CN116063305A - Macrocyclic compounds with BTK and/or RET activity and their use in medicine - Google Patents

Abstract

The present invention relates to compounds of formula (I) and stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers thereof and their use as inhibitors of RET and/or BTK kinase.

Description

Macrocyclic compounds with BTK and/or RET activity and their use in medicine

Technical Field

The present invention relates to compounds and stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers thereof and their use as inhibitors of RET and/or BTK and the like 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 [4], 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,.2017May 4;129 (18): 2519-2525).

In addition, TRK inhibition has unique on-target side effects including dizziness, weight gain, ataxia, abnormal perception, etc., and withdrawal pain occurs when the treatment is discontinued or terminated. The compounds of great interest in the present invention have a low TRK inhibitory effect, and thus are capable of alleviating the associated side effects.

There is a need for new compounds that are useful in the prevention and/or treatment of RET and/or BTK mediated diseases, such as cancer, autoimmune diseases, and the like.

Disclosure of Invention

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 ；

D is selected from (CH) ₂ ) m, 5-10 membered bridged ring; m is selected from 2, 3 and 4;

a is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and C _2-6 Olefins or C _2-6 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 _2-6 Olefins or C _2-6 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) Rc, -C (O) Rc, - (CH 2) nC (O) NHRc, -C (O) NRcRd;

R ₁ selected from hydrogen, fluorine, chlorine, bromine, C _1-4 An alkyl group;

R ₂ selected from hydrogen or C _1-4 An alkyl group;

R ₃ selected from hydrogen or C _1-4 An alkyl group;

R ₄ selected from C _1-4 Alkyl, which may optionally be C _1-4 Alkyl, cyano, nitro, halogen, halogenated C _1-4 Alkyl, C _1-4 Alkoxy, -NRcRd, 6-8 membered aryl, 5-10 membered heteroaryl; rc, rd are each independently selected from hydrogen, C _1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, which alkyl may be substituted byTo be covered by halogen, amino, hydroxy, C _1-4 Alkoxy substituted; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl can be substituted by halogen, amino, hydroxy, C _1-4 Alkyl, C _1-4 Alkoxy substituted; the 6-8 membered aryl, 5-10 membered heteroaryl may be substituted with halogen, amino, hydroxy, C _1-4 Alkoxy groups are substituted.

n is selected from 1 and 2;

further a compound of formula (I) of the invention or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein a is selected from the group consisting of hydrogen, a benzene ring, a 5-6 membered heteroaryl; the benzene ring, 5-6 membered heteroaryl group may be substituted with halogen, C _1-4 Alkyl, cyano, hydroxy, nitro, amino, -NRaRb, -NHRa, - (CH) ₂ )nNRaRb、-NHC(O)ORa、-NHC(O)NHRa、-NHC(O)Ra、-ORa、-OC(O)ORa、-OC(O)Ra、-C(O)Ra、-C(O)NHRa、-(CH ₂ ) nC (O) NHRa, -C (O) NRaRb; ra and Rb are each independently selected from C _1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, said C _1-4 Alkyl groups may be substituted by halogen, amino, hydroxy, C _1-4 Alkoxy substituted; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl can be substituted by halogen, amino, hydroxy, C _1-4 Alkyl, C _1-4 Alkoxy substituted;

further a compound of formula (I) of the present invention or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein A is selected from the group consisting of hydrogen, a benzene ring, a pyridine ring,

Ring A may be substituted with halogen, C _1-4 Alkyl, cyano, hydroxy, nitro, -NRaRb, -NHRa, - (CH) ₂ )nNRaRb、-NHC(O)ORa、-NHC(O)NHRa、-NHC(O)Ra、-ORa、-OC(O)ORa、-OC(O)Ra、-C(O)Ra、-C(O)NHRa、-(CH ₂ ) nC (O) NHRa, -C (O) NRaRb; ra and Rb 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 groups are substituted. Further wherein A is selected from benzene ring or +.>

