CN116063324A - Inhibitors of BTK and/or RET having macrocyclic structure - Google Patents
Inhibitors of BTK and/or RET having macrocyclic structure Download PDFInfo
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- CN116063324A CN116063324A CN202211331237.9A CN202211331237A CN116063324A CN 116063324 A CN116063324 A CN 116063324A CN 202211331237 A CN202211331237 A CN 202211331237A CN 116063324 A CN116063324 A CN 116063324A
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Abstract
The present invention provides compounds of formula (I) or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers thereof and their use in cancer, autoimmune diseases.
Description
Technical Field
The present invention relates to compounds and stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers thereof and their use as inhibitors of RET, BTK and other kinases. More specifically, the present invention provides novel compounds and stereoisomers thereof which are inhibitors of RET and/or BTK and their use in the treatment of RET and/or BTK mediated related diseases.
Background
RET (rearranged during transfection) is a protooncogene located on chromosome 10. RET protein encoded by RET gene is a receptor tyrosine kinase (RTK, receptor tyrosine kinase) existing on cell membrane, belonging to cadherin superfamily member. RET gene plays an important role in the development of kidney and enteric nervous system in embryo stage, and is also critical in the homeostasis of various tissues such as neurons, neuroendocrine, hematopoietic tissues and male germ cells. Classical activation of RTKs requires ligand-receptor interactions, but activation of RET requires interactions between its ligand (glial cell-derived neurotrophic factor family ligand, GFLS) and a co-receptor (GFLS family receptor- α), the resulting GFLS-gfrα complex binds to the extracellular domain of RET, resulting in phosphorylation of intracellular tyrosine kinase domains, recruiting related adaptor proteins, activating cascade of cell proliferation etc. signaling, thus activating several pathways including MAPK, PI3K, JAK-STAT, PKA, PKC, etc.
There are mainly two oncogenic activation mechanisms of RET, one is that chromosomal rearrangements produce a novel fusion protein, typically a kinase domain of RET and a protein fusion comprising a self-dimerization domain; and secondly, point mutation of RET gene. Mutated RET genes may encode RET proteins with aberrant activity, which can transmit aberrant signals and cause a variety of effects: including cell growth, survival, invasion, metastasis, etc. Sustained signaling can cause excessive proliferation of cells, inducing a variety of cancers.
RET rearrangements are present in 1% -2% of NSCLC patients, 5% -10% of papillary thyroid carcinoma patients, and RET point mutations are present in 60% of medullary thyroid carcinomas. The most common RET fusion types are KIF5B-RET, CCDC6-RET, followed by NCOA4-RET, TRIM33-RET, and there are also reports of ZNF477P-RET, ERCC1-RET, HTR4-RET, CLIP 1-RET.
Abnormal RET expression and/or activity has been demonstrated in various cancers and gastrointestinal diseases such as Irritable Bowel Syndrome (IBS).
Most of the RET-resistant drugs are currently multikinase inhibitors such as Vandetanib (mainly used for the treatment of unresectable, locally advanced or metastatic symptomatic or progressive medullary thyroid cancer), sorafenib (liver cancer, renal cancer, locally recurrent or metastatic, progressive, radioiodinated differentiated thyroid-like cancers). The most common adverse drug reactions (> 20%) of vanretanib, which are likely to bring about toxic and side effects while having a broad spectrum of anticancer agents, are diarrhea, rash, acne, nausea, hypertension, headache, fatigue, anorexia and abdominal pain (vanretanib drug description, FDA); the most common drug-related adverse events of Sorafenib were rash (38%), diarrhea (37%), hand-foot skin reactions (35%) and fatigue (33%) (Sorafenib drug instructions, FDA). RET selective inhibitors Selpercatinib and Pralsetinib, which have been marketed in batches, are indicated for thyroid cancer and non-small cell lung (Selpercatinib and Pralsetinib drug Specification, FDA). And not all RET rearrangement/mutation patients respond to these drugs, it is necessary to develop inhibitors that are highly active, have little side effects, are highly specific, and are effective against RET mutations and rearrangements.
The current literature on RET inhibitors is successively reported, as disclosed in WO2019/126121 as macrocyclic compounds of RET kinase inhibitors, and the specific description in this patent is not considered part of the present invention.
After binding of the antigen to the B cell antigen receptor (BCR) at the plasma membrane BCR, PLCG2 is phosphorylated at several specific sites, and then downstream signaling pathways are triggered by calcium mobilization, finally activating Protein Kinase C (PKC) family members. PLCG2 phosphorylation is closely related to the adaptor B cell adaptor protein BLNK, which serves as a platform, aggregates multiple signaling proteins, and is involved in cytokine receptor signaling pathways. And BTK plays an important role in the function of innate immune cells and adaptive immunity as a component of the Toll-like receptor (TLR) pathway. The B Cell Receptor (BCR) dependence of BTK induces activation signal pathways, principally the pool transcription factor NF-. Kappa.B and the nuclear factor of activated T cells (NFAT). Both of these conditions are mediated by Protein Kinase C (PKC).
BTK kinases are involved in the transduction of a variety of important signals in the body, and their activation has a significant impact on a variety of cellular processes. BTK disorders can lead to severe immunodeficiency, affecting the developmental maturation of B cells. When the organism generates immune response, BTK induces gene expression by mediating B cell signal activation, thereby regulating proliferation and apoptosis of B cells. Over-expression of BTK in normal human monocytes will promote TNF- α production, whereas those with abnormal BTK genes will have reduced TNF- α production, resulting in BTK activation to induce macrophage production of pro-inflammatory factors. The structure and the functional activation mechanism of the BTK are integrated, so that the BTK becomes a target point with wide target diseases, such as B cell malignant tumor, asthma, rheumatic arthritis, systemic lupus erythematosus and the like.
Btk is a key molecule in B cell antigen receptor (BCR) coupled signaling, whose activity is regulated by Lyn and Syk. And studies have shown that Src family kinases act upstream of Btk, activated by non-phosphorylating mediated mechanisms (Ronen Gabizon, j.med. Chem.2020,63, 5100-51011). BTK inhibitors inhibit proliferation, chemotaxis, and adhesion of B-cell lymphoma cells. Is mainly used for B cell malignant tumors (IMBRUVICA, SUmmary Review, FDA@drugs) such as Mantle Cell Lymphoma (MCL), chronic Lymphocytic Leukemia (CLL), primary macroglobulinemia (WM) and the like. The mechanism of action of BTK inhibitors is to bind to Cys-481 at the BTK (active) site, preventing BTK activation. There is an urgent need to develop drugs effective in patients with BTK C481S resistance (Lian Xu, blood,.2017 May 4;129 (18): 2519-2525).
The invention comprises the following steps:
in one aspect the invention provides a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer of formula (I):
m is selected from N, CH, CR 1 ;
X 1 、X 3 Each independently selected from CH 2 、CHR 6 、CR 6 R 7 C= O, O, absent;
X 2 、X 4 each independently selectFrom CH 2 、CHR 6 、CR 6 R 7 、C=O、NH、NR 6 O, absent;
Q 1 、Q 2 each independently selected from the group consisting of absent, hydrogen, halogen, C 1-6 Alkyl, amino, -NRaRb, -NHRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -C (O) NHRa, -C (O) NRaRb, - (CRaRb) nC (O) NHRa, - (CHRa) nC (O) NHRa, - (CH 2 )nC(O)NHRa、-S(O) 2 Ra, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyloxy or 3-6 membered heterocycloalkyloxy, 6-8 membered aryl, 5-10 membered heteroaryl; the C is 1-6 Alkyl groups may be substituted with halogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, hydroxy, amino, nitro; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl may be substituted by halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo, cyano; the 6-8 membered aryl, 5-10 membered heteroaryl may be substituted with halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo; the heteroatomic in the heterocycle alkane and the heteroaryl is N, O, S;
a is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and C 2 -C 6 Olefins or C 2 -C 6 Alkynes, 3-6 membered unsaturated cycloalkyl, 3-6 membered unsaturated heterocycloalkyl, 6-8 membered aryl, 5-10 membered heteroaryl, said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 2 -C 6 Olefins or C 2 -C 6 Alkynes, 3-6 membered unsaturated cycloalkyl, 3-6 membered unsaturated heterocycloalkyl, 6-8 membered aryl, 5-10 membered heteroaryl groups may be substituted by halogen, C 1-4 Alkyl, cyano, hydroxy, nitro, -NRcRd, -NHRc, - (CH) 2 )nNRcRd、-NHC(O)ORc、-NHC(O)NHRc、-NHC(O)Rc、-ORc、-OC(O)ORc、-OC(O)Rc、-C(O)Rc、-C(O)NHRc、-(CH 2 ) nC (O) NHRc, -C (O) NRcRd;
R 1 selected from halogen, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 An alkyl acyl group; as the preferable R 1 Selected from F, amino, methyl, methoxy, acetyl;
R 2 、R 8 selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, optionally R 2 、R 8 And adjacent carbon atoms may form a 3-6 membered ring;
R 3 selected from hydrogen or amino;
R 4 、R 5 each independently selected from hydrogen, halogen, C 1-4 An alkyl group;
R 6 、R 7 each independently selected from C 1-4 Alkyl, which may be substituted by halogen, amino, hydroxy;
ra, rb, rc, rd are each independently selected from C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, which alkyl can be substituted by halogen, amino, hydroxy, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl substituted; the cycloalkyl, heterocycloalkyl may be substituted with halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy substituted;
n is selected from 1, 2 or 3;
the conditions are as follows:
when X is 1 、X 2 、X 3 、X 4 Q when it is not present 1 And Q is equal to 2 Not simultaneously being hydrogen or C 1-4 An alkyl group;
when X is 1 、X 2 Q when it is not present 1 Not hydrogen or C 1-4 An alkyl group;
when X is 3 、X 4 Q when it is not present 2 Not hydrogen or C 1-4 An alkyl group.
In one embodiment there is provided according to the invention a compound of the general formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein
M is selected from N, CH.
In one embodiment, there is provided according to the invention a compound of the general formula (I) as defined above, or a stereoisomer, a pharmaceutically acceptable salt, solvate, or a mixture thereofTautomers, wherein R 4 、R 5 Each independently selected from hydrogen.
In one embodiment there is provided according to the invention a compound of the general formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein
A is selected from benzene ring, pyridine ring,Can be halogen, C 1-4 Alkyl, cyano, hydroxy, nitro, -NRcRd, -NHRc, - (CH) 2 )nNRcRd、-NHC(O)ORc、-NHC(O)NHRc、-NHC(O)Rc、-ORc、-OC(O)ORc、-OC(O)Rc、-C(O)Rc、-C(O)NHRc、-(CH 2 ) nC (O) NHRc, -C (O) NRcRd; rc, rd are each independently selected from C 1-4 An alkyl group; the C is 1-4 Alkyl groups may be substituted by halogen, amino, hydroxy, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl groups are substituted.
