT-4) bind to TRKB, and neurotrophic factor 3(NT-3) binds to TRKC.
Gene expression studies have shown that members of the TRK family are widely expressed in neuronal tissues and are involved in the maintenance, signaling, and survival of neuronal cells. The NTRK gene is expressed primarily in the nervous system, and it is expressed both during embryonic development and in adults. When activated by signal induction, TRK may autophosphorylate and activate downstream signaling pathways to perform various physiological functions. Downstream signaling molecules of TRK include SHC, FRS2, PLC gamma, MAPK, PI3K, PKC and the like, and most of the signaling molecules are closely related to functions of cell energy exchange, survival, proliferation and the like. If TRK is dysfunctional, the physiological function of the cell may be out of control, even become a cancer cell. Overexpression, activation, amplification, mutation of TRK proteins, TRK gene fusion, which refers to fusion of NTRK gene family members (NTRK1, NTRK2, NTRK3) with another unrelated gene due to chromosomal variation, and the like, are associated with many cancers. The TRK fusion protein is in a continuous active state, and a permanent signal cascade reaction is initiated to drive the diffusion and growth of the TRK fusion tumor. Wherein the cancer comprises neuroblastoma, ovarian cancer, breast cancer, prostate cancer, stomach cancer, tumor of digestive tract, liver cancer, cholangiocarcinoma, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, colorectal cancer, mammary gland analog secretory carcinoma (MASC), sarcoma, head and neck tumor, renal cancer and the like.
TRK inhibitors are effective in preclinical models of pain, particularly in antagonizing NGF and TRKA antibodies (RN-624) in inflammatory and neuropathic pain animal models and human clinical trials; additionally BDNF/TRKB pathway activation can be used as a modulator of a variety of types of pain, including inflammatory pain, neuropathic pain, and surgical pain. Because TRKA and RKB kinases may serve as mediators of NGF-driven biological responses, TRKA and/or other TRK kinase inhibitors may provide an effective therapeutic modality as chronic pain. TRK inhibitors are effective in treating inflammatory pain, including but not limited to, asthma, interstitial cystitis, inflammatory bowel disease including ulcerative colitis and crohn's disease, eczema, psoriasis, and the like; the TRKA receptor is important for the disease process of Trypanosoma cruzi in parasitic infections in human hosts, and therefore TRKA inhibitors can be used for the treatment of Chagas' disease and related protozoal infections. The TRK/neurotrophic factor pathway, and BDNF/TRKB, is also implicated in the etiology of neurodegenerative diseases, including multiple sclerosis, Parkinson's disease and Alzheimer's disease. TRK inhibitors may also be used to treat diseases associated with imbalances in bone remodeling regulation, such as osteoporosis, rheumatoid arthritis, and bone metastasis.
Anaplastic Lymphoma (ALK) is a member of the insulin receptor superfamily of receptor tyrosine kinases, which is closely related to tumorigenesis of hematopoietic and non-hematopoietic tumors. The ALK gene is located on chromosome 2 and is expressed primarily in neuronal cells, especially during development. The ALK gene is involved in a balanced chromosomal translocation of the Nucleolar Phosphoprotein (NPM) gene on chromosome 5 in a large subset of Anaplastic Large Cell Lymphomas (ALCLs). In ALK + ALCL, as a result of translocation, the NPM ubiquitous promoter drives ectopic expression of fusion proteins, where the NPM partially dimerizes and the ALK kinase domain undergoes autophosphorylation and becomes constitutively active. Abnormal expression of the full-length ALK receptor protein has been reported in neuroblastoma and glioblastoma; and ALK fusion proteins have been found in anaplastic large cell lymphomas. The study of ALK fusion proteins has raised the possibility of new therapeutic approaches for ALK-positive malignant disease patients. ROS1 belong to the insulin receptor superfamily, and like other tyrosine kinase receptor molecules, ROS1 plays a role in relaying growth signals from the cell's external environment into the nucleus. Genetic changes such as gene rearrangements, mutations, or increased copy number of ROS1 produce oncogenes that may cause cancer. ROS1 was found in the form of a fusion protein (6 different partners of ROS 1) in NSCLC patients and was present in approximately 2% of patients with NSCLC (Bergethon et al, 2012; Davies et al, 2012). Two other ROS1 gene rearrangements have been detected in a variety of other cancers, including glioblastoma multiforme, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, and epithelioid angioendothelioma. ROS1 gene rearrangement produces fusion proteins with constitutively active kinase domains that activate downstream signaling pathways in cells that lead to oncogenic properties, including uncontrolled proliferation and resistance to cell death with prolonged tumor cell survival.
In 11 months 2018, the larotretinib, an ALK/TRK/ROS1 inhibitor approved by FDA in feverer, is marketed as a new oral drug for treating patients with metastatic ALK + non-small cell lung cancer who have previously received at least one ALK inhibitor, as well as patients with abnormal TRK variation. Previous studies have shown that the NTRK gene encoding TRK is abnormally fused with other genes, resulting in cancer growth at various sites in the body, and larotretinib selectively inhibits TRK. There are also other TRK kinase inhibitors under investigation, including LOXO-195(Loxo Oncology Inc, phase 2) and reportectinib (TP Therapeutics Inc, phase 2). A series of patent applications for TRK inhibitors have been published, including WO2015089139a1, WO2006082392a1, and WO2007123269a1, etc., and some progress has been made in the research and application of TRK agents, but the increased space remains enormous and there is still a need to continue research and development of new TRK inhibitors.
Disclosure of Invention
In view of the above technical problems, the present invention provides a macrocyclic lactam compound represented by the general formula (I) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:
Figure BDA0002454609730000031
wherein:
ring A is selected from a 4-18 membered N-containing heterocyclic group or a bicyclic fused ring, wherein the heterocyclic group optionally contains one or more O or S (O)r；
Ring B is selected from aryl or heteroaryl;
ring C is selected from aryl or heteroaryl;
provided that when one of ring B and ring C is selected from monocyclic aryl or monocyclic heteroaryl, the other ring is selected from bicyclic aryl or bicyclic heteroaryl, and at least one of ring B and ring C is an N-containing heteroaryl;
L1is selected from- (CR)aRb)m-, any one of them- (CR)aRb) -optionally further substituted with-N (R)c) -, -O-or-S (O) r-is substituted; l is1Is preferably- (CH)2) -or- (CH)2)2-；
L2Is selected from- (CR)dRe)n-, any one of them- (CR)dRe) -optionally further substituted with-N (R)f) -, -O-or-S (O) r-is substituted;
L3selected from the group consisting of a bond and-N (R)c)-；
Each Ra、Rb、RdAnd ReThe same or different, each independently selected from hydrogen atom, deuterium, halogen, hydroxyl group, alkoxy group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group or-NR6R7Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、 -C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, RaAnd RbTogether with the same carbon atom to which they are attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, any two RaTogether with the different carbon atoms to which they are respectively attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, RdAnd ReTogether with the same carbon atom to which they are attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, any two RdAnd each of themThe different carbon atoms linked together form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
each RcAnd RfThe same or different, each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein said alkyl or cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, alkoxy or cycloalkyl; rcAnd RfPreferably a hydrogen atom;
or, when L is1Is selected from- (CR)aRb)m-, any one of them- (CR)aRb) -further by-N (R)c) When substituted, RaOr RbAnd RcTogether with the carbon atom and nitrogen atom to which they are attached, form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、 -OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, when L is2Is selected from- (CR)dRe)n-, any one of them- (CR)dRe) -further by-N (R)f) When substituted, RdOr ReAnd RfTo carbon atoms to which they are respectively attachedTogether with the nitrogen atom to form a 3-to 8-membered heterocyclic group, wherein the 3-to 8-membered heterocyclic group contains one or more of N, O or S (O)rAnd said 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、 -OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
each R1、R2And R3Identical or different, each independently selected from the group consisting of hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、 -C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s); preferably, R1、R2And R3Each independently selected from hydrogen, halogen, cyano, alkyl or alkoxy, more preferably, R1、R2And R3Each independently selected from hydrogen, cyano, F, Cl, Br, methyl, hydroxymethyl, halomethyl or methoxymethyl;
R4selected from the group consisting of hydrogen atoms, alkyl groups or cycloalkyl groups, wherein said alkyl or cycloalkyl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy or cycloalkyl; r4Preferably a hydrogen atom;
R5、R6and R7Each independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10or-NR9C(O)R10Substituted with the substituent(s);
or, R6And R7Together with the atoms to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O or S (O)rAnd said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R8、 -C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10or-NR9C(O)R10Substituted with the substituent(s);
R8、R9and R10Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
m and n are the same or different and are each independently selected from 1,2, 3 or 4;
p, q and s are the same or different and are each independently selected from 0,1, 2,3, 4 or 5; and is
r is selected from 0,1 or 2.
In a preferred embodiment of the present invention, the compound of formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0002454609730000061
wherein:
x is selected from-N (R)c) -, -O-or-S (O)r-(ii) a Preferably NH;
Z1、Z2、Z4～Z6are the same or different and are each independently selected from N, NH, C (═ O) or C (R)3)；
Z3And Z7Identical or different, each independently selected from N or C;
X1～X3are the same or different, each independently selected from the group consisting of a bond, N, NH, C (═ O), and C (R)2)；X1～X3At most one is selected from the group consisting of a bond;
RAselected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, alkoxy or cycloalkyl; rAPreferably methyl;
Rcselected from the group consisting of hydrogen atoms, alkyl groups or cycloalkyl groups, wherein said alkyl or cycloalkyl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy or cycloalkyl; rcPreferably a hydrogen atom;
or, when X is selected from-N (R)c) When is, RAAnd RcTogether with the carbon atom and nitrogen atom to which they are attached, form a 4-to 8-membered heterocyclic group, wherein the 4-to 8-membered heterocyclic group contains one or more of N, O or S (O)rAnd said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s); and is
R1～R7、L1P and r are as defined in formula (I).