The benzene ring or

Can be halogen, C _1-4 Alkyl, cyano, hydroxy, nitro, -NRaRb, -NHRa, - (CH) ₂ )nNRaRb、-NHC(O)ORa、-NHC(O)NHRa、-NHC(O)Ra、-ORa、-OC(O)ORa、-OC(O)Ra、-C(O)Ra、-C(O)NHRa、-(CH ₂ ) nC (O) NHRa, -C (O) NRaRb; ra and Rb 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 substituted; preferably, the A ring substituent is selected from methyl, ethyl, isopropyl, tert-butyl, -NHC (O) OCH ₂ 、-NHC(O)OCH ₂ CH ₃ 。/>

Further a compound of formula (I) of the invention or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R ₄ Selected from C _1-4 Alkyl, which may optionally be C _1-4 Alkyl, cyano, nitro, halogen, halogenated C _1-4 Alkyl, C _1-4 Alkoxy, -NRcRd; rc, rd are each independently selected from hydrogen, C _1-4 Alkyl groups, which may be substituted by halogen, amino, hydroxy, C _1-4 Alkoxy groups are substituted.

As the preferable R ₄ Selected from C _1-4 Alkyl, which may optionally be C _1-4 Alkyl, cyano, nitro, halogen, halomethyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, -NRcRd; rc, rd are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl.

The present invention also provides a compound of formula (II) or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof:

wherein R is ₂ 、R ₃ 、R ₄ As defined above.

The compounds of the invention, or stereoisomers, pharmaceutically acceptable salts, solvates, or tautomers thereof, have the following structure:

in another aspect the invention provides a pharmaceutical composition comprising a compound as described above or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof and a pharmaceutically acceptable excipient.

In another aspect the invention provides the use of a compound as described above, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, in the manufacture of a medicament for the treatment of a disease or condition selected from cancer.

Further wherein the cancer 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 cancer is associated with a disorder: a RET gene, a RET kinase, or a cancer caused by deregulation of the expression or activity or level of any of these.

Further, the cancers are Medullary Thyroid Carcinoma (MTC), non-small cell lung carcinoma (NSCLC), RET gene mutated/fused metastatic solid tumors and advanced solid tumors.

In another aspect, the invention provides the use of a compound as described above, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, in the manufacture of a medicament for the treatment of a BTK mediated disease.

Further the BTK mediated disease is selected from cancer, autoimmune disease or allergic disease.

Still further 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, mature B-cell acute lymphoblastic leukemia, 17 p-deleted chronic lymphocytic leukemia, waldenstrom macroglobulinemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytic 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, C1-6 alkyl, C1-4 alkyl or C1-3 alkyl. C1-6 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:

preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopenteneA radical or cyclohexenyl radical.

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 saturated, non-aromatic, monocyclic, fused, bridged, and spiro rings containing one or more (e.g., 1, 2, 3, or 4) heteroatoms. Wherein the heteroatom may be N, O, S or SO2 (), preferably N, O and/or S. 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.

"bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 5 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

"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" means 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.

"may" means 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) 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; and/or have high activity against mutant RET and/or BTK, and thus can be used for treating related diseases in which resistance has been developed 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 (e.g., glucose, lactose or mannitol), carriers, pH adjusting 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

K ₃ PO ₄ Represents potassium phosphate;

Na ₂ CO ₃ represents sodium carbonate;

DMF means N, N-dimethylformamide;

DCM represents dichloromethane;

EtOH represents ethanol;

MeOH represents methanol;

THF represents tetrahydrofuran;

TEA represents triethylamine;

DIPEA represents N, N-diisopropylethylamine;

LiOH represents lithium hydroxide

HCl represents hydrogen chloride

POCl ₃ Represents phosphorus oxychloride

FDPP represents pentafluorophenyl diphenyl phosphate

NBS represents N-bromosuccinimide

Pd(dppf)Cl ₂ Represents 1,1' -bis-diphenylphosphino ferrocene palladium dichloride

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)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-1 ⁶ -phenyl-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridine heterocycloavidone-9-one (Compound 1)

The synthesis steps are as follows:

step 1: preparation of ethyl 5, 7-dihydroxypyrazolo [1,5-a ] pyrimidine-3-carboxylate (Compound 1A)

Sodium ethoxide (17.5 g,258.0 mmol) was added in portions to a solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (20.0 g,129.0 mmol) and diethyl malonate (22.7 g,142.0 mmol) in EtOH (200.0 mL), the reaction system was then stirred at 80℃for 16 hours, after the reaction was completed, the reaction solution was poured into water, the pH was adjusted to 2-3 with dilute hydrochloric acid, stirred for 30 minutes, filtered, and the cake was dried to obtain Compound 1A.