In one embodiment there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q 1 、Q 2 Each independently selected from the group consisting of absent, hydrogen, halogen, C 1-4 Alkyl, amino, -NRaRb, -NHRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -C (O) NHRa, -C (O) NRaRb, - (CRaRb) nC (O) NHRa, - (CHRa) nC (O) NHRa, - (CH 2 )nC(O)NHRa、-S(O) 2 Ra, cyclopropyl, cyclobutyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl, oxolanyl, azetidinyl, oxolanyl, phenyl, pyridinyl, 5 membered heteroaryl; the C is 1-4 Alkyl groups may be substituted with halogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, hydroxy, amino, nitro; the cyclopropyl, cyclobutyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl may be substituted by halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitroOxo, cyano; the phenyl, pyridyl, 5 membered heteroaryl groups may be substituted with halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo; ra and Rb are each independently selected from C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the alkyl, cycloalkyl, heterocycloalkyl groups may be substituted with halogen, amino, hydroxy, C 1-4 Alkoxy substituted;
ra and Rb are each independently selected from C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the alkyl, cycloalkyl, heterocycloalkyl groups may be substituted with halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl substituted;
n is selected from 1, 2 or 3.
In one embodiment there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q 1 、Q 2 Wherein the 5-membered heteroaryl is selected from halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo, cyano substituted or unsubstituted structures:
in one embodiment, there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer Q thereof 1 、Q 2 Each independently selected from amino, -NRaRb, -NHRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -C (O) NHRa, -C (O) NRaRb, - (CRaRb) nC (O) NHRa, - (CHRa) nC (O) NHRa, - (CH) 2 )nC(O)NHRa、-S(O) 2 Ra, wherein Ra, rb are each independently selected from the group consisting of a halogen, an amino, a hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 C substituted or unsubstituted by alkyl 1-4 Alkyl group,
In one embodiment, there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer Q thereof 1 、Q 2 Each independently selected from the group consisting of absent, hydrogen, halogen, C 1-4 An alkyl group; the C is 1-4 The alkyl group may be substituted with halogen, hydroxy, amino, nitro,Substituted.
In one embodiment there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 Is hydrogen, methyl, trifluoromethyl.
In one embodiment there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 4 、R 5 Each independently selected from hydrogen.
In one embodiment there is provided in accordance with the invention a compound of formula (I) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X 1 、X 3 Each independently selected from CH 2 Is absent; x is X 2 、X 4 Each independently selected from CH 2 、C=O、NH、NR 6 O, absent; r is R 6 Selected from C 1-4 Alkyl which may be substituted by halogen, preferably F, amino, hydroxy.
In one embodiment there is provided according to the invention a compound of the general formula (II) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof
Wherein R is 1 、R 2 、R 3 、A、X 1 、X 2 、Q 1 Is as defined above.
In one embodiment there is provided in accordance with the invention a compound of formula (III) above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof
Wherein R is 2 、X 1 、X 2 、Q 1 Is defined as set forth in the claims.
In one embodiment, a compound according to the present invention is provided having the structure:
In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a particular aspect, the pharmaceutical composition of the invention is provided for use in the prevention or treatment of a disease, such as a disease caused by deregulation of the expression or activity or level of the RET gene, RET kinase, or any one thereof, such as cancer, BTK mediated disease. In a particular aspect, the pharmaceutical composition may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the present invention.
In another aspect of the invention, there is provided a pharmaceutical combination (or pharmaceutical combination product) comprising a compound of the invention and an additional active agent.
The invention also provides the use of a compound or stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer as described above, in the manufacture of a medicament for the treatment of a disease or disorder selected from cancer.
Further, the cancer of the present invention is lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine tumors of type 2A or 2B (MEN 2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma and cervical cancer.
Further, the cancers of the invention are associated with the following disorders: a RET gene, a RET kinase, or a cancer caused by deregulation of the expression or activity or level of any of these. Preferred cancers are Medullary Thyroid Carcinoma (MTC), non-small cell lung carcinoma (NSCLC), metastatic solid tumors and advanced solid tumors of RET gene mutation/fusion.
The present invention provides the use of a compound or stereoisomer in the manufacture of a medicament for the treatment of a BTK mediated disease.
Further, the BTK-mediated disease of the invention is selected from cancer, autoimmune disease or allergic disease. Preferably, the cancer is selected from one or more of diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, mature B-cell acute lymphoblastic leukemia, 17 p-deleted chronic lymphocytic leukemia, waldenstrom macroglobulinemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, intravascular large B-cell lymphoma and primary exudative lymphoma; the autoimmune disease is selected from one or more of systemic lupus erythematosus, rheumatoid arthritis, sjogren's syndrome, multiple sclerosis, inflammatory enteritis such as Crohn's disease and ulcerative colitis, urticaria, immune thrombocytopenia, igA nephropathy, hidradenitis suppurativa, psoriasis, vitiligo, neutrophilic dermatoses, autoimmune vesicular diseases such as pemphigus and pemphigoid, igG 4-related diseases, autoimmune hemolytic anemia, rheumatic fever, antiphospholipid syndrome, systemic sclerosis/scleroderma, autoimmune hepatitis, primary sclerocholangitis, primary biliary cirrhosis, allergic purpura, churg-Strauss syndrome/allergic granulomatosis vasculitis, behcet's disease, ANCA-related small vessel inflammation, dermatitis herpetiformis; the allergic diseases are selected from one or more of allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, and chronic asthma.
Detailed Description
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to an aliphatic hydrocarbon group, and to a saturated hydrocarbon group. The alkyl moiety may be a straight chain alkyl group or a branched alkyl group. For example, C 1-6 Alkyl, C 1-4 Alkyl or C 1-3 An alkyl group. C (C) 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, for example, an alkyl group having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and the like. The alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphonyl, and the like.
"Ring" refers to any covalently closed structure, including, for example, carbocycles (e.g., aryl or cycloalkyl), heterocycles (e.g., heteroaryl or heterocycloalkyl), aromatic groups (e.g., aryl or heteroaryl), non-aromatic groups (e.g., cycloalkyl or heterocycloalkyl). The ring may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings. The ring of the present application typically has 1 to 20 ring atoms, for example 1 ring atom, 2 ring atoms, 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, 11 ring atoms, 12 ring atoms, 13 ring atoms, 14 ring atoms, 15 ring atoms, 16 ring atoms, 17 ring atoms, 18 ring atoms, 19 ring atoms, or 20 ring atoms.
"Yuan" means the number of skeleton atoms constituting a ring. Typical 5-membered rings include, for example, cyclopentyl, pyrrole, imidazole, thiazole, furan, thiophene, and the like; typical 6-membered rings include, for example, cyclohexyl, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, benzene, and the like. Wherein, the ring containing hetero atoms in the skeleton atom is a heterocycle; the heteroatom-containing aryl is heteroaryl; the non-aromatic group containing a heteroatom is a heterocycloalkyl group, which includes heterocycloalkyl groups.
"heteroatom" refers to an atom other than carbon or hydrogen. One or more heteroatoms in the heterocycles of the present application may be independently selected from O, S, N, si and P, but are not limited thereto.
"aryl" refers to a monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group of 6 to 14 carbon atoms (6 to 14 members) with a conjugated pi-electron system, preferably 6 to 10 atoms, such as phenyl and naphthyl. More preferably phenyl.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g., 1, 2,3, or 4) heteroatoms, 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl such as 1H-pyrazol-4-yl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, cycloalkyl ring, or another heteroaryl group, thereby forming a fused heteroaryl group. The fused heteroaryl group is preferably an 8-10 membered fused heteroaryl group including, but not limited to: indolyl such as 1H-indol-5-yl, 2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazolyl such as 2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl, or 1H-benzo [ d ] imidazolyl such as 1H-benzo [ d ] imidazol-6-yl.
"cycloalkyl" refers to a cyclic hydrocarbon substituent comprising 1-3 rings, saturated or partially unsaturated (containing one or more double bonds, but no ring has a fully conjugated pi electron system), which includes monocycloalkyl, bicycloalkyl, and tricycloalkyl groups containing 3-20 ring-formable carbon atoms, preferably 3-10 carbon atoms (i.e., 3-10 membered cycloalkyl groups, which may also be referred to as C3-C10 cycloalkyl groups), such as 3 to 8, 3 to 7, 3 to 6, 5 to 6 carbon atoms. Preferably, the cycloalkyl is selected from monovalent cycloalkyl groups obtained from the following rings:
preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl or cyclohexenyl.
It will be appreciated that when a cycloalkyl group is attached to two groups, for example where the groups are cycloalkyl groups, depending on the structure or context, the cycloalkyl groups are divalent, i.e. there are two attachment sites. In this case, it may be called a cycloalkylene group. Examples of preferred cycloalkylene groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl (e.g., cyclopentyl-1, 2-diyl, cyclopentyl-1, 3-diyl), cyclohexyl (e.g., cyclohexyl-1, 2-diyl, cyclohexyl-1, 3-diyl, cyclohexyl-1, 4-diyl), cycloheptylene, cyclooctyl, and the like.
"heterocycloalkyl" and "cycloheteroalkyl" are used interchangeably to refer to a saturated, non-aromatic, monocyclic, fused, bridged ring containing one or more (e.g., 1, 2, 3, or 4) heteroatomsAnd a spiro ring. Wherein the heteroatom may be N, O, S or SO 2 N, O and/or S are preferred. Heterocycloalkyl groups can be 3-to 10-membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, i.e., contain 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) mono-or bi-or tricyclic groups. Typical heterocycloalkyl groups include, but are not limited to, monovalent groups derived from the following rings:
these heterocycloalkyl groups can also be represented by the commonly understood structural formulae, e.g
It is understood that when a heterocycloalkyl group is attached to two groups, depending on structure or context, the heterocycloalkyl group is a divalent group, i.e., there are two attachment sites. In this case, it may be also called a heterocycloalkylene group.
"oxo" refers to the substitution of hydrogen on carbon with =o.
"halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.
"haloalkyl" means that at least one hydrogen in the alkyl group is replaced by a halogen atom, e.g., CF 3 。
"substituted" means that one or more hydrogen atoms, preferably up to 5 (e.g., 1, 2, 3, 4, 5), more preferably 1 to 3 hydrogen atoms in the group may be substituted independently of each other with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"inhibitor" refers to a substance that decreases the activity of an enzyme.
"optionally," "may" and "may" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not.