In a preferred embodiment of the present invention, the compound of formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is the compound of formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0002454609730000071
wherein: r1、R2、R4、Z1～Z7、X1～X3、RA、X、L1And p is as defined in formula (II).
In a preferred embodiment of the present invention, the compound of formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV), (V), or (VI) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure BDA0002454609730000072
wherein: r1、R2、R4、Rc、X1～X3、RA、L1And p is as defined in formula (II).
In a preferred embodiment of the invention, the compound of formula (IV), (V) or (VI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
R1and R2Each independently selected from hydrogen, cyano, F, Cl, Br, methyl, hydroxymethyl, halomethyl or methoxymethyl;
R4selected from hydrogen atoms or C1-C4An alkyl group;
Rcis a hydrogen atom;
X1～X3is CH;
RAis selected from C1-C4Alkyl, preferably methyl;
L1is selected from- (CH)2) -or- (CH)2)2-; and is
p is 0.
In a preferred embodiment of the invention, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from monocyclic heterocyclyl; preferably 4-6 membered monocyclic heterocyclic group; more preferably the following groups:
Figure BDA0002454609730000081
in a preferred embodiment of the invention, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of bicyclic fused heterocyclyl, bicyclic bridged heterocyclyl or bicyclic spiroheterocyclyl, more preferably the group:
Figure BDA0002454609730000082
in a preferred embodiment of the present invention, the compound of formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from 8-to 10-membered bicyclic fused rings, preferably from 8-to 10-membered bicyclic fused rings
Figure BDA0002454609730000083
Typical compounds of the compounds of formula (I) include, but are not limited to:
Figure BDA0002454609730000084
Figure BDA0002454609730000091
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a method for preparing a compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:
Figure BDA0002454609730000092
carrying out condensation reaction on the compound of the general formula (IIA) under an alkaline condition to obtain a compound of a general formula (II);
wherein: ring A, R1～R2、R4、RA、Z1～Z7、X1～X3、X、L1And p is as defined in formula (II).
Further, the present invention provides a compound represented by the general formula (IIA) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
Figure BDA0002454609730000101
wherein: ring A, R1～R2、R4、RA、Z1～Z7、X1～X3、X、L1And p is as defined in formula (II).
Typical compounds of formula (IIA) include, but are not limited to:
Figure BDA0002454609730000102
Figure BDA0002454609730000111
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.
The invention also provides a method for inhibiting TRK, which comprises contacting the ALK, TRK and/or ROS1 receptor with a compound of formula (I), (II), (III), (IV), (V) or (VI), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, preferably a TRK receptor.
The invention also provides an application of the compound of the general formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, a tautomer or a pharmaceutical salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating diseases mediated by ALK, TRK and/or ROS1, preferably an application in preparing a medicament for treating diseases mediated by TRK, wherein the diseases mediated by ALK, TRK and/or ROS1 are preferably pain, cancer, inflammation, neurodegenerative diseases or trypanosoma infection, and the cancer is preferably neuroblastoma, ovarian cancer, breast cancer, prostatic cancer, gastric cancer, digestive tract tumor, liver cancer, cholangiocarcinoma, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, neuroblastoma, colon cancer, lung cancer and the like, Colorectal cancer, breast analog secreting cancer, sarcoma, head and neck tumors, and renal cancer.
The invention also provides an application of the compound shown in the general formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing ALK, TRK and/or ROS1 inhibitors, preferably an application in preparing TRK inhibitors.
The invention also provides application of the compound shown in the general formula (I), (II), (III), (IV), (V) or (VI) or a stereoisomer, a tautomer or a pharmaceutical salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating pain, cancer, inflammation, neurodegenerative diseases or trypanosoma infection, wherein the cancer is preferably neuroblastoma, ovarian cancer, breast cancer, prostatic cancer, gastric cancer, digestive tract tumor, liver cancer, cholangiocarcinoma, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, colorectal cancer, breast analog secretory cancer, sarcoma, head and neck tumor and renal cancer.
The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcortically, or by inhalation. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any of the methods well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that produces a therapeutic effect.
Dosage forms for topical or transdermal administration of the compounds of the present invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
When the compounds of the present invention are administered to humans and animals as pharmaceuticals, the compounds can be provided alone or in pharmaceutical compositions containing the active ingredient in combination with a pharmaceutically acceptable carrier, e.g., from 0.1% to 99.5% (more preferably, from 0.5% to 90%) of the active ingredient.
Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution (Ringer's solution); (19) ethanol; (20) a phosphate buffer solution; (21) cyclodextrins, e.g., targeting ligands attached to the nanoparticle, e.g., accurins (tm); and (22) other non-toxic compatible materials used in pharmaceutical formulations, such as polymer-based compositions.
Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (e.g., capsules, dragee pills, dragees, powders, granules, and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binding agents, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) humectants, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
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 oxyhydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Ointments, pastes, creams and gels may also contain, in addition to the active compound, excipients, for example animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can also contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may contain other conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:
"chemical bond" refers to the general term for strong interaction between two or more adjacent atoms (or ions) within a pure molecule or crystal. The force that binds ions or atoms is known as a chemical bond. There are three basic types of chemical bonds, namely ionic, covalent and metallic bonds.
"alkyl" when taken as a group or part of a group means including C1-C20Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C10Alkyl, more preferably C1-C6An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be optionally substituted or unsubstituted.
"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferably selected is C2-C10Alkynyl of (2), more preferably C2-C6Alkynyl, most preferably C2-C4Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C3-C12Cycloalkyl, more preferably C3-C8Cycloalkyl, most preferably C3-C6A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.
"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures with single rings sharing a single carbon atom (called the spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-spiro, di-spiro, or multi-spiro cycloalkyl groups, preferably mono-spiro and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
"fused cycloalkyl" refers to a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl or tetradecaphenanthryl.
"bridged cycloalkyl" means a 5 to 18 membered all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s,4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s,5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1r,5r) -bicyclo [3.3.2] decyl.
"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, fused, bridged, and spiro rings. Preferably having a 4 to 6 membered monocyclic ring or a 7 to 10 membered bi-or tricyclic ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.
"spiroheterocyclyl" refers to a 5-to 18-membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which contains 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O)r(wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a mono-spiroheterocyclyl group, a di-spiroheterocyclyl group or a multi-spiroheterocyclyl group according to the number of spiro atoms shared between rings, preferably a mono-spiroheterocyclyl group anda spiro heterocyclic group. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1, 7-dioxaspiro [4.5]]Decyl, 2-oxa-7-azaspiro [4.4]Nonyl, 7-oxaspiro [3.5]]Nonyl and 5-oxaspiro [2.4]]A heptyl group.
"fused heterocyclyl" means a 5-to 18-membered all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)r(wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines).
"bridged heterocyclyl" means a 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O)r(wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]A decyl group.
"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic ringsOr bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C6-C10Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. The aryl group may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Preferred examples of bicyclic heteroaryls, "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1, 2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyrimidyl, or,
Figure BDA0002454609730000161
Heteroaryl groups may be substituted or unsubstituted.
"fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a fully conjugated pi-electron aromatic system, while, at the same time, at least one of the rings does not have a fully conjugated pi-electron aromatic system, wherein 0 or more of the ring atoms are selected from nitrogen, oxygen, or S (O)r(wherein r is selected from 0,1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14, more preferably 8 to 10. Examples of "fused rings" include, but are not limited to:
Figure BDA0002454609730000171
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C1-C6Alkoxy groups of (4) are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carboxy" refers to-C (O) OH.
"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
"DMSO" refers to dimethyl sulfoxide.
"Ts" refers to p-toluenesulfonyl.
A "leaving group", or leaving group, an atom or functional group that is removed from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate (substrate), and the atom or group of atoms cleaved from the substrate molecule with a pair of electrons is called the leaving group. Groups that accept electrons easily and have a strong ability to bear negative charges are good leaving groups. The lower the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to be cleaved from other molecules. The reason is that the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced when the pKa of its conjugate acid is smaller, and the corresponding leaving group does not need to be bound to another atom. Common leaving groups include, but are not limited to, halogen, -OTs, or-OH.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more groups selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxy, carboxylate, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、 -NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
R5、R6and R7Each independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10or-NR9C(O)R10Substituted with the substituent(s);
or, R6And R7Together with the atoms to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O or S (O)rAnd said 4-to 8-membered heterocyclic group is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, ═ orO、-C(O)R8、 -C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10or-NR9C(O)R10Substituted with the substituent(s);
R8、R9and R10Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
Unless otherwise indicated, the structures described herein also include all isomers (e.g., diastereomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms) of such structures, e.g., the R and S configurations of the various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds of formula (I) may be metal salts, amine salts with suitable acids.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention relates to a preparation method of a compound shown in a general formula (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which comprises the following steps:
Figure BDA0002454609730000191
reacting a compound of formula (IIa) with a compound of formula (IIb) under basic conditions to give a compound of formula (IIc); hydrolyzing the compound of the general formula (IIc) under alkaline conditions to obtain a compound of the general formula (IId); further removing the protecting group PG from the compound of the general formula (IId) to obtain a compound of a general formula (IIA); carrying out condensation reaction on a compound of a general formula (IIA) in the presence of a condensation reagent under an alkaline condition to obtain a compound of a general formula (II);
wherein:
R4selected from hydrogen atoms;
Rgselected from alkyl groups;
Rhis a leaving group, preferably halogen;
PG is an amino protecting group, preferably tert-butoxycarbonyl;
ring A, R1～R2、RA、Z1～Z7、X1～X3、X、L1And p is as defined in formula (II).