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 1B)

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) in acetonitrile (100 mL) and the reaction was then stirred at 80deg.C for 16 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the reaction mixture was poured into water, stirred for 30 minutes, extracted 3 times with DCM, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was purified by silica gel column chromatography to give compound 1B.

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 1C)

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 the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed 3 times with a saturated ammonium chloride solution, and the organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration to give compound 1C.

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 1D)

NBS (11.6 g,65.3 mmol) was added portionwise to a solution of ethyl 5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (25.0 g,4.34 mmol) in DCM (250 mL) and the reaction was stirred at room temperature for 16 h. After the completion of the reaction, the reaction solution was washed 3 times with a saturated ammonium chloride solution, the organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was added to ethyl acetate (100 mL) and petroleum ether (300 mL), stirred for 30 minutes, and filtered to obtain a cake, namely compound 1D.

MS(ESI)m/z 499.1(M+H) ⁺

Step 5 preparation of tert-butyl (2- ((2- (dimethylamino) ethyl) amino) ethyl) carbamate (Compound 1E)

Tert-butyl (2-bromoethyl) carbamate (15 g,0.067 mol), N ¹ ,N ¹ Dimethylethane-1, 2-diamine (8.8 g,0.1005 mol) and DIPEA (17.3 g,0.134 mol) were dissolved in acetonitrile (150 mL) and the system was then heated to 80℃for 17 hours. After the reaction is completed, naturally cooling to room temperature, and concentrating the reaction solution under reduced pressure to finally obtain the compound 1E.

MS(ESI)m/z 232.19(M+H) ⁺

Step 6: preparation of tert-butyl (2- ((3-cyano-5-fluoropyridin-2-yl) (2- (dimethylamino) ethyl) amino) ethyl) carbamate (Compound 1F)

Tert-butyl (2- ((2- (dimethylamino) ethyl) amino) ethyl) carbamate (4.4 g,0.019 mol), 2-chloro-5-fluoronicotinonitrile (2 g,0.013 mol), DIPEA (7.4 g,0.057 mol) and acetonitrile (40 mL) were charged into a tube sealer and heated to 100 ℃ for reaction for 17 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 1F.

MS(ESI)m/z 352.21(M+H) ⁺

Step 7: preparation of tert-butyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) (2- (dimethylamino) ethyl) amino) ethyl) carbamate (Compound 1G)

Tert-butyl (2- ((3-cyano-5-fluoropyridin-2-yl) (2- (dimethylamino) ethyl) amino) ethyl) carbamate (2 g,5.7 mmol) was dissolved in MeOH (50 mL), raney nickel (about 0.2 g) was added, and the mixture was reacted under normal temperature and pressure with hydrogen for 16 hours. After completion of the reaction, filtration was carried out, and the obtained filtrate was concentrated to obtain compound 1G.

MS(ESI)m/z 356.24(M+H) ⁺

Step 8: preparation of ethyl 6-bromo-5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (compound 1H)

Tert-butyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) (2- (dimethylamino) ethyl) amino) ethyl) carbamate (2 g,5.6 mmol), ethyl 6-bromo-5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (2.7 g,5.6 mmol) and DIPEA (2.2 g,16.8 mmol) were dissolved in acetonitrile (40 mL) and the system was reacted at 80 ℃ for 16 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 819.1(M+H) ⁺

Step 9: preparation of ethyl 5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino)) -6-phenylpyrazolo [1,5-a ] pyrimidine-3-carboxylate (compound 1I)

6-bromo-5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (500 mg,0.61 mmol), phenylboronic acid (111.6 mg,0.92 mmol), pd (dppf) Cl ₂ (45mg，0.061mmol)，K ₃ PO ₄ (258 mg,1.22 mmol), 1, 4-dioxane (15 mL) and water (5 mL) were placed in a 50mL reaction flask and reacted at 100℃for 16 hours under nitrogen. After the reaction was completed, a proper amount of water was added to the reaction solution to dilute, extraction was performed 3 times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtration and concentration were performed, and the obtained crude product was separated and purified by column chromatography to obtain compound 1I.