The term "substituted or unsubstituted" as used herein means that any group is mono-or polysubstituted by the indicated substituents to the extent chemically permitted by such mono-or polysubstituted (including polysubstituted at the same moiety), each substituent being able to be located at any available position on the group and being able to be attached by any available atom on said substituent. By "any available position" is meant any position on the group that is chemically available by methods known in the art or taught herein and that does not result in an unduly labile molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent and thus may be the same or different.
"stereoisomers" as used herein, refers to "stereoisomers" that when a compound of the invention contains one or more asymmetric centers, it may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The compounds of the invention may have asymmetric centers and thus result in the presence of two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. If the compounds of the present invention contain olefinic double bonds, the scope of the present invention includes cis-isomers and trans-isomers unless specified otherwise. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms which have different points of attachment of hydrogen through one or more double bond shifts, for example, the keto and his enol forms are keto-enol tautomers. Each tautomer and mixtures thereof are within the scope of the present invention. Enantiomers of all compounds. Diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof, and the like are within the scope of the present invention.
The term "compound of the invention" as used herein is intended to encompass compounds of the general formula (I) as defined herein or any preferred or specific embodiment thereof, including compounds of the formulae (I), (II), (III) and the like, and example compounds, stereoisomers, pharmaceutically acceptable salts, tautomers or solvates thereof.
The term "pharmaceutically acceptable" as used herein means molecular entities and compositions approved by or by the corresponding agency of the respective country or listed in the generally recognized pharmacopoeia for animals, and more particularly humans, or which do not produce adverse, allergic or other untoward reactions when administered in appropriate amounts to animals, such as humans.
The term "pharmaceutically acceptable salt" as used herein means a salt of a compound of the invention which is pharmaceutically acceptable and which has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts.
The term "individual" as used herein includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
The term "pharmaceutical composition" as used herein refers to a composition comprising one or more compounds of formula (I) or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof, and a carrier or excipient commonly accepted in the art for delivering a biologically active compound to an organism (e.g., a human).
The term "pharmaceutical combination" as used herein means that the compounds of the present invention may be combined with other active agents for the purpose of the present invention. The other active agent may be one or more additional compounds of the present invention, or may be a second or additional (e.g., third) compound that is compatible with, i.e., does not adversely affect each other, or has complementary activity to, the compounds of the present invention. Such agents are suitably present in combination in an amount effective to achieve the intended purpose. The other active agents may be co-administered with the compounds of the present invention in a single pharmaceutical composition or may be administered separately in separate discrete units from the compounds of the present invention, either simultaneously or sequentially when administered separately. The successive administrations may be close or distant in time.
It is to be understood that the structures, groups, etc. of the compounds of the present invention conform to the chemical valence rules. Some groups or structures have their linkages omitted when written. For example, in some cases, it is described that M in formula I is selected from N, and M is=N-based on the general structure. Whether written M is selected from N or M is selected from = N-, is understood by those skilled in the art. Other groups may be similarly understood and interpreted.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Advantageous effects of the invention
The invention provides a compound with the structural characteristics of a general formula (I), and researches show that the compound can effectively inhibit the activity of RET and/or BTK and other kinases (wild type or mutant type), thereby preventing or treating RET and/or BTK and other kinase related diseases.
The compound of the invention has the following beneficial effects:
high RET and/or BTK kinase inhibitory activity; preferred compounds of the invention show IC50 in the range of 0.1nM to 1. Mu.M, preferably in the range of 0.1nM to 0.1. Mu.M in assay experiments;
has high activity on mutant RET and/or BTK, and can be used for treating related diseases with drug resistance due to mutation. Based on the beneficial effects of the compound, the invention also provides the following technical schemes.
Pharmaceutical composition and administration thereof
The pharmaceutical compositions of the invention may be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences, 20 th edition. For example, the pharmaceutical compositions of the invention described above may be prepared by mixing a compound of the invention with one or more pharmaceutically acceptable excipients. The preparation may further comprise the step of mixing one or more additional active ingredients with the compound of the invention and one or more pharmaceutically acceptable excipients.
The choice of excipients included in a particular composition will depend on a variety of factors, such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, howard C., et al, ansel's Pharmaceutical Dosage Forms and Drug Delivery systems, philadelphia: lippincott, williams & Wilkins,2004, including, for example, adjuvants, diluents, carriers, pH modifying agents, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, flavoring agents, other known additives.
The pharmaceutical compositions of the present invention may be administered in a standard manner. For example, suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ocular, nasal, buccal, or pulmonary (inhalation), wherein parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. For these purposes, the compounds of the present invention may be formulated by methods known in the art into the form of, for example, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops, aerosols, dry powder formulations and sterile injectable aqueous or oily solutions or suspensions.
The size of the prophylactic or therapeutic dose of a compound of the invention will vary depending on a number of factors, including the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 5000mg, e.g., about 0.01 to about 1000 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg person, this amounts to about 0.007 mg/day to about 7000 mg/day, for example about 0.7 mg/day to about 1500 mg/day. Depending on the mode of administration, the compounds of the invention may be present in the pharmaceutical composition in an amount of about 0.01mg to about 1000mg, suitably 0.1 to 500mg, preferably 0.5 to 300mg, more preferably 1 to 150mg, particularly preferably 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg, etc.; accordingly, the pharmaceutical composition of the invention will comprise from 0.05 to 99% w/w (weight percent), such as from 0.05 to 80% w/w, such as from 0.10 to 70% w/w, such as from 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be appreciated that it may be necessary in some circumstances to use doses beyond these limits.
Detailed Description
To further illustrate the present invention, the following describes in detail the active compounds for inhibiting BTK, the preparation method and the application thereof, which are provided in the present invention, in conjunction with examples
The following abbreviations have the meanings indicated below:
K 2 CO 3 represents potassium carbonate;
Na 2 CO 3 represents sodium carbonate;
DMF means N, N-dimethylformamide;
DCM represents dichloromethane;
EtOH represents ethanol;
MeOH represents methanol
THF represents tetrahydrofuran;
EA represents ethyl acetate
TEA represents triethylamine;
DIPEA represents N, N-diisopropylethylamine;
DIAD means diisopropyl azodicarboxylate
PPh 3 Representing triphenylphosphine
LiOH represents lithium hydroxide
HCl represents hydrogen chloride
POCl 3 Represents phosphorus oxychloride
FDPP represents pentafluorophenyl diphenyl phosphate
K 3 PO 4 Represents anhydrous potassium phosphate
Pd(dppf)cl 2 Represents [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Pd(PPh 3 ) 4 Represents tetrakis triphenylphosphine palladium;
NBS represents N-bromosuccinimide
CDI represents N, N' -carbonyldiimidazole
MeNH 2 ·H 2 O represents 40% aqueous methylamine solution
The patent also provides a synthesis method of the compound, and the synthesis method of the invention mainly comprises a preparation method reported in chemical literature or related synthesis by taking a commercial chemical reagent as a starting material.
Example 1: (1 3 E,1 4 E) -6- (aminomethyl) -1 7 - (amino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]The preparation and synthesis steps of pyrimidine-4 (3, 2) -pyridine heterocycle nona-tomato-9-one (compound 1) are shown as follows:
Step 1: preparation of 2- ((5-fluoro-2-methoxypyridin-3-yl) methyl) isoindoline-1, 3-dione (Compound 1A)
(5-fluoro-2-methoxypyridin-3-yl) methanol (3.14 g,20 mmol) and TEA (2.83 g,28 mmol) were dissolved in DCM (100 mL) under argon, methanesulfonyl chloride (2.4 g,21 mmol) was added dropwise to the above solution at 0deg.C, then the reaction system was stirred at room temperature for 2h, quenched with water, the ethyl acetate was extracted, the organic layer was washed with water, the saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated by filtration, the residue was dissolved in DMF (50 mL), then potassium phthalimide (5.55 g,30 mmol) was added at 0deg.C, then the mixture was stirred at room temperature overnight, quenched with water, the ethyl acetate was extracted, the organic layer was washed with saturated sodium chloride solution, anhydrousDrying with sodium sulfate, filtering and concentrating to obtain a compound 1A. MS (ESI) M/z 287.0 (M+H) +
Step 2: preparation of 2- ((5-fluoro-2-hydroxypyridin-3-yl) methyl) isoindoline-1, 3-dione (Compound 1B)
2- ((5-fluoro-2-methoxypyridin-3-yl) methyl) isoindoline-1, 3-dione (2 g,6.99 mmol) was dissolved in EtOH (30 mL), 4N HCl dioxane solution (50 mL,209.7 mmol) was added and the system stirred at 80℃overnight. After the reaction was completed, the reaction solution was concentrated, a small amount of water was added to the residue, and the resultant solid was filtered, rinsed with water, and dried in vacuo to obtain compound 1B.
MS(ESI)m/z 273.1(M+H) + 。
Step 3: preparation of ethyl 5, 7-dihydroxy-6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 1C)
Ethyl 5-amino-1H-pyrazole-4-carboxylate (15.0 g,96.77 mmol) was dissolved in EtOH (96 mL) and diethyl phenylmalonate (45.6 g,193.50 mmol) and sodium ethoxide (13.2 g,193.50 mmol) were added at room temperature. After the reaction is heated to 80 ℃, stirring is carried out for 20 hours, after the reaction is completed, the system is cooled to room temperature, filtered, and washed by ethanol, and finally the compound 1C is obtained.
MS(ESI)m/z 300.2(M+H) +
Step 4: preparation of ethyl 5, 7-dichloro-6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 1D)
5, 7-dihydroxy-6-phenylpyrazolo [1,5-a ]]Pyrimidine-3-carboxylic acid ethyl ester (14.5 g,42.27 mmol) was slowly dissolved in POCl 3 (70 mL) followed by room temperatureN, N-dimethylaniline (4.0 mL,31.70 mmol) was added. After the reaction was stirred for 12 hours at 110 ℃, after the reaction was completed, the remaining reaction solution was poured into an ice-water bath after the reaction was concentrated, DCM was extracted 3 times, and the organic phase was concentrated and purified by silica gel column chromatography to obtain compound 1D.
MS(ESI)m/z 336.2(M+H) +
Step 5: preparation of 5-chloro-7-dibenzylamino-6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester (Compound 1E)
Ethyl 5, 7-dichloro-6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylate (2.0 g,6.0 mmol) was dissolved in DCM (12 mL) and DIPEA (2.0 mL,12.0 mmol) and dibenzylamine (2.3 mL,12.0 mmol) were added at room temperature. The reaction was stirred for 13 hours, after the reaction was completed, the reaction was quenched by adding saturated aqueous citric acid, extracted 3 times with DCM, and the concentrated organic phase was separated and purified by silica gel column chromatography to obtain compound 1E.