The basic condition is provided by an organic base selected from N, N-diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine and 4-dimethylaminopyridine or an inorganic base selected from potassium phosphate, potassium phosphate trihydrate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride and potassium hydride, preferably N, N-diisopropylethylamine, sodium hydroxide, potassium hydroxide or lithium hydroxide.
The condensation reagent is selected from 2- (7-benzotriazole oxide) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N ' -dicyclohexylcarbodiimide, N, N ' -diisopropylcarbodiimide, 1-hydroxy-7-azobenzotriazole, 2- (7-azobenzotriazole) -N, N, N ', n' -tetramethyluronium hexafluorophosphate, pentafluorophenyl diphenyl phosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate; pentafluorophenyldiphenylphosphate is preferred.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Examples
The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention.1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification, unless otherwise indicated, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Prov Chemical technology Inc. and Sci Chemical technology Inc.
CD3OD: deuterated methanol.
CDCl3: deuterated chloroform.
DMSO-d6: deuterated dimethyl sulfoxide.
The argon atmosphere means that the reaction flask is connected with an argon balloon having a volume of about 1L.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
Purifying the compound by silica gel column chromatography using an eluent system selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane and ethyl acetate systems; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.
Preparative liquid phase conditions for compound purification: a separation column AKZONOBEL Kromasil; 250 × 21.2mm i.d.; 5 mu m, 20 mL/min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH (CH)3CN。
Example 1
6-fluoro-3-methyl-2,10,15,19,20,23- hexaazapentacyclo[15.5.2.210,13.04 ,9.020,24]hexacosa-1(23),4,6,8,17(24),18,21-heptaen-16-one 6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.2 ]10,13.04,9.020,24]Hexacosane-1 (23),4,6,8,17(24),18, 21-hepten-16-one
Figure BDA0002454609730000211
First step of
((1- (4-fluoro-2-formylphenyl) piperidin-4-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (piperidin-4-ylmethyl) carbamate 1a (2.14g,0.01mol) was dissolved in 10mL of N, N-dimethylformamide, and 2, 5-difluorobenzaldehyde 1b (1.42g,0.01mol) and potassium carbonate (4.83g,0.035mol) were added thereto, followed by stirring at 110 ℃ for 4 hours. LC-MS monitored completion of the reaction of the starting materials, 30mL of water was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1- (4-fluoro-2-formylphenyl) piperidin-4-yl) methyl) carbamate 1c (2.7g), yield: 80 percent.
MS m/z(ESI)：337.2[M+1]
Second step of
(R, E) - ((1- (2- (((tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (4-fluoro-2-formylphenyl) piperidin-4-yl) methyl) carbamate 1c (2.7g,8.0mmol), (R) -2-methylpropane-2-sulfinamide 1d (1.1g,8.8mmol), and tetraethyltitanate (3.7g,16.0mmol) were dissolved in 20mL of tetrahydrofuran and reacted at 80 ℃ overnight. LC-MS monitors the reaction for completion, 30mL of water is added, extraction is performed with ethyl acetate (30mL × 3), the organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue is further analytically purified by silica gel column chromatography (eluent: system a) to give tert-butyl (R, E) - ((1- (2- (((tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamate 1E (3.3g), yield: 95 percent.
MS m/z(ESI)：440.2[M+1]
The third step
((1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (R, E) - ((1- (2- (((tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamate 1E (3.3g,7.5mmol) was added to 20mL of tetrahydrofuran, cooled to-75 ℃ and methyl magnesium bromide (2 mL,20mmol,10mol/L) was added dropwise, after completion of the addition, the reaction was transferred to room temperature and reacted at room temperature for 2 hours. The reaction was terminated by TLC, the reaction was quenched by adding 50mL of ice water to the reaction solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further analytically purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamate 1f (1.7g), yield: 50 percent.
MS m/z(ESI)：456.2[M+1]
The fourth step
((1- (2- (1-aminoethyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamate 1f (1.7g,3.7mmol) was dissolved in 40mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 4:1), and elemental iodine (189 mg,0.75mmol) was added to the solution, and the mixture was reacted at 50 ℃ for 3 hours, and LC-MS monitored for completion of the reaction, and the sodium thiosulfate solution was quenched, and 30mL of water was added, and the mixture was extracted with ethyl acetate (30 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further purified by silica gel column chromatography (eluent: A system) to obtain 1g (600mg) of tert-butyl ((1- (2- (1-aminoethyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamate, yield: 35 percent.
MS m/z(ESI)：352.2[M+1]
The fifth step
5- ((1- (2- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester
Tert-butyl ((1- (2- (1-aminoethyl) -4-fluorophenyl) piperidin-4-yl) methyl) carbamate 1g (600mg,1.7mmol), ethyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate 1h (385mg,1.7mmol) and N, N-diisopropylethylamine (1.3g, 10.2mmol) were dissolved in 20mL of N-butanol and reacted at 110 ℃ for 6 hours. LC-MS monitored completion of the reaction, cooled to room temperature, added with 30mL of water, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was further analytically purified by silica gel column chromatography (eluent: system a) to give ethyl 5- ((1- (2- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 1i (600mg), yield: 61 percent.
MS m/z(ESI)：541.3[M+1]
The sixth step
5- ((1- (2- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
Ethyl 5- ((1- (2- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 1i (600mg,1.1mmol) was dissolved in 6mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V: V ═ 10:1:1), and lithium hydroxide monohydrate (466mg,11.1mmol) was added thereto, followed by stirring at 70 ℃ overnight. LC-MS monitors that the reaction is finished, cooling is carried out, dilute hydrochloric acid is slowly added dropwise to adjust the reaction to acidity, 30mL of water is added, ethyl acetate (30mL multiplied by 3) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, and reduced pressure concentration is carried out to obtain a crude product of 5- ((1- (2- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 1j, and the product is subjected to the next reaction without purification.
Seventh step
5- ((1- (2- (4- (aminomethyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
The crude product of 5- ((1- (2- (4- (((tert-butoxycarbonyl) amino) methyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 1j obtained in the above step was dissolved in 5mL of dioxane hydrochloride and reacted at room temperature for 2 hours. After the LC-MS monitoring reaction is finished, the reaction liquid is decompressed and concentrated to obtain a crude product of 5- ((1- (2- (4- (aminomethyl) piperidine-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 1k, and the product is used for the next reaction step without treatment.
Eighth step
6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.210,13.04,9.020,24]Twenty-fourHexadecane-1 (23),4,6,8,17(24),18, 21-hepten-16-one
5- ((1- (2- (4- (aminomethyl) piperidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1, 5-a) obtained in the last step]Crude pyrimidine-3-carboxylic acid 1k, pentafluorophenyl diphenyl phosphate (461mg,1.20mmol), and N, N-diisopropylethylamine (1.1g, 8mmol) were dissolved in 2.5mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V: V ═ 1:4) and reacted at room temperature overnight. LC-MS monitors the reaction completion, adds 20mL of water, extracts with dichloromethane (20 mL. times.3), combines the organic phases, dries over anhydrous sodium sulfate, concentrates under reduced pressure, and prepares the liquid phase to give 6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclo [15.5.2.2 ]10,13.04,9.020,24]Hexacosane-1 (23),4,6,8,17(24),18, 21-hepten-16-one 1(118 mg).
MS m/z(ESI)：395.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.59(d,J＝7.5Hz,1H),8.11(s,1H),8.06(d,J＝7.2Hz,1H), 7.98(s,1H),7.36(d,J＝10.4Hz,1H),7.20-7.26(m,1H),7.10(d,J＝8.8Hz,1H),6.49(d,J＝ 7.8Hz,1H),5.58-5.62(m,2H),2.70-2.79(m,4H),2.43-2.47(m,1H),1.98-2.03(m,3H), 1.51-1.61(m,4H),1.45(d,J＝6.5Hz,3H).
Example 2
(13S)-6-fluoro-3-methyl-2,10,15,19,20,23- hexaazapentacyclo[15.5.2.110,13.04,9.020,24]pentacosa-1(23),4(9),5,7,17(24),18,21-heptaen-16-one (13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
Figure BDA0002454609730000241
Figure BDA0002454609730000251
First step of
((1- (4-fluoro-2-formylphenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (pyrrolidin-3-ylmethyl) carbamate 2a (1.0g,5.0mmol) was dissolved in 10mL of N, N-dimethylformamide, and 2, 5-difluorobenzaldehyde 1b (780mg,5.5mmol) and potassium carbonate (2.42g,17.5mmol) were added, followed by stirring at 110 ℃ for 4 hours. LC-MS monitored completion of the reaction of the starting materials, 30mL of water was added, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl ((1- (4-fluoro-2-formylphenyl) pyrrolidin-3-yl) methyl) carbamate 2b (800mg), yield: 50 percent.
MS m/z(ESI)：323.2[M+1]
Second step of
((S) -1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (4-fluoro-2-formylphenyl) pyrrolidin-3-yl) methyl) carbamate 2b (630mg,2.0mmol), (R) -2-methylpropane-2-sulfinamide 1d (355mg,2.9mmol), and tetraethyltitanate (892mg,2.7mmol) were dissolved in 5mL of tetrahydrofuran and reacted for 4 hours under reflux. LC-MS monitoring completion of the reaction, concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) gave tert-butyl (((S) -1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 2c (450mg) in yield: and 43 percent.