MS(ESI)m/z 816.43(M+H) ⁺

Step 10: (1 ³ E,1 ⁴ E)-1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-1 ⁶ -phenyl-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (Compound 1J)

5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino)) -6-phenylpyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (400 mg,0.49 mmol), liOH (235.0 mg,9.8 mmol), meOH (6 mL), THF (2 mL), H ₂ O (2 mL) was added to a 50mL reaction flask, reacted overnight at 60℃and after completion of the reaction of the starting materials, the heating was stopped, naturally cooled to room temperature, pH was adjusted to 4-5 with 2M hydrochloric acid, extracted 3 times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, HCl/dioxane solution (4.0M, 50 mL) was added to the resulting crude product, stirred at room temperature for 1 hour, after completion of the reaction, the reaction solution was concentrated, and then the resulting crude product was dissolved in DMF (60 mL) and DCM (120 mL), DIPEA (300 mg) and FDPP (300 mg) were added in this order, and the system was stirred at room temperature for 16 hours. After the reaction was completed, 2M Na was added ₂ CO ₃ The solution was quenched, extracted 3 times with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography on silica gel to give compound 1J.

MS(ESI)m/z 670.33(M+H) ⁺

Step 11: (1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-1 ⁶ -phenyl-2, 5, 8-triaza-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)-1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-1 ⁶ -phenyl-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (150 mg,0.22 mmol) was dissolved in DCM (10.0 mL) and trifluoromethanesulfonic acid (1 mL) was added at 0deg.C and stirred for 1 min. After the reaction is completed, TEA is added to adjust the pH value of the reaction system to 7-8, the reaction solution is concentrated, and the obtained crude product is separated and purified by high-pressure preparation to obtain the compound 1 of the example 1.

MS(ESI)m/z 490.24(M+H) ⁺

¹ H NMR(400MHz,DMSO)δ9.39(dd,J＝6.3,3.1Hz,1H),8.09–7.98(m,2H),7.66–7.45(m,5H),7.36(s,2H),7.04(t,J＝5.7Hz,1H),6.66(s,2H),4.89(dd,J＝14.3,4.7Hz,1H),4.00–3.88(m,2H),3.58–3.50(m,1H),3.21(m,2H),3.05(m,1H),2.31(m,2H),2.06(s,6H).

Example 2: (1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-1 ⁶ - (1-methyl-1H-pyrrol-3-yl) -2,5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridine heterocycloavidone (Compound 2)

The same preparation as in example 1 was used to obtain compound 2 of example 2, substituting 1-methyl-3-pyrroleboronic acid pinacol ester for phenylboronic acid in step 9 of example 1.

MS(ESI)m/z 493.25(M+H) ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.40(dd,J＝6.4,3.3Hz,1H),8.05(d,J＝3.1Hz,1H),7.99(s,1H),7.65(dd,J＝9.4,3.0Hz,1H),7.21(t,J＝5.8Hz,1H),6.97(t,J＝2.4Hz,1H),6.91(t,J＝2.0Hz,1H),6.54(s,2H),6.10(dd,J＝2.6,1.8Hz,1H),4.88(m,1H),3.98(m,2H),3.73(s,3H),3.59–3.51(m,1H),3.22(m,2H),3.07(m,1H),2.54-2.43(m,2H),2.37–2.31(m,1H),2.08(s,6H).