MS(ESI)m/z 497.2(M+H) +
Step 6: preparation of benzyl tert-butyl (2-hydroxypropane-1, 3-diyl) dicarbamate (Compound 1F)
Tert-butyl (3-amino-2-hydroxypropyl) carbamate (3.8 g,21.1 mmol) was weighed into a flask, after nitrogen substitution, DIPEA (3.07 g,17.5 mmol) was added followed by drying DCM (128 mL) at room temperature. The reaction solution was cooled to 0 ℃, then benzyloxycarbonyl chloroformate (3.4 ml,24.0 mmol) was added, stirred for 30 minutes after the addition was completed and then allowed to warm to room temperature, stirring was continued for 12 hours, after the completion of the reaction, a proper amount of water was added for dilution reaction, DCM was extracted 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was separated and purified by silica gel column chromatography to obtain compound 1F.
MS(ESI)m/z 325.2(M+H) +
Step 7: preparation of benzyl tert-butyl (2- ((3- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-fluoropyridin-2-yl) oxy) propane-1, 3-diyl) dicarbamate (Compound 1G)
Benzyl tert-butyl (2-hydroxypropane-1, 3-diyl) dicarbamate (3.0 g,11.0 mmol) was dissolved in dry THF (30 mL), after nitrogen substitution, 2- ((5-fluoro-2-hydroxypyridin-3-yl) methyl) isoindoline-1, 3-dione (5.0 g,15.0 mmol) was added sequentially at 0deg.C, PPh 3 (5.0 g,19.08 mmol) and DIAD (3.7 mL,19.08 mmol). After the addition was completed, the reaction was warmed to room temperature and stirred for 3 hours, after the reaction was completed, a proper amount of water was added to dilute the reaction, DCM was extracted 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain compound 1G.
MS(ESI)m/z 579.2(M+H) +
Step 8: preparation of benzyl tert-butyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) oxy) propane-1, 3-diyl) dicarbamate (Compound 1H)
Benzyl tert-butyl (2- ((3- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-fluoropyridin-2-yl) oxy) propane-1, 3-diyl) dicarbamate was dissolved in EtOH (50 mL) and hydrazine hydrate (683. Mu.L, 22.0 mmol) was added. After the addition was complete, the reaction was raised to 80℃and stirring was continued for 12 hours. After the reaction is completed, the reaction solution is concentrated, and the obtained crude product is separated and purified by silica gel column chromatography to obtain the compound 1H.
MS(ESI)m/z 449.2(M+H) +
Step 9: preparation of ethyl 7- (dibenzylamino-5- ((2- ((11, 11-dimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadodecan-6-yl) oxy) -5-fluoropyridin-3-yl) methyl) amino) -6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 1I)
5-chloro-7- (dibenzylamino) -6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester (4.8 g,9.78 mmol) was dissolved in n-butanol (65 mL) and benzyl tert-butyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) oxy) propane-1, 3-diyl) dicarbamate (2.92 g,6.5 mmol) and DIPEA (1.6 mL,9.78 mmol) were then added sequentially at room temperature. After the addition, the temperature was raised to 100℃and stirred for 11 hours. After the reaction is completed, the reaction solution is concentrated, and the obtained crude product is separated and purified by silica gel column chromatography to obtain the compound 1I.
MS(ESI)m/z 909.4(M+H) +
Step 10: preparation of 5- ((((2- ((1-amino-3- ((tert-butoxycarbonyl) amino) propan-2-yl) oxy) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino) -6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylic acid (compound 1J)
5- ((((2- ((1-amino-3- ((tert-butoxycarbonyl) amino) propan-2-yl) oxy) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino) -6-phenylpyrazolo [1, 5-a)]Pyrimidine-3-carboxylic acid ethyl ester (2.3 g,2.53 mmol) was weighed into a round bottom flask followed by sodium hydroxide (2.0 g,50.7 mmol) and THF/MeOH/H 2 O mixed solvent (3:1:1, 25 mL). After the addition, the reaction was warmed to 70 ℃ and stirred for 24 hours, after the reaction was completed, 1N aqueous hydrochloric acid was added to adjust the PH of the reaction solution to acidity, then DCM/MeOH (9/1) was used for extraction 3 times, the organic phase was dried over anhydrous sodium sulfate, and the compound 1J was obtained by filtration and concentration and was directly used for the next reaction.
MS(ESI)m/z 747.3(M+H) +
Step 11: (((1 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5 ]a]Preparation of tert-butyl pyrimidin-4 (3, 2) -pyridineheterocycloalkyi-6-yl) methyl carbamate (compound 1K)
5- ((((2- ((1-amino-3- ((tert-butoxycarbonyl) amino) propan-2-yl) oxy) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino) -6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylic acid was dissolved in DCM (400 mL) and DMF (200 mL), then the reaction solution was cooled to 0 ℃, DIPEA (6.1 mL,36.9 mmol) and FDPP (3.6 g,9.4 mmol) were added sequentially to the reaction solution and stirred at room temperature for 12 hours, after completion of the reaction, saturated aqueous sodium carbonate solution was added to quench the reaction solution, DCM was extracted 3 times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting crude product was isolated and purified by silica gel column chromatography to give compound 1K.
MS(ESI)m/z 729.3(M+H) +
Step 12: (1 3 E,1 4 E) -6- (aminomethyl) -1 7 - (dibenzylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (Compound 1L)
Will (((1) 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 Fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle nona-6-yl) methyl carbamate (330 mg,0.45 mmol) was dissolved in DCM (10.0 mL), HCl (4M in 1,4-dioxane,5.0 mL) was then slowly added to the reaction solution and stirred at this temperature for 30 min, after the reaction was complete, TEA was slowly added to adjust pH to 7-8 at 0deg.C, concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography to give compound 1L.
MS(ESI)m/z 629.2(M+H) +
Step 13: (1 3 E,1 4 E) -6- (aminomethyl) -1 7 - (amino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridine heterocycloavidone-9-one (Compound 1)
Will (1) 3 E,1 4 E) -6- (aminomethyl) -1 7 - (dibenzylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle nonatomato-9-one (45 mg,0.07 mmol) was dissolved in DCM (4.5 mL), then the reaction solution was cooled to 0deg.C, trifluoromethanesulfonic acid (225 μL) was added dropwise to the reaction solution and stirred at that temperature for 15 min, after the reaction was complete, TEA was slowly added at 0deg.C to adjust pH to 7-8, concentrated under reduced pressure, and the crude product obtained was isolated and purified by high pressure preparation to give Compound 1 of example 1.
MS(ESI)m/z 629.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.76(dd,J=8.6,2.0Hz,1H),8.06(s,1H),7.98(d,J=3.1Hz,1H),7.66(dd,J=8.9,3.1Hz,1H),7.59(t,J=7.5Hz,2H),7.50(t,J=7.4Hz,1H),7.35(s,2H),6.98(t,J=6.1Hz,1H),6.71(s,2H),4.92(m,2H),4.09(m,1H),3.88(dd,J=14.7,5.8Hz,1H),3.26–3.18(m,3H),3.04(dd,J=12.9,4.7Hz,1H),2.84(dd,J=12.9,7.2Hz,1H).
Example 2: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidin-4 (3, 2) -pyridine heterocycloalkyi-6-yl) methyl) isobutyramide (compound 2):
the synthesis steps are as follows:
step 1: n- (((1) 3 E,1 4 E)-1 7 - (dibenzylamine)Radical) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl) isobutyramide (Compound 2A)
Will (1) 3 E,1 4 E) -6- (aminomethyl) -1 7 - (dibenzylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle 9-ketone (50 mg,0.08 mmol) was dissolved in dry DCM (5 mL), then the reaction solution was cooled to 0deg.C, TEA (17 μL,0.12 mmol) and isobutyryl chloride (10 μL,0.1 mmol) were added dropwise to the reaction solution in sequence, stirring was continued for 30 min, after the reaction was complete, sodium bicarbonate saturated aqueous solution was slowly added at 0deg.C, DCM was extracted 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was isolated and purified by silica gel column chromatography to give compound 2A.
MS(ESI)m/z 699.2(M+H) +
Step 2: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl isobutyramide (Compound 2)
N- (((1) 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle Jiujin tomato-6-yl) methyl isobutyramide is dissolved in DCM (5.0 mL), then the reaction solution is cooled to 0 ℃, trifluoromethyl sulfonic acid (0.25 mL) is added into the reaction solution drop by drop, and stirring is carried out for 15 minutes at the temperature, TEA is slowly added at 0 ℃ to adjust the PH to 7-8 after the reaction is completed, decompression concentration is carried out, and the obtained crude product is separated and purified by high-pressure preparation to obtain the solidCompound 2 of example 2.
MS(ESI)m/z 699.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.74(d,J=8.0Hz,1H),8.06(s,1H),8.04–7.93(m,2H),7.69(dd,J=8.9,3.1Hz,1H),7.60(t,J=7.5Hz,2H),7.51(t,J=7.4Hz,1H),7.36(s,2H),6.97(t,J=6.1Hz,1H),6.72(s,2H),5.11(h,J=5.1Hz,1H),4.98–4.87(m,1H),3.98–3.84(m,2H),3.61–3.47(m,2H),3.24–3.13(m,1H),2.44–2.31(m,1H),1.01(dd,J=6.8,4.6Hz,6H).
Example 3: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl cyclopropanecarboxamide (Compound 3)
The same preparation as in example 2 was used to obtain compound 3 of example 3, substituting (cyclopropyl) formyl chloride for isobutyryl chloride in step 1 of example 2.
MS(ESI)m/z 517.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.75(d,J=7.7Hz,1H),8.34(t,J=5.9Hz,1H),8.06(s,1H),7.99(d,J=3.0Hz,1H),7.69(dd,J=9.0,3.1Hz,1H),7.60(t,J=7.5Hz,2H),7.51(m,J=7.4,1.4Hz,1H),7.35(s,2H),6.97(t,J=6.1Hz,1H),6.71(s,2H),5.14–5.00(m,1H),4.93(dd,J=14.4,5.8Hz,1H),4.01–3.81(m,2H),3.66–3.45(m,2H),3.25–3.12(m,1H),1.69–1.46(m,1H),0.67(m,J=7.5,2.3Hz,4H).
Example 4: n- (((1) 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-9-oxo 1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl methanesulfonamide (compound 4):
the same preparation as in example 2 was used to obtain compound 4 of example 4, substituting methanesulfonyl chloride for isobutyryl chloride in step 1 of example 2.