MS m/z(ESI)：426.2[M+1]
The third step
((3S) -1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (((S) -1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 2c (450mg,1.06mmol) was added to 3mL of tetrahydrofuran, cooled to-65 ℃ and methylmagnesium bromide (4.22mL,4.22mmol,1mol/L) was added dropwise, and after completion of the addition, the reaction was transferred to room temperature and allowed to react at room temperature for 2 hours. The reaction was terminated by TLC, the reaction was quenched by adding 20mL of ice water to the reaction solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (((3S) -1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 2d (440mg) in yield: 94.4 percent.
MS m/z(ESI)：442.2[M+1]
The fourth step
((3S) -1- (2- (1-aminoethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (((3S) -1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 2d (340mg,0.78mmol) was dissolved in 3.5mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 6:1), elemental iodine (38mg,0.17mmol) was added, the reaction was carried out at 50 ℃ for 3 hours, LC-MS monitored for completion of the reaction, a sodium thiosulfate solution was quenched, 20mL of water was added, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (((3S) -1- (2- (1-aminoethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate Ester 2e (336mg), yield: 100 percent.
MS m/z(ESI)：338.2[M+1]
The fifth step
5- ((1- (2- ((S) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid ethyl ester
Tert-butyl (((3S) -1- (2- (1-aminoethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 2e (260mg, 0.78mmol), ethyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate 1h (174mg,0.77mmol) and N, N-diisopropylethylamine (606mg,4.63mmol) were dissolved in 4mL of N-butanol and reacted at 120 ℃ for 5 hours. LC-MS monitored completion of the reaction, cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give ethyl 5- ((1- (2- ((S) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylate 2f (340mg), yield: 66 percent.
MS m/z(ESI)：527.3[M+1]
The sixth step
5- ((1- (2- ((S) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid
Ethyl 5- ((1- (2- ((S) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylate 2f (340mg,0.65mmol) was dissolved in 4mL of a mixed solvent of methanol, tetrahydrofuran and water (V: V: V ═ 6:1:1), and lithium hydroxide monohydrate (163mg,3.87mmol) was added, followed by stirring at 70 ℃ overnight. LC-MS monitors the reaction to be finished, cooling is carried out, dilute hydrochloric acid is slowly added dropwise to adjust the reaction to acidity, 20mL of water is added, ethyl acetate (20mL multiplied by 3) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, and reduced pressure concentration is carried out to obtain 2g of crude 5- ((1- (2- ((S) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidine-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid, and the product is subjected to the next reaction without purification.
Seventh step
5- ((1- (2- ((S) -3- (aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid
2g of crude 5- ((1- (2- ((S) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid obtained in the above step was dissolved in 5mL of dioxane hydrochloride solution and reacted at room temperature for 2 hours. After the LC-MS monitoring reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product of 5- ((1- (2- ((S) -3- (aminomethyl) pyrrolidine-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid for 2h, and the product is subjected to the next reaction without purification.
Eighth step
(13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
5- ((1- (2- ((S) -3- (aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1, 5) obtained in the previous step-a]]Crude pyrimidine-3-carboxylic acid 2h, pentafluorophenyl diphenyl phosphate (297mg,0.77mmol), and N, N-diisopropylethylamine (840mg,6.5mmol) were dissolved in 5mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V: V ═ 1.5:1), and reacted at room temperature overnight. LC-MS monitored reaction completion, water 20mL was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the liquid phase was prepared to give (13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclo [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one 2(110mg), yield: 48.6 percent.
MS m/z(ESI)：381.4[M+1]
1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝8.3Hz,1H),8.51(d,J＝7.6Hz,1H),8.45(s,1H), 8.05(s,1H),7.24(d,J＝10.0Hz,1H),6.98(dd,J＝6.8,1.7Hz,2H),6.26(d,J＝7.6Hz,1H), 5.74-5.77(m,2H),3.60(dt,J＝13.4,4.2Hz,1H),3.52(t,J＝8.5Hz,1H),3.22(d,J＝9.8Hz, 2H),2.86(d,J＝9.2Hz,1H),2.76(s,1H),2.15-2.31(m,1H),1.96-1.97(m,1H),1.55(d,J＝ 7.0Hz,3H).
Example 3
(13R)-6-fluoro-3-methyl-2,10,15,19,20,23- hexaazapentacyclo[15.5.2.110,13.04,9.020,24]pentacosa-1(23),4(9),5,7,17(24),18,21-heptaen-16-one (13R) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
Figure BDA0002454609730000281
First step of
((R) -1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (4-fluoro-2-formylphenyl) pyrrolidin-3-yl) methyl) carbamate 2b (630mg,2.0mmol), (R) -2-methylpropane-2-sulfinamide 1d (355mg,2.9mmol), and tetraethyltitanate (892mg,2.7mmol) were dissolved in 5mL of tetrahydrofuran and reacted for 4 hours under reflux. LC-MS monitoring completion of the reaction, concentration under reduced pressure and purification of the obtained residue by silica gel column chromatography (eluent: system a) gave tert-butyl (((R) -1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 3a (460mg) in yield: 44 percent.
MS m/z(ESI)：426.2[M+1]
Second step of
((3R) -1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (((R) -1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 3a (460mg,1.08mmol) was added to 3mL of tetrahydrofuran, cooled to-65 ℃ and methylmagnesium bromide (4.3mL,4.3mmol,1mol/L) was added dropwise, and after completion of the addition, the reaction was transferred to room temperature and allowed to react at room temperature for 2 hours. The reaction was terminated by TLC, the reaction was quenched by adding 20mL of ice water to the reaction solution, extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system a) to obtain tert-butyl (((3R) -1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 3b (430mg) in yield: 90.1 percent.
MS m/z(ESI)：442.2[M+1]
The third step
((3R) -1- (2- (1-aminoethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (((3R) -1- (2- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 3b (430mg,0.99mmol) was dissolved in 3.5mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 6:1), an elemental iodine (48mg,0.22mmol) was added, the reaction was carried out at 50 ℃ for 3 hours, LC-MS (LC-MS) was followed to monitor completion of the reaction, a sodium thiosulfate solution was quenched, 20mL of water was added, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (((3R) -1- (2- (1-aminoethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate Ester 3c (330mg), yield: 100 percent.
MS m/z(ESI)：338.2[M+1]
The fourth step
5- ((1- (2- ((R) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid ethyl ester
Tert-butyl (((3R) -1- (2- (1-aminoethyl) -4-fluorophenyl) pyrrolidin-3-yl) methyl) carbamate 3c (310mg, 0.93mmol), ethyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate 1h (207mg,0.92mmol) and N, N-diisopropylethylamine (722mg,5.60mmol) were dissolved in 4mL of N-butanol and reacted at 120 ℃ for 5 hours. LC-MS monitored completion of the reaction, cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system a) to give ethyl 5- ((1- (2- ((R) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylate 3d (270mg), yield: 56 percent.
MS m/z(ESI)：527.3[M+1]
The fifth step
5- ((1- (2- ((R) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid
Reacting 5- ((1- (2- ((R) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a]]Pyrimidine-3-carboxylic acid ethyl ester 3d (270mg,0.52mmol) was dissolved in 4mL of a mixed solution (CH)3OH: THF:H2O6: 1:1), lithium hydroxide monohydrate (129mg,3.06mmol) was added, and the mixture was stirred at 70 ℃ overnight. LC-MS (liquid chromatography-Mass Spectrometry) monitoring the reaction, cooling, slowly dropwise adding dilute hydrochloric acid to adjust the pH to acidity, adding 20mL of water, extracting with ethyl acetate (20mL multiplied by 3), combining organic phases, drying over anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 5- ((1- (2- ((R) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a]]Crude pyrimidine-3-carboxylic acid 3e, which is subjected to the next reaction without purification.
The sixth step
5- ((1- (2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid
5- ((1- (2- ((R) -3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid 3e was dissolved in 5mL of dioxane hydrochloride and reacted at room temperature for 2 hours. And monitoring the reaction by LC-MS, and concentrating the reaction solution under reduced pressure to obtain a crude product of 5- ((1- (2- ((R) -3- (aminomethyl) pyrrolidine-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylic acid 3f, wherein the product is subjected to the next reaction without purification.
Seventh step
(13R) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
Reacting 5- ((1- (2- ((R) -3- (aminomethyl) pyrrolidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a]]Pyrimidine-3-carboxylic acid 3f, pentafluorophenyl diphenylphosphate (236mg,0.61mmol) and N, N-diisopropylethylamine (662mg,5.12 mmol) were dissolved in 5mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V: V ═ 1.5:1) and reacted at room temperature overnight. LC-MS monitored reaction completion, water 20mL was added, extraction was performed with dichloromethane (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the liquid phase was prepared to give (13R) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclo [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one 3(90mg), yield: 46 percent.
MS m/z(ESI)：381.4[M+1]
1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝8.3Hz,1H),8.51(d,J＝7.6Hz,1H),8.46(s,1H), 8.05(s,1H),7.24(d,J＝9.8Hz,1H),6.90-7.02(m,2H),6.26(d,J＝7.6Hz,1H),5.74-5.78(m, 2H),3.60(d,J＝13.1Hz,1H),3.52(t,J＝8.5Hz,1H),3.22(d,J＝10.1Hz,2H),2.85(d,J＝ 9.2Hz,1H),2.73-2.77(m,1H),2.23(q,J＝10.4,9.0Hz,1H),1.92-2.03(m,1H),1.55(d,J＝ 7.0Hz,3H).