Example 3: (4- ((1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl) -4 ⁵ Fluoro-9-oxo-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycles nine-tomato-1 ⁶ Preparation of phenyl) carbamic acid ethyl ester (Compound 3)

The synthesis steps are as follows:

step 1: preparation of ethyl 5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -6- (4-tert-butoxycarbonyl) amino) phenyl) -7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (compound 3A)

6-bromo-5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (Compound 1H) (500 mg,0.621 mmol), (4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamic acid tert-butyl ester (294 mg,0.932 mmol), pd (dppf) Cl ₂ (45mg,0.062mmol)，K ₃ PO ₄ (263 mg,1.242 mmol), 1, 4-dioxane (15 mL) and H ₂ O (5 mL) was put into a 50mL reaction flask, and reacted at 100℃for 16 hours under nitrogen protection. After the reaction is completed, H is added into the reaction solution ₂ O (50 mL) was diluted, extracted 3 times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give compound 3A.

MS(ESI)m/z 932.13(M+H) ⁺

Step 2: (1 ³ E,1 ⁴ E)-1 ⁶ - (4-aminophenyl) -1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (Compound 3B)

5- (((2- ((2- ((tert-Butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -6- (4-tert-butoxycarbonyl) amino) phenyl) -7- (dibenzylamino) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (400 mg,0.44 mmol), liOH (202 mg,8.8 mmol), meOH (6 mL), THF (2 mL), H ₂ O (2 mL) was added to a 50mL reaction flask, reacted overnight at 60℃and after completion of the reaction, the heating was stopped, naturally cooled to room temperature, the pH was adjusted to 4-5 with 2M hydrochloric acid, extracted 3 times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, HCl/dioxane solution (4.0M, 50 mL) was added to the resulting crude product, stirred at room temperature for 1 hour, the solvent was removed by concentration, the crude product was dissolved in DMF (60 mL) and DCM (120 mL), stirred at room temperature, DIPEA (284 mg,2.2 mmol) and FDPP (803 mg,0.66 mmol) were added sequentially, and stirring was continued at room temperature for 16 hours. After the reaction was completed, 2M Na was added ₂ CO ₃ The solution was quenched, extracted 3 times with DCM, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give compound 3B. MS (ESI) M/z 685.34 (M+H) ⁺

Step 3: (4- ((1 ³ E,1 ⁴ E)-1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-9-oxo-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycles nine-tomato-1 ⁶ Preparation of phenyl) carbamic acid ethyl ester (Compound 3C)

Will (1) ³ E,1 ⁴ E)-1 ⁶ - (4-aminophenyl) -1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle nonatomato-9-one (160 mg,0.234 mmol) and DIPEA (91 mg,0.702 mmol) were dissolved in THF (5 mL), the system was cooled to 0deg.C, ethyl chloroformate (38 mg,0.351 mmol) was then added dropwise, and after the addition was completed, the reaction was carried out at room temperature for 2 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 3C.

MS(ESI)m/z 757.37(M+H) ⁺

Step 4: (4- ((1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl)Radical) -4 ⁵ -fluoro-9-oxo-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycles nine-tomato-1 ⁶ Preparation of phenyl) carbamic acid ethyl ester (Compound 3)

Will (4- ((1) ³ E,1 ⁴ E)-1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-9-oxo-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycles nine-tomato-1 ⁶ -phenyl) carbamate (110 mg,0.145 mmol) was dissolved in DCM (10.0 mL), trifluoromethanesulfonic acid (1 mL) was added at 0 ℃, after completion of the reaction, TEA (1 mL) was added to adjust the ph=7-8 of the reaction system, the reaction solution was concentrated, and the crude product obtained was isolated and purified by high pressure preparation to give compound 3.

MS(ESI)m/z 577.27(M+H) ⁺

¹ H NMR(400MHz,DMSO)δ9.85(s,1H),9.45–9.34(m,1H),8.05(t,J＝6.6Hz,1H),8.01(s,1H),7.69(d,J＝8.5Hz,2H),7.57(dd,J＝9.2,2.8Hz,1H),7.26(s,2H),7.05(t,J＝5.7Hz,1H),6.66(s,2H),4.88(dd,J＝13.8,5.4Hz,1H),4.18(q,J＝7.1Hz,2H),3.94(m,2H),3.55(dd,J＝12.8,6.2Hz,1H),3.28–3.13(m,2H),3.09–2.97(m,1H),2.65(d,J＝23.4Hz,1H),2.37–2.21(m,2H),2.07(s,6H),1.34–1.14(m,3H).