MS(ESI)m/z 707.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.74(d,J=9.1Hz,1H),8.07(s,1H),8.01(s,1H),7.75(d,J=3.0Hz,1H),7.60(m,2H),7.58-7.52(m,1H),7.48-7.32(m,3H),6.97(s,1H),6.72(s,2H),5.04-4.91(m,2H),4.05(s,1H),3.85(s,1H),3.50-3.35(m,2H),3.25(s,1H),2.91(s,3H).
Example 5: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidin-4 (3, 2) -pyridine heterocycloalkyi-6-yl) methyl) ethylamide (compound 5:
the synthesis steps are as follows:
step 1: n- (((1) 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3)) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl) ethylamide (Compound 5A)
Will (1) 3 E,1 4 E) -6- (aminomethyl) -1 7 - (dibenzylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycloap-9-one (50 mg,0.08 mmol) was dissolved in dryIn dry DCM (1.0 mL), then cooled to 0 ℃, TEA (22. Mu.L, 0.16 mmol) and acetic anhydride (10. Mu.L, 0.1 mmol) were added dropwise in sequence to the reaction solution, stirring was continued for 30 min, after the reaction was complete, sodium bicarbonate saturated aqueous solution was slowly added at 0℃and extracted 3 times with DCM, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was isolated and purified by silica gel column chromatography to give compound 5A.
MS(ESI)m/z 671.2(M+H) +
Step 2: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl) ethylamide (Compound 5)
N- (((1) 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]The crude pyrimidine-4 (3, 2) -pyridineheterocycloazepan-6-yl) methyl ethyl amide was dissolved in DCM (5.0 mL), then the reaction solution was cooled to 0deg.C, trifluoromethanesulfonic acid (0.25 mL) was added dropwise to the reaction solution and stirred at this temperature for 15 min, after the reaction was complete, TEA was slowly added at 0deg.C to adjust pH to 7-8, concentrated under reduced pressure, and the crude product obtained was isolated and purified by high pressure preparation to give Compound 5 of example 5.
MS(ESI)m/z 491.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.75(dd,J=8.4,2.0Hz,1H),8.12(t,J=5.9Hz,1H),8.06(s,1H),7.99(d,J=3.1Hz,1H),7.68(dd,J=8.9,3.1Hz,1H),7.59(t,J=7.6Hz,2H),7.50(m,1H),7.35(s,2H),6.97(t,J=6.1Hz,1H),6.71(s,2H),5.06(m,1H),4.92(m,1H),4.00–3.82(m,2H),3.60–3.45(m,2H),3.19(m,1H),1.85(s,3H).
Example 6:1- (((1 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidin-4 (3, 2) -pyridine heterocycloalp-yl-6-ylmethyl) -3-methylurea (compound 6):
the synthesis steps are as follows:
step 1:1- (((1 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidin-4 (3, 2) -pyridine heterocycloalp-yl-6-ylmethyl) -3-methylurea (compound 6A):
will (1) 3 E,1 4 E) -6- (aminomethyl) -1 7 - (dibenzylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (50 mg,0.08 mmol) was dissolved in dry DCM (0.5 mL), CDI (16.2 mg,0.1 mmol) was added and stirred for 8 hours, followed by MeNH-containing reaction mixture 2 ·H 2 A solution of O (8.1 mg,0.12 mmol) and DIPEA (40. Mu.L, 0.24 mmol) in DCM (0.5 mL) was stirred for 2 h, after completion of the reaction, an appropriate amount of water was added to quench the reaction, the mixture was extracted 3 times with DCM, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography over silica gel to give Compound 6A.
MS(ESI)m/z 686.2(M+H) +
Step 2:1- (((1 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidin-4 (3, 2) -pyridine heterocycloalp-yl-6-ylmethyl) -3-methylurea (compound 6):
1- (((1) 3 E,1 4 E)-1 7 - (dibenzylamino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle Jiujin tomato-6-yl) methyl) -3-methyl urea crude product is dissolved in DCM (5.0 mL), then the reaction solution is cooled to 0 ℃, trifluoromethyl sulfonic acid (0.25 mL) is added dropwise into the reaction solution, stirring is carried out for 15 minutes at the temperature, TEA is slowly added at 0 ℃ to adjust the PH to 7-8 after the reaction is completed, decompression concentration is carried out, and the obtained crude product is separated and purified by high-pressure preparation to obtain the compound 6 of the example 6.
MS(ESI)m/z 506.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.73(d,J=7.7Hz,1H),8.06(s,1H),7.99(d,J=3.0Hz,1H),7.68(dd,J=8.9,3.0Hz,1H),7.59(t,J=7.5Hz,2H),7.55–7.46(m,1H),7.35(s,2H),6.97(t,J=6.0Hz,1H),6.71(s,2H),6.20(t,J=5.9Hz,1H),5.01(m,1H),4.92(dd,J=14.5,5.7Hz,1H),4.01–3.82(m,2H),3.53(m,2H),3.43(t,J=6.5Hz,1H),3.19(dd,J=12.6,9.4Hz,1H),2.57(d,J=4.6Hz,3H).
Example 7: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl isobutyramide (Compound 7)
The synthesis steps are as follows:
step 1: preparation of ethyl 5, 7-dihydroxypyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 7A)
Sodium ethoxide (17.5 g,258.0 mmol) was added portionwise to 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (20.0 g,129.0 mmol) and diethyl malonate (22.7 g,142.0 mmol) in EtOH (200.0 mL). And finally, placing the reaction system at 80 ℃ and stirring for 16 hours, pouring the reaction solution into water after the reaction is completed, regulating the PH value to 2-3 by dilute hydrochloric acid, stirring for 30 minutes, filtering, and drying a filter cake to obtain the compound 7A.
MS(ESI)m/z 224.1(M+H) +
Step 2: preparation of 5, 7-dichloropyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester (preparation of Compound 7B)
POCl (point of care testing) 3 (41.2 g,268.8 mmol) and pyridine (7.09 g,89.6 mmol) were added to 5, 7-dihydroxypyrazolo [1,5-a ]]Pyrimidine-3-carboxylic acid ethyl ester (20.0 g,89.6 mmol) and acetonitrile (100 mL), finally the reaction system is placed at 80 ℃ and stirred for 16 hours, after the reaction is completed, the solvent is removed by distillation under reduced pressure, the reaction solution is poured into water, after stirring for 30 minutes, DCM is used for extraction for 3 times, the organic phases are combined and dried by anhydrous sodium sulfate, the crude product obtained by distillation under reduced pressure is concentrated, and the obtained crude product is separated and purified by silica gel column chromatography to obtain the compound 7B.
MS(ESI)m/z 260.0(M+H) +
Step 3: preparation of 5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester (Compound 7C)
Dibenzylamine (15.0 g,76.0 mmol) was added to a solution of ethyl 5, 7-dichloropyrazolo [1,5-a ] pyrimidine-3-carboxylate (18.0 g,69.0 mmol) and DIPEA (17.9 g,138.0 mmol) in DCM (360 mL), and finally the reaction system was stirred at room temperature for 16 hours, after completion of the reaction, the reaction solution was washed 3 times with saturated ammonium chloride solution, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtering and concentrating to obtain the compound 7C.
MS(ESI)m/z 421.1(M+H) +
Step 4: preparation of ethyl 6-bromo-5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 7D)
NBS (11.6 g,65.3 mmol) was added portionwise to a mixture of ethyl 5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (25.0 g,4.34 mmol) and DCM (250 mL), and finally the reaction was stirred at room temperature for 16 hours, after completion of the reaction, the reaction was washed 3 times with saturated ammonium chloride solution, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Filtering and concentrating by distillation under reduced pressure, adding ethyl acetate (100 mL) and petroleum ether (300 mL) into the crude product, stirring for 30 min, and filtering to obtain a filter cake which is the compound 7D.
MS(ESI)m/z 499.1(M+H) +
Step 5: preparation of 6-bromo-5- ((2- (1- (((tert-butoxycarbonyl) amino) methyl) -2- (dimethylamino) ethoxy) -5-fluoro-3-pyridinyl) methylamino) -7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester (preparation of compound 7E):
Ethyl 6-bromo-5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (2.0 g,4.0 mmol), N- (2- ((3- (aminomethyl) -tert-butyl) 5-fluoro-2-pyridinyl) oxy) -3- (dimethylamino) propyl) carbamate (1.37 g,4.0 mmol) and DIPEA (1.03 g,8.0 mmol) were added to N-butanol (20 mL), and the reaction system was left to react at 100deg.C for 16 hours, after which the reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 7E.
MS(ESI)m/z 911.2(M+H) +
Step 6: preparation of ethyl 7- (dibenzylamino) -5- (((2- ((11, 11-dimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadodecane-6-yl) oxy) -5-fluoropyridin-3-yl) methyl) amino) -6- (p-tolyl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (compound 7F):
6-bromo-5- ((2- (1- (((tert-butoxycarbonyl) amino) methyl) -2- (dimethylamino) ethoxy) -5-fluoro-3-pyridinyl) methylamino) -7- (dibenzylamino) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (2.0 g,2.2 mmol), p-tolylboronic acid (447.31 mg,3.3 mmol), pd (PPh) 3 ) 4 (253.0mg,0.22mmol)、Na 2 CO 3 (465.0 mg,4.39 mmol) 1, 4-dioxane (20 mL) and H were added 2 O (2 mL), the reaction system was finally stirred at 80℃for 16 hours, and after completion of the reaction, water was added for dilution and extraction with EA for 3 times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, then filtered and concentrated, and the crude product obtained was separated and purified by silica gel column chromatography to give compound 7F.
MS(ESI)m/z 924.04(M+H) +
Step 7: ((((1 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-9-oxo-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Preparation of benzyl pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl carbamate (Compound 7G)
7- (dibenzylamino) -5- (((2- ((11, 11-dimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadodecan-6-yl) oxy) -5-fluoropyridin-3-yl) methyl) amino) -6- (p-tolyl) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (1.2 g,0.80 mmol) was dissolved in a mixed solution of MeOH and THF. Subsequently, an aqueous solution of lithium hydroxide (288 mg,12.09 mmol) was added thereto, and the reaction system was stirred at 60℃for 16 hours after the addition. After completion of the reaction, the reaction system was cooled to 0 ℃, PH was adjusted to 2-3 with 2N hydrochloric acid, extracted 3 times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, distilled under reduced pressure, the crude product obtained was added to a 1, 4-dioxane solution (20.0 mL) of hydrochloric acid, stirred at room temperature for 1 hour, after completion of the reaction, the solvent was removed by distillation under reduced pressure, DCM (200.0 mL) and DMF (100.0 mL) were then added, DIPEA (1.37 g,10.58 mmol) and FDPP (90.97 mg,1.06 mmol) were sequentially added. After the addition was completed, the mixture was stirred at room temperature for 16 hours, after the reaction was completed, the mixture was quenched by adding a saturated aqueous sodium carbonate solution, extracted 3 times with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 7G.