Example 4
(13S)-6-fluoro-3-methyl-2,10,15,19,20,23- hexaazapentacyclo[15.5.2.110,13.04,9.020,24]pentacosa-1(23),4,6,8,17(24),18,21-heptaene-11,16-dio ne
(13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4,6,8,17(24),18, 21-heptene-11, 16-dione
Figure BDA0002454609730000311
First step of
(13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4,6,8,17(24),18, 21-heptene-11, 16-dione
Reacting (13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclo [15.5.2.110,13.04,9.020 ,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one 2(43mg,0.11mmol), iodine (429mg,1.7mmol) and sodium bicarbonate (185mg,2.2mmol) were dissolved in 4.5mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 2.5:1) and stirred at room temperature for 5 days. LC-MS monitors the reaction is completed, 20mL of sodium thiosulfate solution is added to quench the reaction, ethyl acetate (20 mL. times.3) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, reduced pressure concentration is carried out, and (13S) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.1 ] is obtained through preparation of a liquid phase10,13.04,9.020,24]Pentacosane-1 (23),4,6,8,17(24),18, 21-heptene-11, 16-dione 4(4.6mg), yield: 10 percent.
MS m/z(ESI)：395.2[M+1]
1H NMR(400MHz,DMSO-d6)δ8.70(d,J＝8.7Hz,1H),8.53(d,J＝7.7Hz,1H),8.07(s,1H), 7.77(s,1H),7.39(d,J＝9.3Hz,2H),7.16(s,1H),6.28(d,J＝7.5Hz,1H),5.10-5.20(m,1H), 3.64-3.68(m,1H),3.46(d,J＝10.8Hz,1H),3.29(d,J＝9.3Hz,1H),3.05(s,2H),2.56-2.74(m, 2H),1.56(d,J＝6.7Hz,3H).
Example 5
(3R)-6-fluoro-3-methyl-2,8,10,15,19,20,23- heptaazapentacyclo[15.5.2.110,13.04,9.020,24]pentacosa-1(23),4(9),5,7,17(24),18,21-heptaen-16-one (3R) -6-fluoro-3-methyl-2, 8,10,15,19,20, 23-pentaazapentacyclic [15.5.2.1 ]10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
Figure BDA0002454609730000321
First step of
2-chloro-5-fluoro-N-methoxy-N-methylnicotinamide
2-chloro-5-fluoronicotinic acid 5a (20g,113.93mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (32.8g,170.90mmol), 1-hydroxybenzotriazole (23.1g,170.90mmol) and N, O-dimethylhydroxylamine 5b (20g,113.93mmol) were dissolved in 300mL of dichloromethane, and N, N-diisopropylethylamine (37.7 mL,227.86mmol) was added thereto, and the mixture was stirred at room temperature overnight. LC-MS monitors the reaction completion, adds 200mL of water, extracts with dichloromethane (100mL × 3), combines the organic phases, washes with saturated sodium chloride solution, dries over anhydrous sodium sulfate, concentrates under reduced pressure, and the resulting residue is further analytically purified by silica gel column chromatography (eluent: system a) to give 2-chloro-5-fluoro-N-methoxy-N-methylnicotinamide 5c (23g), yield: 92.6 percent.
MS m/z(ESI)：219.0[M+1]
Second step of
1- (2-chloro-5-fluoropyridin-3-yl) ethan-1-one
Dissolving 2-chloro-5-fluoro-N-methoxy-N-methylnicotinamide 5c (23g,105.21mmol) in 250mL of anhydrous tetrahydrofuran, cooling to-78 ℃ under argon protection, dropwise adding methyl magnesium bromide (45.6mL,136.77mmol,3mol/L in THF), keeping the temperature between-78 ℃ and-60 ℃ during dropwise adding, and naturally heating to room temperature overnight after dropwise adding. And monitoring the reaction by LC-MS, cooling, and adding a saturated ammonium chloride solution for quenching. 200mL of water was added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by analytical chromatography on a silica gel column (eluent: System A) to give 1- (2-chloro-5-fluoropyridin-3-yl) ethan-1-one 5d (15.6g), yield: 85.7 percent.
MS m/z(ESI)：174.0[M+1]
The third step
(R, Z) -N- (1- (2-chloro-5-fluoropyridin-3-yl) ethylene) -2-methylpropane-2-sulfinamide
1- (2-chloro-5-fluoropyridin-3-yl) ethan-1-one 5d (200mg,1.15mmol), (R) -2-methylpropane-2-sulfinamide 1d (210mg,1.73mmol), tetraethyltitanate (1.05g,4.60mmol) was dissolved in tetrahydrofuran and reacted at 80 ℃ overnight. LC-MS monitored completion of the reaction, and 20mL of water was added to the reaction solution, a solid was precipitated, and the filtrate was filtered, extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further analytically purified by silica gel column chromatography (eluent: system a) to give (R, Z) -N- (1- (2-chloro-5-fluoropyridin-3-yl) ethylidene) -2-methylpropane-2-sulfinamide 5e (250mg), yield: 78 percent.
MS m/z(ESI)：277.1[M+1]
The fourth step
((1- (3- ((Z) -1- (((R) -tert-butylsulfinyl) imino) ethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
(R, Z) -N- (1- (2-chloro-5-fluoropyridin-3-yl) ethylene) -2-methylpropane-2-sulfinamide 5e (250mg,0.90 mmol), (pyrrolidin-3-ylmethyl) carbamic acid tert-butyl ester 5f (198.3mg,0.99mmol), sodium bicarbonate (226.8mg, 2.70mmol) were dissolved in N-butanol and reacted at 100 ℃ overnight. LC-MS monitored completion of the reaction of the starting materials, 20mL of water was added for cooling, extraction was performed with ethyl acetate (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further purified by analysis by silica gel column chromatography (eluent: System A) to obtain 5g (120mg) of tert-butyl ((1- (3- ((Z) -1- (((R) -tert-butylsulfinyl) imino) ethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamate in 30% yield.
MS m/z(ESI)：441.2[M+1]
The fifth step
((1- (3- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (3- ((Z) -1- (((R) -tert-butylsulfinyl) imino) ethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamate 5g (120mg,0.27mmol) was dissolved in methanol, and sodium borohydride (22.5mg,0.59mmol) was added and reacted at 60 ℃ for 1 hour until the reaction was complete. After cooling, 20mL of water was added, and extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl ((1- (3- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamate as a crude product for 5h (90 mg).
MS m/z(ESI)：443.2[M+1]
The sixth step
((1- (3- (1-aminoethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamic acid tert-butyl ester
Crude tert-butyl ((1- (3- (1- (((R) -tert-butylsulfinyl) amino) ethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamate 5h (90mg) was dissolved in 20mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 4:1), and elemental iodine (5.08mg,0.02mmol) was added to react at 50 ℃ for 3 hours, monitoring the reaction by LC-MS, quenching by sodium thiosulfate solution, adding 20mL of water, extraction was performed with ethyl acetate (20 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude tert-butyl ((1- (3- (1-aminoethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamate 5i (50 mg).
MS m/z(ESI)：339.2[M+1]
Seventh step
5- ((1- (2- (3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester
Crude tert-butyl ((1- (3- (1-aminoethyl) -5-fluoropyridin-2-yl) pyrrolidin-3-yl) methyl) carbamate 5i (100mg), ethyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate 1h (81.23mg,0.36mmol) and N, N-diisopropylethylamine (293.8mg,1.8mmol) were dissolved in N-butanol and reacted at 120 ℃ for 5 hours. LC-MS monitored completion of the reaction, cooled to room temperature, added with 20mL of water, extracted with ethyl acetate (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was further purified by column chromatography on silica gel (eluent: system A) to give ethyl 5- ((1- (2- (3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 5j (40 mg).
MS m/z(ESI)：528.2[M+1]
Eighth step
5- ((1- (2- (3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
Ethyl 5- ((1- (2- (3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 5j (40mg,0.076mmol) was dissolved in 5mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V: V ═ 3:1:1), and lithium hydroxide monohydrate (10.93mg,0.26mmol) was added to the solution, followed by reaction at 50 ℃ for 5 hours. LC-MS monitors that the reaction is finished, cooling is carried out, dilute hydrochloric acid is slowly added dropwise to adjust the reaction to acidity, 10mL of water is added, ethyl acetate (10mL multiplied by 3) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, and reduced pressure concentration is carried out to obtain a crude product of 5- ((1- (2- (3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidine-1-yl) -5-fluoropyridine-3-yl) ethyl) amino) pyrazole [1,5-a ] pyrimidine-3-carboxylic acid 5k, and the product is subjected to the next reaction without purification.
MS m/z(ESI)：500.2[M+1]
The ninth step
5- ((1- (2- (3- (aminomethyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
5- ((1- (2- (3- (((tert-butoxycarbonyl) amino) methyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 5k obtained in the above step was dissolved in 20mL of dioxane hydrochloride solution and reacted at room temperature for 1 hour. After the LC-MS monitoring reaction, the reaction solution is decompressed and concentrated to obtain a crude product of 5- ((1- (2- (3- (aminomethyl) pyrrolidine-1-yl) -5-fluoropyridine-3-yl) ethyl) amino) pyrazole [1,5-a ] pyrimidine-3-carboxylic acid 5l, and the product is subjected to the next reaction without purification.