Example 4: (1 ³ E,1 ⁴ E)-1 ⁷ -amino-4 ⁵ -fluoro-5- (2-methoxyethyl) -1 ⁶ - (1-methyl-1H-pyrrol-3-yl) -2,5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridinium heterocycloagulan-9-one (Compound 4)

Replacement of N in step 1 of example 1 with 2-methoxyethane-1-amine ¹ ,N ¹ Dimethylethane-1, 2-diamine compound 4 of example 4 was obtained by the same production method as in example 2.

MS(ESI)m/z 480.22(M+H) ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ9.42(dd,J＝6.8,2.9Hz,1H),8.05(d,J＝3.1Hz,1H),7.98(s,1H),7.63(dd,J＝9.3,3.1Hz,1H),7.21(t,J＝5.9Hz,1H),6.96(t,J＝2.4Hz,1H),6.90(t,J＝2.0Hz,1H),6.53(s,2H),6.08(t,J＝2.2Hz,1H),4.97–4.82(m,1H),3.96(m,2H),3.73(s,3H),3.49(m,3H),3.27(m,3H),3.15(s,4H).

Example 5: (4- ((1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2-methoxyethyl) -4 ⁵ -fluoro-9-oxo-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycles nine-tomato-1 ⁶ Preparation of phenyl) carbamic acid ethyl ester (Compound 5)

Replacement of N in step 1 of example 1 with 2-methoxyethane-1-amine ¹ ,N ¹ Dimethylethane-1, 2-diamine compound 5 of example 5 was obtained by the same production method as in example 3.

MS(ESI)m/z 564.24(M+H) ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.84(s,1H),9.43(dd,J＝6.9,2.9Hz,1H),8.05(d,J＝3.1Hz,1H),8.00(s,1H),7.68(d,J＝8.3Hz,2H),7.55(dd,J＝9.3,3.1Hz,1H),7.25(s,2H),7.04(t,J＝5.9Hz,1H),6.63(s,2H),4.89(dd,J＝14.2,5.6Hz,1H),4.17(m,2H),4.03–3.85(m,2H),3.62–3.51(m,1H),3.45(m,2H),3.26(m,3H),3.15(s,4H),1.28(t,J＝7.1Hz,3H).

Example 6: (1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]The pyrimidine-4 (3, 2) -pyridine heterocycle nona-tomato-9-one (compound 6) is prepared and synthesized as follows:

step 1: preparation of ethyl 5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino)) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (compound 6A)

Ethyl 5-chloro-7- (dibenzylamino) pyrazolo [1,5-a ] pyrimidine-3-carboxylate (4.2 g,100.0 mmol) and tert-butyl (2- ((3- (aminomethyl) -5-fluoropyridin-2-yl) (2- (dimethylamino) ethyl) amino) ethyl) carbamate (3.6 g,101 mmol) were dissolved in n-butanol (15 mL) under nitrogen and TEA (30.3 g,300.0 mmol) was added at room temperature and the reaction was allowed to react 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 column chromatography to obtain the compound 6A.

MS(ESI)m/z 740.4(M+H) ⁺

Step 2: (1 ³ E,1 ⁴ E)-1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridineheterocycloamphan-9-one (Compound 6B)

5- (((2- ((2- ((tert-butoxycarbonyl) amino) ethyl) (2- (dimethylamino) ethyl) amino) -5-fluoropyridin-3-yl) methyl) amino) -7- (dibenzylamino)) pyrazolo [1,5-a]Pyrimidine-3-carboxylic acid ethyl ester (325 mg,0.44 mmol), liOH (202 mg,8.8 mmol), meOH (6 mL), THF (2 mL), H ₂ O (2 mL) was added to a 50mL reaction flask, reacted overnight at 60℃and after completion of the reaction, the mixture was cooled naturally to room temperature, the pH was adjusted to 4-5 with 2M hydrochloric acid, extracted 3 times with EA, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, HCl/dioxane solution (4.0M, 50 mL) was added to the resulting crude product, stirred at room temperature for 1 hour, and after completion of the reaction, the solvent was removed by distillation under reduced pressure to dissolve the crude product in DMF (60 mL) and DCM (120 mL) DIPEA (284 mg,2.2 mmol) and FDPP (255 mg,0.66 mmol) were added in sequence and stirring was continued at room temperature for 16h. After the reaction was completed, 2M Na was added ₂ CO ₃ The solution was quenched, extracted 3 times with DCM, the organic phases combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography over silica gel to give compound 6B.