MS(ESI)m/z 777.3(M+H) +
Step 8: (1 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (Compound 7H)
Will ((((1) 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-9-oxo-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Benzyl pyrimidin-4 (3, 2) -pyridylazepin-6-yl) methyl carbamate (360 mg,1.29 mmol) was dissolved in MeOH (20 mL) followed by addition of wet palladium on carbon (345.0 mg) and three hydrogen substitutions after the addition was completed and the reaction was stirred at room temperature under hydrogen atmosphere (one atmosphere) for 2 hours. After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain compound 7H.
MS(ESI)m/z 643.4(M+H) +
Step 9: n- (((1) 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-9-oxo-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6 yl) methyl isobutyramide (Compound 7I)
Will (1) 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Pyrimidine-4 (3, 2) -pyridineheterocycloamphen-9-one (150 mg,0.23 mmol) was dissolved in DCM (15.0 mL), TEA (47.23 mg,0.47 mmol) was added followed by slow dropwise addition of isobutyric anhydride (36.92 mg,0.23 mmol) at 0deg.C. After the addition was completed, the reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water, the aqueous phase was extracted with EA for 2 times, the organic phase was combined with saturated brine and washed, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was separated and purified by silica gel column chromatography to obtain compound 7I.
MS(ESI)m/z 713.8(M+H) +
Step 10: n- (((1) 3 E,1 4 E)-1 7 -amino-4 5 -fluoro-9-oxo-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi nona-6 yl) methyl) isobutyramide (Compound 7)
N- (((1) 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-9-oxo-1 6 - (p-methylphenyl) -5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]]Pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi nona-6 yl) methyl isobutyric acid amine (140.0 mg,0.20 mmol) was dissolved in DCM (5.0 mL) and trifluoromethanesulfonic acid (0.5 mL) was added at 0deg.C and the temperature was maintained for reaction for 1 hour. After the reaction was completed, TEA was slowly added at 0℃to adjust pH to 7-8, the reaction mixture was concentrated, and the crude product was isolated and purified by high-pressure preparation to give Compound 7 of example 7.
MS(ESI)m/z 533.6(M+H) +
1 H NMR(400MHz,DMSO-d 6 ):δ9.74(d,J=9.1Hz,1H),8.03(s,1H),8.01-7.90(m,2H),7.65(d,J=3.0Hz,1H),7.38(m,2H),7.21(s,2H),6.93(s,1H),6.65(s,2H),5.08(s,1H),4.90-4.85(m,1H),4.00-3.80(m,2H),3.60-3.40(m,2H),3.18(s,1H),2.40-2.30(m,4H),1.00(d,J=3.0Hz,6H).
Example 8: n- (((1) 3 E,1 4 E)-1 7 - (amino) -1 6 - (4-chlorophenyl) -4 5 -fluoro-9-oxo-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl isobutyramide (Compound 8)
The same preparation method as in example 7 was used to obtain compound 8 of example 8 by substituting p-chlorobenzoic acid for p-tolueneboronic acid in step 6 of example 7.
MS(ESI)m/z 554.1(M+H) +
1 H-NMR(400MHz,DMSO-d 6 )δ9.70(d,J=7.4Hz,1H),8.01(s,1H),7.98-7.94(m,2H),7.63-7.58(m,3H),7.32(s,2H),6.98(t,J=5.9Hz,1H),6.85(s,2H),5.04(q,J=5.0Hz,1H),4.88(dd,J=13.9,5.6Hz,1H),3.93-3.87(m,1H),3.80(dd,J=14.4,5.4Hz,1H),3.50(t,J=5.1Hz,1H),3.45(t,J=6.9Hz,1H),3.14(d,J=10.2Hz,1H),2.37-2.29(m,1H),0.97(dd,J=6.6,4.7Hz,6H).
Example 9: n- (((1) 3 E,1 4 E)-1 7 - (amino) -1 6 - (1-methyl-1H-pyrrol-3-yl) -4 5 -fluoro-9-oxo-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a ]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl isobutyramide (Compound 9)
The same preparation method as in example 7 was used to obtain compound 9 of example 9, substituting 1-methyl-3-pyrroleboronic acid pinacol ester for p-tolueneboronic acid in step 6 of example 7.
MS(ESI)m/z 522.3(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.71(d,J=9.1Hz,1H),8.04-7.95(m,2H),7.93(s,1H),7.78(d,J=3.0Hz,1H),7.15(m,1H),6.92(s,1H),6.85(s,1H),6.55(s,2H),6.02(s,1H),5.05(s,1H),7.90-4.83(m,1H),3.85(s,2H),3.70(s,3H),3.56(s,2H),3.15(s,1H),2.33(s,1H),0.95(d,J=6.1Hz,6H).
Example 10: (1 3 E,1 4 E) -6- ((methylamino) methyl) -1 7 -amino-4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloavidone-9-one (Compound 10)
The synthesis steps are as follows:
step 1: preparation of tert-butyl (oxiranylmethyl) carbamate (Compound 10A)
Tert-butyl allyl carbamate (10.0 g,63.61 mmol) was dissolved in DCM (640.0 mL) and 3-chloroperoxybenzoic acid (25.8 g,127.22 mmol) was added in portions at 0deg.C. After the addition was completed, the reaction system was left at room temperature and stirred for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated aqueous sodium sulfite, the aqueous phase was extracted 3 times with DCM, the organic phases were combined, washed with saturated aqueous sodium bicarbonate and saturated brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 10A.
Step 2: preparation of tert-butyl (2-hydroxy-3- (methylamino) propyl) carbamate (Compound 10B)
Tert-butyl (oxiranylmethyl) carbamate (8.5 g,49.07 mmol) was dissolved in EtOH (85.0 mL) followed by the addition of methylamine in THF (2M, 67.0 mL). After the addition was completed, the reaction system was stirred at 40℃for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound 10B, which was directly used for the next reaction.
Step 3: preparation of benzyl (3- ((tert-Butoxycarbonyl) amino) -2-hydroxypropyl) methyl) carbamate (Compound 10C)
Tert-butyl (2-hydroxy-3- (methylamino) propyl) carbamate (10.0 g,49.05 mmol) was dissolved in DCM (150.0 mL), TEA (9.9 g,98.11 mmol) was added followed by slow dropwise addition of benzyl chloroformate (9.2 g,53.96 mmol) at 0deg.C. After the addition was completed, the reaction system was left at room temperature and stirred for 2 hours. After the reaction was completed, the reaction solution was diluted with water, the aqueous phase was extracted 3 times with DCM, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was isolated and purified by silica gel column chromatography to give compound 10C.
MS(ESI)m/z 339.3(M+H) +
Step 4: preparation of benzyl (3- ((tert-Butoxycarbonyl) amino) -2- ((3- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-fluoropyridin-2-yl) oxy) propyl) methyl) carbamate (Compound 10D)
Benzyl (3- ((tert-butoxycarbonyl) amino) -2-hydroxypropyl) (methyl) carbamate (7.5 g,22.04 mmol), 2- [ (5-fluoro-2-hydroxy-3-pyridinyl) methyl ]Isoindoline-1, 3-dione (4.0 g,14.69 mmol) and PPh 3 (7.7 g,29.39 mmol) was dissolved in DCM (200.0 mL) and DIAD (9.2 g,53.96 mmol) was added dropwise at 0deg.C. AddingAfter completion, the reaction system was left at room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was diluted with water, the aqueous phase was extracted 3 times with DCM, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel chromatography to give compound 10D.
MS(ESI)m/z 593.3(M+H) +
Step 5: preparation of benzyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) oxy) -3- ((tert-butoxycarbonyl) amino) propyl) methyl) carbamate (Compound 10E)
Benzyl (3- ((tert-butoxycarbonyl) amino) -2- ((3- ((1, 3-dioxoisoindolin-2-yl) methyl) -5-fluoropyridin-2-yl) oxy) propyl) methyl) carbamate (8.7 g,14.70 mmol) was dissolved in EtOH (150.0 mL) followed by hydrazine hydrate (1.8 g,29.40 mmol) and after addition the reaction was stirred at 80℃for 16 h. After the reaction is completed, the reaction solution is filtered, the filtrate is concentrated, and the obtained crude product is separated and purified by a silica gel chromatographic column to obtain the compound 10E.
MS(ESI)m/z 463.1(M+H) +
Step 6: preparation of ethyl 6-bromo-7- (dibenzylamino) -5- ((5-fluoro-2- ((4,11,11-trimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadodecan-6-yl) oxy) pyridin-3-yl) methyl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 10F)
Benzyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) oxy) -3- ((tert-butoxycarbonyl) amino) propyl) (methyl) carbamate (5.6 g,11.20 mmol) and ethyl 6-bromo-5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (5.2 g,11.20 mmol) were dissolved in n-butanol (50.0 mL) followed by DIPEA (2.9 g,22.40 mmol). After the addition was completed, the reaction system was stirred at 100℃for 16 hours. After the reaction is completed, the reaction solution is concentrated, and the obtained crude product is separated and purified by a silica gel chromatographic column to obtain the compound 10F.
MS(ESI)m/z 927.4(M+H) +
Step 7: preparation of 7- (dibenzylamino) -5- (((5-fluoro-2- ((4,11,11-trimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadodecan-6-yl) oxy) pyridin-3-yl) methyl) amino) -6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylic acid ethyl ester (Compound 10G)
6-bromo-7- (dibenzylamino) -5- ((5-fluoro-2- ((4,11,11-trimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadodecan-6-yl) oxy) pyridin-3-yl) methyl) amino) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (5.5 g,5.94 mmol), phenylboronic acid (869.2 mg,7.13 mmol) and K 2 CO 3 (1.6 g,11.88 mmol) was dissolved in a mixed solution of dioxane and water (4:1, 75.0 mL), followed by Pd (PPh) 3 ) 4 (682.3 mg,0.59 mmol). After the completion of the addition, the reaction system was stirred at 80℃for 16 hours. After the completion of the reaction, the reaction mixture was diluted with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined and washed with saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was separated and purified by silica gel column chromatography to give compound 10G.