MS m/z(ESI)：400.2[M+1]
The tenth step
(3R) -6-fluoro-3-methyl-2, 8,10,15,19,20, 23-pentaazapentacyclic [15.5.2.110,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
Reacting 5- ((1- (2- (3- (aminomethyl) pyrrolidin-1-yl) -5-fluoropyridin-3-yl) ethyl) amino) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid 5l, pentafluorophenyl diphenylphosphate (35mg,0.09mmol) and N, N-diisopropylethylamine (99.6mg,0.61mmol) were dissolved in 20mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V: V ═ 1:2) and reacted at room temperature overnight. LC-MS monitors the reaction is finished, 20mL of saturated ammonium chloride is added, 20mL of water is added, ethyl acetate (20mL multiplied by 3) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, reduced pressure concentration is carried out, and (3R) -6-fluoro-3-methyl-2, 8,10,15,19,20, 23-pentaazapentacyclic [15.5.2.1 ] is obtained by preparative liquid phase separation10,13.04,9.020,24]Pentacosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one 5(11 mg).
MS m/z(ESI)：382.1[M+1]
1H NMR(400MHz,DMSO-d6)δ8.72(d,J＝8.1Hz,1H),8.52(d,J＝7.6Hz,1H),8.35(s, 1H),8.10(m,1H),8.05(s,1H),7.66(d,J＝9.7Hz,1H),6.27(d,J＝7.6Hz,1H),5.32(m,1H), 3.82(m,1H),3.59(m,2H),3.07(m,2H),1.95-2.04(m,1H),1.59(d,J＝7.0Hz,3H),0.85(m, 2H).
Example 6
(3R)-6-fluoro-3-methyl-2,10,15,19,20,23- hexaazapentacyclo[15.5.2.04 ,9.010,13.020,24]Tetracosa-1(23),4(9),5,7,17(24),18,21-heptaen-16-one (3R) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.0 ]4,9.010,13.020,24]Tetracosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
Figure BDA0002454609730000361
Figure BDA0002454609730000371
First step of
((1- (4-fluoro-2-formylphenyl) azetidin-2-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl (azetidin-2-ylmethyl) carbamate 6a (900mg,4.83mmol) was dissolved in 5mL of N, N-dimethylformamide, and 2, 5-difluorobenzaldehyde 1b (1.03g,7.25mmol) and potassium carbonate (2.34g,16.9mmol) were added and stirred at 120 ℃ for 6 hours. LC-MS monitored completion of the starting material reaction, added 20mL of water, extracted with ethyl acetate (20mL × 3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further analytically purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1- (4-fluoro-2-formylphenyl) azetidin-2-yl) methyl) carbamate 6b (420mg), yield: 28 percent.
MS m/z(ESI)：309.1[M+1]
Second step of
((1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (4-fluoro-2-formylphenyl) azetidin-2-yl) methyl) carbamate 6b (420mg,1.36 mmol), (R) -2-methylpropane-2-sulfinamide 1d (250mg,2.06mmol), tetraethyltitanate (621mg,2.72mmol) was dissolved in 20mL of tetrahydrofuran and reacted at 75 ℃ overnight. The reaction was concentrated under reduced pressure, and the resulting residue was further purified by analytical chromatography on a silica gel column (eluent: system a) to give tert-butyl ((1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamate 6c (560mg), yield: 100 percent.
MS m/z(ESI)：412.2[M+1]
The third step
((1- (2- ((R) -1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (2- ((E) - (((R) -tert-butylsulfinyl) imino) methyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamate 6c (560mg,1.36mmol) was added to 8mL of tetrahydrofuran, cooled to-65 ℃ and methylmagnesium bromide (5.44mL,5.44mmol,1mol/L) was added dropwise, after which time the reaction was transferred to room temperature and allowed to react overnight at room temperature. The reaction was monitored by TLC for completion, the reaction was quenched by adding 30mL of ice water, extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further analytically purified by silica gel column chromatography (eluent: system a) to give tert-butyl ((1- (2- ((R) -1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamate 6d (90mg), yield: 15.5 percent.
MS m/z(ESI)：428.2[M+1]
The fourth step
((1- (2- ((R) -1-aminoethyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamic acid tert-butyl ester
Tert-butyl ((1- (2- ((R) -1- (((R) -tert-butylsulfinyl) amino) ethyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamate 6d (90mg,0.21mmol) was dissolved in 5mL of a mixed solvent of tetrahydrofuran and water (V/V ═ 4:1), elemental iodine (11mg,0.042mmol) was added, the reaction was carried out at 50 ℃ for 3 hours, LC-MS monitored for completion of the reaction, the sodium thiosulfate solution was quenched, 15mL of water was added, extraction was carried out with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product of tert-butyl ((1- (2- ((R) -1-aminoethyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamate 6e, the product was taken to the next reaction without purification.
The fifth step
5- (((1R) -1- (2- (2- (((tert-butoxycarbonyl) amino) methyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester
Crude tert-butyl ((1- (2- ((R) -1-aminoethyl) -4-fluorophenyl) azetidin-2-yl) methyl) carbamate 6e obtained in the previous step, ethyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate 1h (52mg,0.23mmol) and N, N-diisopropylethylamine (218mg,1.69mmol) were dissolved in 3mL of N-butanol and reacted at 120 ℃ for 6 hours. LC-MS monitoring completion of the reaction, concentration under reduced pressure and further analytical purification of the resulting residue by silica gel column chromatography (eluent: system a) gave ethyl 5- (((1R) -1- (2- (2- (((tert-butoxycarbonyl) amino) methyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylate 6f (65mg) yield: 60.2 percent.
MS m/z(ESI)：513.2[M+1]
The sixth step
5- (((1R) -1- (2- (2- (((tert-butoxycarbonyl) amino) methyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
Ethyl 5- (((1R) -1- (2- (2- (((tert-butoxycarbonyl) amino) methyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] ] pyrimidine-3-carboxylate 6f (65mg,0.13mmol) was dissolved in 3mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V: V ═ 1:4:1), and lithium hydroxide monohydrate (54mg,1.27mmol) was added, followed by stirring at 70 ℃ overnight. LC-MS monitors the reaction, cools, slowly adds dilute hydrochloric acid dropwise to adjust to acidity, adds 10mL of water, extracts with ethyl acetate (20mL × 3), combines organic phases, dries with anhydrous sodium sulfate, and concentrates under reduced pressure to obtain 6g of crude 5- (((1R) -1- (2- (2- (((tert-butoxycarbonyl) amino) methyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid, which is subjected to the next reaction without purification.
Seventh step
5- (((1R) -1- (2- (2- (aminomethyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
6g of crude 5- (((1R) -1- (2- (2- (((tert-butoxycarbonyl) amino) methyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid obtained in the above step was dissolved in 2mL of a dichloromethane solution, and 3mL of a dioxane hydrochloride solution was added thereto, and the reaction was carried out at room temperature for 2 hours. After the reaction was monitored by LC-MS, the reaction solution was concentrated under reduced pressure to give a crude product of 5- (((1R) -1- (2- (2- (aminomethyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid for 6h, which was subjected to the next reaction without purification.
Eighth step
(3R) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.0 ]4,9.010,13.020,24]Tetracosane-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one
The 5- (((1R) -1- (2- (2- (aminomethyl) azetidin-1-yl) -5-fluorophenyl) ethyl) amino) pyrazolo [1, 5-a) obtained in the previous step]Pyrimidine-3-carboxylic acid 6h (50mg), pentafluorophenyl diphenylphosphate (60mg,0.16mmol) and N, N-diisopropylethylamine (135mg,1.04mmol) were dissolved in 5mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V: V ═ 1.5:1) and reacted at room temperature overnight. LC-MS monitored reaction completion, water 20mL was added, extraction was performed with dichloromethane (20 mL. times.3), organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the liquid phase was prepared to give (3R) -6-fluoro-3-methyl-2, 10,15,19,20, 23-hexaazapentacyclic [15.5.2.0 ]4,9.010,13.020,24]Tetracosan-1 (23),4(9),5,7,17(24),18, 21-hepten-16-one 6(30mg), yield: 73.7 percent.
MS m/z(ESI)：367.4[M+1]
1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝7.6Hz,1H),8.22(d,J＝7.0Hz,2H),8.12(s,1H), 7.22(d,J＝10.3Hz,1H),6.92-7.11(m,2H),6.44(d,J＝7.7Hz,1H),5.37(s,1H),4.63(s,1H), 3.55(d,J＝15.4Hz,1H),3.14(s,1H),3.03(d,J＝9.8Hz,1H),2.24(s,1H),1.66(s,1H),1.20 (d,J＝6.6Hz,3H).
Example 7
(3R,14S)-6-fluoro-3-methyl-13-oxa-2,10,16,20,21,24-hexaazapentacyclo[16.5.2.110,14.04,9.021,25]h exacosa-1(24),4(9),5,7,18(25),19,22-heptaen-17-one
(3R,14S) -6-fluoro-3-methyl-13-oxa-2, 10,16,20,21, 24-hexaazapentacyclic [16.5.2.1 ]10, 14.04,9.021,25]Hexacosane-1 (24),4(9),5,7,18(25),19, 22-hepten-17-one
Figure BDA0002454609730000401
First step of
(R) -1- (5-fluoro-2- (2- (hydroxymethyl) morpholino) phenyl) ethan-1-one
1- (2, 5-difluorophenyl) ethan-1-one 7a (12.9g,82.6mmol), (R) -morpholin-2-ylmethanol 7b (4.86g,41.4 mmol) and potassium carbonate (22.9g,165.7mmol) were dissolved in 50mL of N, N-dimethylformamide and heated to 120 ℃ for 6 h. After completion of the reaction, it was cooled to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (50 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further purified by analysis with a silica gel column chromatography (eluent: System A) to obtain (R) -1- (5-fluoro-2- (2- (hydroxymethyl) morpholino) phenyl) ethan-1-one 7c (2.1g), yield: 20 percent.