MS(ESI)m/z 594.3(M+H) ⁺

Step 3: (1 ³ E,1 ⁴ E)-1 ⁷ -amino-5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Preparation of pyrimidine-4 (3, 2) -pyridine heterocycloavidone-9-one (Compound 6)

Will (1) ³ E,1 ⁴ E)-1 ⁷ - (dibenzylamino) -5- (2- (dimethylamino) ethyl) -4 ⁵ -fluoro-2, 5, 8-triaza-1 (5, 3) -pyrazolo [1,5-a]Pyrimidine-4 (3, 2) -pyridine heterocycle 9-ketone (86.0 mg,0.145 mmol) is dissolved in DCM (10.0 mL), trifluoromethanesulfonic acid (1 mL) is added at 0 ℃, after the reaction is completed, TEA (1 mL) is added to adjust the pH value of the reaction system to be alkaline, the reaction solution is concentrated, and the obtained crude product is separated and purified by high-pressure preparation to obtain the compound 6.

MS(ESI)m/z 414.4(M+H) ⁺

¹ H NMR(400MHz,DMSO)δ9.47(dd,J＝6.4,3.0Hz,1H),8.23(t,J＝5.7Hz,1H),8.05(d,J＝3.0Hz,1H),7.95(s,1H),7.54(dd,J＝9.1,2.9Hz,1H),7.32(s,2H),5.40(s,1H),4.91–4.83(m,1H),3.94(m,2H),3.55–3.47(m,1H),3.21(dd,J＝9.0,4.1Hz,2H),3.14–3.04(m,1H),2.69–2.64(m,1H),2.33(dd,J＝7.8,6.1Hz,2H),2.10(s,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

Experimental purposes IC with compounds ₅₀ (half inhibitory concentration) values are used as indicators to evaluate the inhibition of compounds against RET wild-type, RET mutant, TRKa, SRC, BTK and/or mutated 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, TRKa, SRC, 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
SRC	Carna	08-173	10CBS-1134K
				TRKa	Carna	08-186	13CBS-0565G
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-wellplate	Corning	3573	12619003
				384-wellplate	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
SRC	19	30min
			TRKa	47.8	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 384source 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:

"-" 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 (16)

1. A compound or stereoisomer, pharmaceutically acceptable salt, solvent compound, or tautomer of formula (I):

m is selected from N, CH, CR ₁ ；

D is selected from (CH) ₂ ) m, 5-10 membered bridged ring; m is selected from 2, 3 and 4;

a is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, and C _2-6 Olefins or C _2-6 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 _2-6 Olefins or C _2-6 Alkynes, 3-6 membered unsaturated cycloalkyl, 3-6 membered unsaturated heterocycloalkyl, 6-8 membered aryl, 5-10 membered heteroaryl may be substituted with halo, C1-4 alkyl, cyano, hydroxy, nitro, -NRcRd, -NHRc, - (CH 2) nNRcRd, -NHC (O) ORc, -NHC (O) NHRc, -NHC (O) Rc, -ORc, -OC (O) ORc, -C (O) Rc, -C (O) NHRc, - (CH 2) nC (O) NHRc, -C (O) NRcRd;

R ₁ selected from hydrogen, fluorine, chlorine, bromine, C _1-4 An alkyl group;

R ₂ selected from hydrogen or C _1-4 An alkyl group;

R ₃ selected from hydrogen or C _1-4 An alkyl group;

R ₄ selected from C _1-4 Alkyl, which may optionally be C _1-4 Alkyl, cyano, nitro, halogen, halogenated C _1-4 Alkyl, C _1-4 Alkoxy, -NRcRd, 6-8 membered aryl, 5-10 membered heteroaryl; rc, rd are each independently selected from hydrogen, 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 substituted; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl can be substituted by halogen, amino, hydroxy, C _1-4 Alkyl, C _1-4 Alkoxy substituted; the 6-8 membered aryl, 5-10 membered heteroaryl may be substituted with halogen, amino, hydroxy, C _1-4 Alkoxy groups are substituted.

n is selected from 1 and 2.

2. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein a is selected from the group consisting of hydrogen, a benzene ring, a 5-6 membered heteroaryl; the benzene ring, 5-6 membered heteroaryl group may be substituted with halogen, C _1-4 Alkyl, cyano, hydroxy, nitro, amino, -NRaRb, -NHRa, - (CH) ₂ )nNRaRb、-NHC(O)ORa、-NHC(O)NHRa、-NHC(O)Ra、-ORa、-OC(O)ORa、-OC(O)Ra、-C(O)Ra、-C(O)NHRa、-(CH ₂ ) nC (O) NHRa, -C (O) NRaRb; ra and Rb are each independently selected from C _1-4 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, said C _1-4 Alkyl groups may be substituted by halogen, amino, hydroxy, C _1-4 Alkoxy substituted; the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl can be substituted by halogen, amino, hydroxy, C _1-4 Alkyl, C _1-4 Alkoxy groups are substituted.

3. The compound of claim 2, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein

A is selected from hydrogen, benzene ring, pyridine ring,

Wherein A may be halogen, C _1-4 Alkyl, cyano, hydroxy, nitro, -NRaRb, -NHRa, - (CH) ₂ )nNRaRb、-NHC(O)ORa、-NHC(O)NHRa、-NHC(O)Ra、-ORa、-OC(O)ORa、-OC(O)Ra、-C(O)Ra、-C(O)NHRa、-(CH ₂ ) nC (O) NHRa, -C (O) NRaRb; ra and Rb 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 groups are substituted.

4. A compound according to claim 3, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein a is selected from the group consisting of benzene rings or

Said benzene ring or->

Can be halogen, C _1-4 Alkyl, cyano, hydroxy, nitro, -NRaRb, -NHRa, - (CH) ₂ )nNRaRb、-NHC(O)ORa、-NHC(O)NHRa、-NHC(O)Ra、-ORa、-OC(O)ORa、-OC(O)Ra、-C(O)Ra、-C(O)NHRa、-(CH ₂ ) nC (O) NHRa, -C (O) NRaRb; ra and Rb 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 substituted; preferably, the A ring substituent is selected from methyl, ethyl, isopropyl, tert-butyl, -NHC (O) OCH ₂ 、-NHC(O)OCH ₂ CH ₃ 。

5. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R ₄ Selected from C _1-4 Alkyl, which may optionally be C _1-4 Alkyl, cyano, nitro, halogen, halogenated C _1-4 Alkyl, C _1-4 Alkoxy, -NRcRd; rc, rd are each independently selected from hydrogen, C _1-4 Alkyl groups, which may be substituted by halogen, amino, hydroxy, C _1-4 Alkoxy groups are substituted.

6. The compound of claim 5, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein R ₄ Selected from C _1-4 Alkyl, which may optionally be C _1-4 Alkyl, cyano, nitro, halogen, halomethyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, -NRcRd; rc, rd are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl.

7. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, having the structure of formula (II):

wherein R is ₂ 、R ₃ 、R ₄ As defined in any one of claims 1 to 6.

8. The compound of claim 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, having the structure:

9. a pharmaceutical composition comprising a compound according to any one of claims 1-8, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable excipient.

10. Use of a compound according to any one of claims 1-8, 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.

11. The use of claim 10, 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.

12. The use of claim 11, 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.

13. The use according to claim 11 or 12, 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.

14. Use of a compound according to any one of claims 1-8, or a stereoisomer, pharmaceutically acceptable salt, solvate, or tautomer thereof, in the manufacture of a medicament for the treatment of a BTK mediated disease.

15. The use of claim 14, wherein the BTK-mediated disease is selected from cancer, autoimmune disease, or allergic disease.

16. The use of claim 15, 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.