MS(ESI)m/z 923.5(M+H) +
Step 8: ((((1 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-1 6 -phenyl-9-oxo-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Preparation of benzyl pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl) carbamate (Compound 10H)
7- (dibenzylamino) -5- (((5-fluoro-2- ((4,11,11-trimethyl-3, 9-dioxo-1-phenyl-2, 10-dioxa-4, 8-diazadeca) s)Di-alkyl-6-yl) oxy) pyridin-3-yl) methyl) amino) -6-phenylpyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (3.8 g,4.12 mmol) was dissolved in a mixed solution of EtOH (228.0 mL) and THF (76.0 mL). LiOH (3.5 g,82.34 mmol), H was then added 2 O (76.0 mL) and then the reaction was warmed to 60℃and stirred for 16 hours. After completion of the reaction, the reaction system was cooled to 0 ℃, pH was adjusted to 2-3 with 2N hydrochloric acid, extracted 3 times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the resulting crude product was added to a 1, 4-dioxane solution (20.0 mL) of hydrochloric acid, stirred at room temperature for 1 hour, after completion of the reaction, the reaction solution was concentrated, the resulting crude product was dissolved in DCM (520.0 mL) and DMF (260.0 mL), and DIPEA (5.3 g,41.26 mmol) and FDPP (1.6 g,4.13 mmol) were added in this order. After the addition, the system was stirred at room temperature for 16 hours, after the reaction was completed, the mixture was quenched by adding a saturated aqueous sodium carbonate solution, extracted 3 times with DCM, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to give compound 10H. MS (ESI) M/z 778.5 (M+H) +
Step 9: (1 3 E,1 4 E) -6- ((methylamino) methyl) -1 7 - (benzhydrylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (Compound 10I)
Will ((((1) 3 E,1 4 E)-1 7 - (benzhydrylamino) -4 5 -fluoro-1 6 -phenyl-9-oxo-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Benzyl pyrimidine-4 (3, 2) -pyridineheterocycloalpan-6-yl) methyl) carbamate (1.0 g,1.29 mmol) was dissolved in MeOH (20 mL), followed by addition of wet palladium on carbon (1.0 g) and stirring of the system under hydrogen atmosphere (one atmosphere) at room temperature for 16 h. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain compound 10I.
MS(ESI)m/z 643.4(M+H) +
Step 10: (1 3 E,1 4 E) -6- ((methylamine) radical) methyl) -1 7 -amino-4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloavidone-9-one (Compound 10)
Will (1) 3 E,1 4 E) -6- ((methylamino) methyl) -1 7 - (benzhydrylamino) -4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle nona-9-one (300.0 mg,0.47 mmol) was dissolved in DCM (10.0 mL), trifluoromethanesulfonic acid (0.1 mL) was added at 0deg.C, and the system was stirred in an ice bath for 1 hr after the addition was completed. After completion of the reaction, the pH of the system was adjusted to 7-8 with TEA at 0℃and the reaction mixture was concentrated to give a crude product which was isolated and purified by high pressure preparation to give compound 10 of example 10.
MS(ESI)m/z 463.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.76-9.71(m,1H),8.05(s,1H),7.98(d,J=3.1Hz,1H),7.66(m,1H),7.60(t,J=7.4Hz,2H),7.51(m,1H),7.35(m,2H),7.00-6.93(m,1H),6.70(s,2H),5.19-5.04(m,1H),4.91(m,1H),4.05(m,1H),3.88(m,1H),3.24(m,1H),2.97(m,1H),2.79(m,1H),2.34(s,3H).
Example 11: n- (((1) 3 E,1 4 E)-1 7 -amino-4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl) -N-methylisobutylamine (Compound 11)
The same preparation as in example 7 was used to obtain compound 11 of example 11, substituting compound 10I for compound 7H of step 9 of example 7.
MS(ESI)m/z 533.3(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ9.82-9.61(m,1H),8.06(d,J=6.7Hz,1H),7.96(t,J=3.5Hz,1H),7.71-7.46(m,4H),7.35(m,2H),7.02-6.93(m,1H),6.72(s,2H),5.47-5.21(m,1H),4.98-4.78(m,1H),4.11-3.53(m,4H),3.10(s,3H),2.94-2.79(m,2H),1.03-0.82(m,6H).
Example 12: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl neopentanamide (Compound 12)
The same preparation as in example 5 was used to obtain compound 12 of example 12 using pivalic anhydride instead of acetic anhydride in example 5.
MS(ESI)m/z 533.2 3(M+H) +
1 H-NMR(400MHz,DMSO-d 6 )δ9.71(d,J=7.4Hz,1H),8.01(s,1H),7.94(d,J=3.0Hz,1H),7.72(t,J=5.5Hz,1H),7.64(dd,J=8.8,2.7Hz,1H),7.56(t,J=7.0Hz,2H),7.47(t,J=7.3Hz,1H),7.31(s,2H),6.94(t,J=6.0Hz,1H),6.69(s,2H),5.26-5.11(m,1H),4.90-4.85(m,1H),3.92-3.81(m,2H),3.51-3.42(m,2H),3.15-3.10(m,1H),1.21-0.90(m,9H).
Example 13: n- (((1) 3 E,1 4 E)-1 7 - (amino) -4 5 -fluoro-9-oxo-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloalkyi-6-yl) methyl) -3-methylbutanamide (Compound 13)
The same preparation method as in example 5 was used to obtain compound 13 of example 13 using isovaleric anhydride instead of acetic anhydride of example 5.
m/z 533.57(M+H) +
1 H-NMR(400MHz,DMSO-d 6 )δ9.69(d,J=7.7Hz,1H),8.02(d,J=7.7Hz,2H),7.95(d,J=2.7Hz,1H),7.66-7.63(m,1H),7.56(s,2H),7.47(t,J=7.1Hz,1H),7.32(s,2H),6.94-6.91(m,1H),6.68(s,2H),5.06(s,1H),4.88(d,J=13.2Hz,1H),3.91-3.80(m,2H),3.51(d,J=5.2Hz,2H),3.16(t,J=11.3Hz,1H),1.95(s,2H),1.20(d,J=6.9Hz,1H),0.84(s,6H).
Example 14: (1 3 E,1 4 E) -6- ((dimethylamino) methyl) -1 7 -amino-4 5 -fluoro-1 6 -phenyl-5-oxa-2, 8-diaza-1 (5, 3) -pyrazoline [1,5-a ]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloavidone-9-one (Compound 14)
The same preparation method as in example 10 was used to obtain compound 14 of example 14, substituting tert-butyl (3- (dimethylamino) -2-hydroxypropyl) carbamate for compound 10C in step 3 of example 10.
MS(ESI)m/z 477.2(M+H) +
1 H NMR(400MHz,DMSO-d 6 )δ8.02(s,1H),7.81(s,1H),7.57-7.48(m,6H),7.25(s,1H),6.62(t,J=8.8Hz,2H),4.90-4.85(m,1H),4.75-4.65(m,1H),4.32-4.18(m,1H),3.85-3.75(m,1H),3.70-3.50(m,1H),3.30-3.15(m,1H),2.50-2.40(m,1H),2.30(d,J=6.1Hz,6H).
Biological test data:
unless otherwise indicated, the experimental materials, reagents, procedures and methods used in the following active examples are all available from commercial sources or are readily known or prepared based on the prior art.
Experimental example 1: in vitro kinase Activity test of the Compounds of the invention
Purpose of experiment
IC with compounds 50 (half inhibitory concentration) values are used as indicators to evaluate the inhibition of compounds against RET wild-type, RET mutant, BTK and/or mutant BTK kinase.
Experimental method
Using the method of Mobility shift assay, compounds were tested for their inhibitory activity against the following kinases: RET wild-type, RET mutant, BTK and/or mutated BTK. The initial concentration of the compound used was 1000nM, 3-fold dilution, 10 concentrations, single well assay.
Reagent and consumable:
reagent name | Suppliers of goods | Goods number | Lot number |
RET | Carna | 08-159 | 13CBS-0134F |
RETG810R | Proqinase | 1724-0000-1 | 002 |
RET V804M | signalchem | R02-12GG | Y985-2 |
BTK | Carna | 08-180 | 14CBS-0619Q |
BTK C481S | Carna | 08-547 | 14CBS-0633H |
Kinase substrate 2 | GL | 190861 | P200807-YS190861 |
Kinase substrate 4 | GL | 112395 | P171211-XY112395 |
Kinase substrate 22 | GL | 112393 | P200403-CL112393 |
DMSO | Sigma | D8418-1L | SHBG3288V |
384-well plate | Corning | 3573 | 12619003 |
384-well plate | Corning | 3575BC | 31316039 |
MgCl2 | Sigma | M1028 | / |
ATP | Promeg | V910B | / |
DTT | Sigma | D0632 | / |
Instrument:
centrifuge (manufacturer: eppendorf type 5430)
Enzyme label instrument (manufacturer: perkin Elmer model Caliper EZ Reader)
Echo 550 (manufacturer: labcyte, model: echo 550)
Preparation of kinase reaction buffer:
20mM hydroxyethylpiperazine ethylsulfuric acid (Hepes) (pH 7.5) buffer, 10mM MgCl 2 1mM ethylene glycol bis (aminoethyl) ether tetraacetic acid (EGTA), 0.02% polyoxyethylene lauryl ether (Brij 35), 0.02mg/ml N, O-bis (trimethylsilyl) acetamide (BSA), 0.1mM Na 3 VO 4 2mM Dithiothreitol (DTT), 1% DMSO.
A compound:
the compound to be tested is dissolved in a 100% dimethyl sulfoxide (DMSO) system and is prepared to be 10mM for later use, and is stored in a nitrogen cabinet in a dark place.
Reaction conditions:
ATP(μM) | Reaction time | |
RET | 16 | 60min |
RET G810R | 201 | 4h |
RET V804M | 5.4 | 60min |
BTK | 71 | 30min |
BTK C481S | 90 | 30min |
kinase reaction process:
(1) 1 Xkinase reaction buffer was prepared.
(2) Preparing a compound concentration gradient: the initial concentration of the compound was 1000nM, diluted to 100% dimethyl sulfoxide (DMSO) in 384 well plates at 100-fold final concentration, and the compound was diluted 3-fold precisely with kinase buffer at 10 concentrations at 0.0508nM. 100% DMSO solutions were diluted to 100-fold final concentration in 384 source plates. 250nl of 100-fold final concentration of compound was transferred to the destination plate 384-well plate using a dispenser Echo 550. Positive and negative control wells were added with 250nl DMSO.
(3) A2.5-fold final concentration of kinase solution was prepared with 1 Xkinase buffer.
(4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; mu.L of 1 Xkinase buffer was added to the negative control wells.
(5) Centrifugation at 1000rpm for 30 seconds, the reaction plate was shaken and mixed well and incubated at room temperature for 10 minutes.
(6) A25/15-fold final concentration of a mixed solution of Adenosine Triphosphate (ATP) and kinase substrate was prepared with 1 Xkinase buffer.
(7) The reaction was initiated by adding 15. Mu.L of a 25/15-fold final concentration of a mixed solution of Adenosine Triphosphate (ATP) and substrate.