MS m/z(ESI)：254.1[M+1]
Second step of
(R) - (4- (2-acetyl-4-fluorophenyl) morpholin-2-yl) methylmethanesulfonate
(R) -1- (5-fluoro-2- (2- (hydroxymethyl) morpholino) phenyl) ethan-1-one 7c (6g,23.68mmol) and triethylamine (9.9 mL,70.92mmol) were dissolved in 60mL of dichloromethane, methanesulfonyl chloride (5.42g,47.32mmol) was slowly added dropwise at 0 deg.C, and the mixture was transferred to room temperature for reaction overnight. After the reaction was completed, the reaction was quenched by adding 30mL of a saturated ammonium chloride solution, extracted with dichloromethane (20 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of (R) - (4- (2-acetyl-4-fluorophenyl) morpholin-2-yl) methylmethanesulfonate salt 7d (510mg), which was subjected to the next reaction without purification.
The third step
(R) -1- (2- (2- (azidomethyl) morpholino) -5-fluorophenyl) ethan-1-one
(R) - (4- (2-acetyl-4-fluorophenyl) morpholin-2-yl) methylmethanesulfonate salt 7d (510mg) was dissolved in 3mL of a solution in N, N-dimethylformamide, and sodium azide (200mg,3.08mmol) was added thereto, followed by reaction at room temperature overnight. After the reaction, 30mL of water was added, and the mixture was extracted with ethyl acetate (20 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of (R) -1- (2- (2- (azidomethyl) morpholino) -5-fluorophenyl) ethan-1-one 7e (428mg), which was subjected to the next reaction without purification.
MS m/z(ESI)：279.1[M+1]
The fourth step
(R) -N- ((E) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethylene) -2-methylpropyl-2-sulfinamide
(R) -1- (2- (2- (azidomethyl) morpholino) -5-fluorophenyl) ethan-1-one 7e (428mg,1.54mmol), (R) -2-methylpropane-2-sulfinamide 1d (373mg,3.08mmol), tetraethyltitanate (1.41mg,6.18mmol) was dissolved in 5mL of tetrahydrofuran and reacted at 70 ℃ overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was further purified by analysis with silica gel column chromatography (eluent: system a) to obtain (R) -N- ((E) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethylene) -2-methylpropyl-2-sulfinamide 7f (280mg), yield: 47.7 percent.
MS m/z(ESI)：382.2[M+1]
The fifth step
(R) -N- ((R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide
(R) -N- ((E) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethylene) -2-methylpropyl-2-sulfinamide 7f (280mg,0.73mmol) was dissolved in 5mL of tetrahydrofuran, and 9-borabicyclo [3,3,1] -nonane (3mL,1.5 mmol,0.5mol/L) was added and reacted at room temperature overnight. After the reaction was completed, 10mL of water was added to quench, extraction was performed with ethyl acetate (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was further purified by analytical analysis by silica gel column chromatography (eluent: System A) to obtain 7g (160mg) of (R) -N- ((R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide, yield: 57 percent.
MS m/z(ESI)：384.2[M+1]
The sixth step
(R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethan-1-amine
7g (160mg,0.42mmol) of (R) -N- ((R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide was dissolved in 3mL of a dichloromethane solution, and 3mL of a dioxane hydrochloride solution was added thereto, and the reaction was carried out at room temperature for 1 hour. After the LC-MS monitoring reaction is finished, the reaction solution is decompressed and concentrated to obtain a crude product of (R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethan-1-amine for 7h, and the product is subjected to the next reaction without purification.
Seventh step
5- (((R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester
Crude (R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethan-1-amine 7h (116mg), ethyl 5-chloropyrazolo [1,5-a ] pyrimidine-3-carboxylate 1h (115mg,0.51mmol) and N, N-diisopropylethylamine (434mg,3.36 mmol) were dissolved in 3mL of N-butanol and reacted at 120 ℃ for 6 h. LC-MS monitoring completion of the reaction, concentration under reduced pressure and further analytical purification of the resulting residue by silica gel column chromatography (eluent: system a) gave ethyl 5- (((R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 7i (80mg) in yield: 40.6 percent.
Eighth step
5- (((R) -1- (2- ((S) -2- (((tert-butoxycarbonyl) amino) methyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester
Ethyl 5- (((R) -1- (2- ((R) -2- (azidomethyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 7i (80mg,0.17mmol) was dissolved in 5mL of methanol, and di-tert-butyl pyrocarbonate (45mg, 0.21mmol) and 30mg of wet palladium on charcoal were added and reacted at room temperature for 5 hours under hydrogen protection. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of ethyl 5- (((R) -1- (2- ((S) -2- (((tert-butoxycarbonyl) amino) methyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 7j (93mg), which was subjected to the next reaction without purification.
The ninth step
5- (((R) -1- (2- ((S) -2- (((tert-butoxycarbonyl) amino) methyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
Ethyl 5- (((R) -1- (2- ((S) -2- (((tert-butoxycarbonyl) amino) methyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate 7j (93mg) was dissolved in 3mL of a mixed solvent of tetrahydrofuran, methanol and water (V: V: V ═ 1:4:1), and lithium hydroxide monohydrate (72mg,1.71mmol) was added thereto, followed by stirring at 75 ℃ overnight. LC-MS monitors the reaction is finished, cooling is carried out, dilute hydrochloric acid is slowly added dropwise to adjust the reaction to acidity, 10mL of water is added, ethyl acetate (20mL multiplied by 3) is used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, and reduced pressure concentration is carried out to obtain a crude product of 5- (((R) -1- (2- ((S) -2- (((tert-butoxycarbonyl) amino) methyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 7k, and the product is subjected to the next reaction without purification.
The tenth step
5- (((R) -1- (2- ((S) -2- (aminomethyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid
5- (((R) -1- (2- ((S) -2- (((tert-butoxycarbonyl) amino) methyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid 7k (87mg) was dissolved in 2mL of a dichloromethane solution, and 3mL of a dioxane hydrochloride solution was further added to the solution, and the reaction was carried out at room temperature for 1 hour. After the reaction was monitored by LC-MS, the reaction solution was concentrated under reduced pressure to obtain 7l crude product of 5- (((R) -1- (2- ((S) -2- (aminomethyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid, which was subjected to the next reaction without purification.
The eleventh step
(3R,14S) -6-fluoro-3-methyl-13-oxa-2, 10,16,20,21, 24-hexaazapentacyclic [16.5.2.1 ]10, 14.04,9.021,25]Hexacosane-1 (24),4(9),5,7,18(25),19, 22-hepten-17-one
Reacting 5- (((R) -1- (2- ((S) -2- (aminomethyl) morpholino) -5-fluorophenyl) ethyl) amino) pyrazolo [1,5-a]7l (70mg) of pyrimidine-3-carboxylic acid, pentafluorophenyl diphenylphosphate (78mg,0.20mmol) and N, N-diisopropylethylamine (176mg, 1.36mmol) were dissolved in 3mL of a mixed solvent of dichloromethane and N, N-dimethylformamide (V: V ═ 2:1) and reacted at room temperature overnight. LC-MS monitored the completion of the reaction, saturated ammonium chloride solution (20 mL. times.3) was added, extraction was performed with methylene chloride (20 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the liquid phase was prepared to give (3R,14S) -6-fluoro-3-methyl-13-oxa-2, 10,16,20,21, 24-hexaazapentacyclic ring [16.5.2.110,14.04,9.021,25]Hexacosane-1 (24),4(9),5,7,18(25),19, 22-hepten-17-one 7(8mg), yield: 12 percent.
MS m/z(ESI)：397.4[M+1]
Biological evaluation
Test example 1 determination of kinase Activity of the Compounds of the present invention on TRKA, TRKB, TRKC, TRKA (G595R), TRKA (G667C) and TRKC (G623R)
The following method was used to determine the degree of inhibition of the activity of recombinant human NTRK family kinase by the compounds of the invention under in vitro conditions. The method uses Cisbio
Figure BDA0002454609730000431
KinEASE-TK tyrosine kinase kit (cat # 62TK0PEB), the principle of which is based on time-resolved fluorescence energy resonance transfer (TF-FRET), reflects the strong or weak inhibition of NTRK kinase activity by compounds by measuring the extent of phosphorylation of biotinylated polypeptide substrates mediated by NTRK kinase. The detailed experimental procedures can be referred to the kit instructions. Recombinant human wild-type NTRK proteins were purchased from Carna bioscience (Cat Nos. TRKA #08-186, TRKB #08-187, TRKC #08-197), recombinant human mutant NTRK proteins were purchased from SignalChem (Cat Nos. TRKA G595R # N16-12BG-10, TRKC G623R # N18-12CH-10)
The experimental procedure is briefly described as follows: test compounds were first dissolved in DMSO to prepare stock solutions, and then diluted in a gradient of buffer solution provided in the kit, to give a final concentration of test compounds in the reaction system in the range of 1000nM to 0.004 nM. The ATP Km value concentration of each NTRK protein was measured using a gradient diluted ATP solution (Bio-engineering, Shanghai, Ltd., A600311), and the ATP concentrations in the reaction system were set to TRKA 100. mu.M, TRKB 10. mu.M, TRKC 50. mu.M, TRKA (G595R) 7. mu.M, TRKA (G667C) 1. mu.M and TRKC (G623R) 100. mu.M, respectively, based on the obtained Km value. The reaction is carried out in a 384-well microplate by first adding the compound and a certain amount of the corresponding NTRK protein to the wells and incubating at room temperature for 5-10 minutes, and then adding ATP solution and biotinylated polypeptide substrate to the reaction solutionThe solution was incubated at room temperature for 60 minutes with shaking. Subsequently, an anti-phosphotyrosine antibody conjugated with a europium-based element compound and streptavidin conjugated with modified allophycocyanin XL665 were added to the reaction, and incubation was continued for 1 hour with shaking at room temperature. After the incubation, the fluorescence intensity values of each well at an excitation wavelength of 304nM, an emission wavelength of 620nM and 665nM are measured in a microplate reader in TF-FRET mode. Percent inhibition of compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control (0.1% DMSO), and non-linear regression analysis was performed by GraphPad Prism 5 software at compound concentration log-inhibition, or IC of compound50Values, see table 1.
TABLE 1 inhibition of NTRK enzymatic Activity IC by Compounds of the invention50Data of
Figure BDA0002454609730000441
And (4) conclusion: the compound of the invention has better inhibition effect on TRKA, TRKB and TRKC kinase of wild type and mutant type.
Remarking: ND stands for not determined.

Claims (16)

1. A compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:
Figure FDA0002454609720000011
wherein:
ring A is selected from a 4-18 membered N-containing heterocyclic group or a bicyclic fused ring, wherein the heterocyclic group optionally contains one or more O or S (O)r；
Ring B is selected from aryl or heteroaryl;
ring C is selected from aryl or heteroaryl;
provided that when one of ring B and ring C is selected from monocyclic aryl or monocyclic heteroaryl, the other ring is selected from bicyclic aryl or bicyclic heteroaryl, and at least one of ring B and ring C is an N-containing heteroaryl;
L1is selected from- (CR)aRb)m-, any one of them- (CR)aRb) -optionally further substituted with-N (R)c) -, -O-or-S (O) r-is substituted; l is1Is preferably- (CH)2) -or- (CH)2)2-；
L2Is selected from- (CR)dRe)n-, any one of them- (CR)dRe) -optionally further substituted with-N (R)f) -, -O-or-S (O) r-is substituted;
L3selected from the group consisting of a bond and-N (R)c)-；
Each Ra、Rb、RdAnd ReThe same or different, each independently selected from hydrogen atom, deuterium, halogen, hydroxyl group, alkoxy group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group or-NR6R7Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, RaAnd RbTogether with the same carbon atom to which they are attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, any two RaTogether with the different carbon atoms to which they are respectively attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, RdAnd ReTogether with the same carbon atom to which they are attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, any two RdTogether with the different carbon atoms to which they are respectively attached form C3-C8Cycloalkyl or 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said C is3-C8Cycloalkyl or 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
each RcAnd RfThe same or different, each independently selected from a hydrogen atom, an alkyl group or a cycloalkyl group, wherein said alkyl or cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, alkoxy or cycloalkyl; rcAnd RfPreferably a hydrogen atom;
or, when L is1Is selected from- (CR)aRb)m-, any one of them- (CR)aRb) -further by-N (R)c) When substituted, RaOr RbAnd RcTogether with the carbon atom and nitrogen atom to which they are attached, form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
or, when L is2Is selected from- (CR)dRe)n-, any one of them- (CR)dRe) -further by-N (R)f) When substituted, RdOr ReAnd RfTogether with the carbon atom and nitrogen atom to which they are attached, form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group contains one or more of N, O or S (O)rAnd said 3-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s);
each R1、R2And R3Identical or different, each independently selected from the group consisting of hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s); preferably, R1、R2And R3Each independently selected from hydrogen, halogen, cyano, alkyl or alkoxy, more preferably, R1、R2And R3Each independently selected from hydrogen, cyano, F, Cl, Br, methyl, hydroxymethyl, halomethyl or methoxymethyl;
R4selected from the group consisting of hydrogen atoms, alkyl groups or cycloalkyl groups, wherein said alkyl or cycloalkyl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy or cycloalkyl; r4Preferably a hydrogen atom;
R5、R6and R7Each independently selected from the group consisting of hydrogen, hydroxy, halo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -C (O) R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10or-NR9C(O)R10Substituted with the substituent(s);
or, R6And R7Together with the atoms to which they are attached form a 4-8 membered heterocyclic group containing one or more of N, O or S (O)rAnd said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10or-NR9C(O)R10Substituted with the substituent(s);
R8、R9and R10Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;
m and n are the same or different and are each independently selected from 1,2, 3 or 4;
p, q and s are the same or different and are each independently selected from 0,1, 2,3, 4 or 5; and is
r is selected from 0,1 or 2.
2. The compound according to claim 1, which is a compound of the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure FDA0002454609720000031
wherein:
x is selected from-N (R)c) -, -O-or-S (O)r-; preferably NH;
Z1、Z2、Z4～Z6are the same or different and are each independently selected from N, NH, C (═ O) or C (R)3)；
Z3And Z7Identical or different, each independently selected from N or C;
X1～X3are the same or different, each independently selected from the group consisting of a bond, N, NH, C (═ O), and C (R)2)；X1～X3At most one is selected from the group consisting of a bond;
RAselected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy, alkoxy or cycloalkyl; rAPreferably methyl;
Rcselected from the group consisting of hydrogen atoms, alkyl groups or cycloalkyl groups, wherein said alkyl or cycloalkyl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy or cycloalkyl; rcPreferably a hydrogen atom;
or, when X is selected from-N (R)c) When is, RAAnd RcTogether with the carbon atom and nitrogen atom to which they are attached, form a 4-to 8-membered heterocyclic group, wherein the 4-to 8-membered heterocyclic group contains one or more of N, O or S (O)rAnd said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═ O, -c (O) R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR6R7、-SO2NR6R7Or NR6C(O)R7Substituted with the substituent(s); and is
R1～R7、L1P and r are as defined in claim 1.
3. The compound according to claim 2, which is a compound of the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,
Figure FDA0002454609720000041
wherein: r1、R2、R4、Z1～Z7、X1～X3、RA、X、L1And p is as defined in claim 2.
4. A compound according to claim 2 or 3, which is a compound of general formula (IV), (V) or (VI), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
Figure FDA0002454609720000042
wherein: r1、R2、R4、Rc、X1～X3、RA、L1And p is as defined in claim 2.
5. The compound of claim 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R1and R2Each independently selected from hydrogen, cyano, F, Cl, Br, methyl, hydroxymethyl, halomethyl or methoxymethyl;
R4selected from hydrogen atoms or C1-C4An alkyl group;
Rcis a hydrogen atom;
X1～X3is CH;
RAis selected from C1-C4Alkyl, preferably methyl;
L1is selected from- (CH)2) -or- (CH)2)2-; and is
p is 0.
6. A compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from monocyclic heterocyclyl; preferably 4-6 membered monocyclic heterocyclic group; more preferably the following groups:
Figure FDA0002454609720000051
7. a compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a bicyclic fused heterocyclyl, a bicyclic bridged heterocyclyl or a bicyclic spiroheterocyclyl, more preferably the group:
Figure FDA0002454609720000052
8. a compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 8-to 10-membered bicyclic fused rings, preferably from
Figure FDA0002454609720000053
9. A compound according to claims 1-8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Figure FDA0002454609720000054
10. a process for the preparation of a compound of general formula (II) according to claim 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which comprises:
Figure FDA0002454609720000061
carrying out condensation reaction on the compound of the general formula (IIA) under an alkaline condition to obtain a compound of a general formula (II);
wherein: ring A, R1～R2、R4、RA、Z1～Z7、X1～X3、X、L1And p is as defined in claim 2.
11. A compound of formula (IIA) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
Figure FDA0002454609720000062
wherein: ring A, R1～R2、R4、RA、Z1～Z7、X1～X3、X、L1And p is as defined in claim 2.
12. A compound according to claim 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Figure FDA0002454609720000063
13. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
14. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of a disease mediated by ALK, TRK and/or ROS1, preferably for the manufacture of a medicament for the treatment of a TRK mediated disease; wherein the disease mediated by ALK, TRK and/or ROS1 is preferably pain, cancer, inflammation, neurodegenerative disease or trypanosoma infection, and wherein the cancer is preferably a neuroblastoma, ovarian cancer, breast cancer, prostate cancer, gastric cancer, tumor of the digestive tract, liver cancer, cholangiocarcinoma, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, colorectal cancer, breast analog secreting cancer, sarcoma, head and neck tumors, and renal cancer.
15. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the preparation of an ALK, TRK and/or ROS1 inhibitor, preferably for the preparation of a TRK inhibitor.
16. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the treatment of pain, cancer, inflammation, neurodegenerative disease or trypanosoma infection, wherein the cancer is preferably neuroblastoma, ovarian cancer, breast cancer, prostate cancer, gastric cancer, tumors of the digestive tract, liver cancer, cholangiocarcinoma, pancreatic cancer, multiple myeloma, astrocytoma, medulloblastoma, glioma, melanoma, thyroid cancer, lung cancer, large cell neuroendocrine tumor, colorectal cancer, breast analog secreting cancer, sarcoma, head and neck tumors, and renal cancer.
CN202010302699.2A 2020-04-17 2020-04-17 Macrocyclic lactam derivative, preparation method and application thereof Pending CN113527298A (en)

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