(8) The 384-well plate is centrifuged at 1000rpm for 30 seconds, and is incubated for 30-240 minutes at room temperature after shaking and mixing.
(9) After stopping the kinase reaction, the mixture was centrifuged at 1000rpm for 30 seconds and mixed with shaking.
(10) The conversion was read with Caliper EZ Reader.
Data analysis
Calculation formula
Wherein: conversion% _sample is a Conversion reading of the sample; convertion% _min: negative control Kong Junzhi, representing conversion reading without enzyme wells; convesion% _max: positive control Kong Junzhi, represents a conversion reading without compound inhibition wells.
Fitting dose-response curve
The log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and the graph pad 6.0 analysis software is adopted to simulate a quantitative response curve, so that the IC of each compound on the enzyme activity is obtained 50 Values.
The experimental results are shown in table 1:
TABLE 1
"-" represents undetected.
It will be appreciated by those skilled in the art that the foregoing description is exemplary and illustrative in nature and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, those skilled in the art will appreciate that obvious modifications and variations can be made without departing from the spirit of the invention. All such modifications are intended to be included within the scope of the following claims. Accordingly, it is intended that the invention be defined not by the above description but by the scope of the following claims and their equivalents. All publications cited in this specification are herein incorporated by reference.
Claims (22)
1. A compound or stereoisomer, pharmaceutically acceptable salt, solvent compound, or tautomer of formula (I):
m is selected from N, CH, CR 1 ;
X 1 、X 3 Each independently selected from CH 2 、CHR 6 、CR 6 R 7 C= O, O, absent;
X 2 、X 4 each independently selected from CH 2 、CHR 6 、CR 6 R 7 、C=O、NH、NR 6 O, absent;
Q 1 、Q 2 each independently selected from the group consisting of absent, hydrogen, halogen, C 1-6 Alkyl, amino, -NRaRb, -NHRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -C (O) NHRa, -C (O) NRaRb, - (CRaRb) nC (O) NHRa, - (CHRa) nC (O) NHRa, - (CH 2 )nC(O)NHRa、-S(O) 2 Ra, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, 3-6 membered cycloalkyloxy or 3-6 membered heterocycloalkyloxy, 6-8 membered aryl, 5-10 membered heteroaryl; the C is 1-6 The alkyl group may be substituted by halogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkylSubstituted by hydroxy, amino, nitro; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl may be substituted by halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo, cyano; the 6-8 membered aryl, 5-10 membered heteroaryl may be substituted with halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo; the heteroatomic in the heterocycle alkane and the heteroaryl is N, O, S;
a is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and C 2 -C 6 Olefins or C 2 -C 6 Alkynes, 3-6 membered unsaturated cycloalkyl, 3-6 membered unsaturated heterocycloalkyl, 6-8 membered aryl, 5-10 membered heteroaryl, said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C 2 -C 6 Olefins or C 2 -C 6 Alkynes, 3-6 membered unsaturated cycloalkyl, 3-6 membered unsaturated heterocycloalkyl, 6-8 membered aryl, 5-10 membered heteroaryl groups may be substituted by halogen, C 1-4 Alkyl, cyano, hydroxy, nitro, -NRcRd, -NHRc, - (CH) 2 )nNRcRd、-NHC(O)ORc、-NHC(O)NHRc、-NHC(O)Rc、-ORc、-OC(O)ORc、-OC(O)Rc、-C(O)Rc、-C(O)NHRc、-(CH 2 ) nC (O) NHRc, -C (O) NRcRd;
R 1 selected from halogen, cyano, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 An alkyl acyl group; as the preferable R 1 Selected from F, amino, methyl, methoxy, acetyl;
R 2 、R 8 selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, optionally R 2 、R 8 And adjacent carbon atoms may form a 3-6 membered ring;
R 3 selected from hydrogen or amino;
R 4 、R 5 each independently selected from hydrogen, halogen, C 1-4 An alkyl group;
R 6 、R 7 each independently selected from C 1-4 Alkyl groups, which may be substituted by halogen, amino groupsA hydroxyl group;
ra, rb, rc, rd are each independently selected from C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, which alkyl can be substituted by halogen, amino, hydroxy, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl substituted; the cycloalkyl, heterocycloalkyl may be substituted with halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy substituted;
n is selected from 1, 2 or 3;
the conditions are as follows:
when X is 1 、X 2 、X 3 、X 4 Q when it is not present 1 And Q is equal to 2 Not simultaneously being hydrogen or C 1-4 An alkyl group;
when X is 1 、X 2 Q when it is not present 1 Not hydrogen or C 1-4 An alkyl group;
when X is 3 、X 4 Q when it is not present 2 Not hydrogen or C 1-4 An alkyl group.
2. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein
M is selected from N, CH.
3. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 4 、R 5 Each independently selected from hydrogen.
4. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein
A is selected from benzene ring, pyridine ring,Can be halogen, C 1-4 Alkyl, cyano, hydroxy, nitro, -NRcRd, -NHRc, - (CH) 2 )nNRcRd、-NHC(O)ORc、-NHC(O)NHRc、-NHC(O)Rc、-ORc、-OC(O)ORc、-OC(O)Rc、-C(O)Rc、-C(O)NHRc、-(CH 2 ) nC (O) NHRc, -C (O) NRcRd; rc, rd are each independently selected from C 1-4 An alkyl group; the C is 1-4 Alkyl groups may be substituted by halogen, amino, hydroxy, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl groups are substituted.
5. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q 1 、Q 2 Each independently selected from the group consisting of absent, hydrogen, halogen, C 1-4 Alkyl, amino, -NRaRb, -NHRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -C (O) NHRa, -C (O) NRaRb, - (CRaRb) nC (O) NHRa, - (CHRa) nC (O) NHRa, - (CH 2 )nC(O)NHRa、-S(O) 2 Ra, cyclopropyl, cyclobutyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl, oxolanyl, azetidinyl, oxolanyl, phenyl, pyridinyl, 5 membered heteroaryl; the C is 1-4 Alkyl groups may be substituted with halogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, hydroxy, amino, nitro; the cyclopropyl, cyclobutyl, aziridinyl, oxetanyl, azetidinyl, oxetanyl may be substituted by halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo, cyano; the phenyl, pyridyl, 5 membered heteroaryl groups may be substituted with halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo; ra and Rb are each independently selected from C 1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; the alkyl, cycloalkyl, heterocycloalkyl groups may be substituted with halogen, amino, hydroxy, C 1-4 Alkoxy substituted;
ra and Rb are each independently selected from C 1-4 Alkyl, 3-6 membered cycloalkylOr 3-6 membered heterocycloalkyl; the alkyl, cycloalkyl, heterocycloalkyl groups may be substituted with halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Alkyl substituted;
n is selected from 1, 2 or 3.
6. The compound of claim 5, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein Q 1 、Q 2 Wherein the 5-membered heteroaryl is selected from halogen, C 1-4 Alkyl, cyano, hydroxy-substituted C 1-4 Alkyl, halogenated C 1-4 Alkyl, amino substituted C 1-4 Alkyl, nitro, oxo, cyano substituted or unsubstituted structures: />
7. A compound according to claim 5 or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer Q thereof 1 、Q 2 Each independently selected from amino, -NRaRb, -NHRa, -C (O) Ra, -C (O) ORa, -OC (O) Ra, -C (O) NHRa, -C (O) NRaRb, - (CRaRb) nC (O) NHRa, - (CHRa) nC (O) NHRa, - (CH) 2 )nC(O)NHRa、-S(O) 2 Ra, wherein Ra, rb are each independently selected from the group consisting of halogen, amino, hydroxy, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxy C 1-4 Substituted or not by alkyl groups 1-4 Alkyl group,
8. According to the weightsA compound of claim 5, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, Q 1 、Q 2 Each independently selected from the group consisting of absent, hydrogen, halogen, C 1-4 An alkyl group; the C is 1-4 The alkyl group may be substituted with halogen, hydroxy, amino, nitro,Substituted.
9. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 2 Is hydrogen, methyl, trifluoromethyl.
10. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R 4 、R 5 Each independently selected from hydrogen.
11. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein X 1 、X 3 Each independently selected from CH 2 Is absent; x is X 2 、X 4 Each independently selected from CH 2 、C=O、NH、NR 6 O, absent; r is R 6 Selected from C 1-4 Alkyl which may be substituted by halogen, preferably F, amino, hydroxy.
15. a pharmaceutical composition comprising a compound according to any one of claims 1-14, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable excipient.
16. Use of a compound according to any one of claims 1-15, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or disorder selected from cancer.
17. The use of claim 16, wherein the cancer is lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN 2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gastrointestinal mucosal gangliocytoma, and cervical cancer.
18. The use of claim 16, wherein the cancer is associated with a disorder selected from the group consisting of: a RET gene, a RET kinase, or a cancer caused by deregulation of the expression or activity or level of any of these.
19. The use of claim 16 or 16, wherein the cancer is Medullary Thyroid Cancer (MTC), non-small cell lung cancer (NSCLC), metastatic solid tumors of RET gene mutation/fusion, and advanced solid tumors.
20. Use of a compound according to any one of claims 1-14, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, in the manufacture of a medicament for the treatment of a BTK mediated disease.
21. The use of claim 20, wherein the BTK-mediated disease is selected from cancer, autoimmune disease, or allergic disease.
22. The use of claim 21, wherein the cancer is selected from one or more of a diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic lymphoma, extranodal marginal zone B-cell lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, acute lymphoblastic leukemia of mature B-cells, 17 p-deleted chronic lymphocytic leukemia, waldenstrom macroglobulinemia, lymphoplasmacytomegaloma, splenic marginal zone lymphoma, plasmacytomenoma, intranodal marginal zone B-cell lymphoma, mantle cell lymphoma, intravascular large B-cell lymphoma, and primary exudative lymphoma; the autoimmune disease is selected from one or more of systemic lupus erythematosus, rheumatoid arthritis, sjogren's syndrome, multiple sclerosis, inflammatory enteritis such as Crohn's disease and ulcerative colitis, urticaria, immune thrombocytopenia, igA nephropathy, hidradenitis suppurativa, psoriasis, vitiligo, neutrophilic dermatoses, autoimmune vesicular diseases such as pemphigus and pemphigoid, igG 4-related diseases, autoimmune hemolytic anemia, rheumatic fever, antiphospholipid syndrome, systemic sclerosis/scleroderma, autoimmune hepatitis, primary sclerocholangitis, primary biliary cirrhosis, allergic purpura, churg-Strauss syndrome/allergic granulomatosis vasculitis, behcet's disease, ANCA-related small vessel inflammation, dermatitis herpetiformis; the allergic diseases are selected from one or more of allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, and chronic asthma.
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