RU2811484C1 - Substituted aromatic derivative with condensed rings and composition including it and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (II), where ring A represents isoxazolyl; R₁ represents -C(R_a1)(R_a2)(R_a3), where R_a1, R_a2 and R_a3 independently represent H, C_1-6 alkyl or C_1-6 haloalkyl; alternatively R_a1, R_a2 and R_a3 are independently C_1-4 alkyl or C_1-4 haloalkyl; alternatively R_a1, R_a2 and R_a3 are independently methyl or halomethyl; R₂ represents H; m is selected from 0, 1, 2 and 3; L₁ represents CH₂; R_Y is H or halogen, alternatively fluorine; Y₄ represents CH or N; Z₂ represents N or CR_Z2 where R_Z2 represents H; Z₃ represents N or C; Z₅ represents N, NR_Z5 or CR_Z5, where R_Z5 represents H; Z₆ represents NR_Z6 or CR_Z6, where R_Z6 represents C_1-6 alkyl; alternatively R_Z6 is C_1-4 alkyl; each of R_n1 and R_n2 is independently selected from H; or a pharmaceutically acceptable salt thereof; alternatively, wherein at most one of Z₅ and Z₆ represents a substituted or unsubstituted carbon atom. The invention relates to specific compounds (shown in the claims). The invention relates to a pharmaceutical composition used for inhibiting wild-type and mutant RET, KIF5B-RET, FLT3 and FLT3-ITD kinases, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable excipient.

(II)

EFFECT: aromatic derivative used in the production of a medicinal product for the treatment and/or prevention of a disease wherein the disease is mediated by protein kinases selected from wild type and mutant RET, KIF5B-RET, FLT3 and FLT3-ITD kinases.

28 cl, 6 dwg, 10 tbl, 13 ex

Description

Field of technology to which the invention relates

The present invention relates to the technical field of medicine and, in particular, relates to a substituted aromatic fused ring derivative having a protein tyrosine kinase inhibitory effect, a pharmaceutical composition containing it, and a method of preparation and use thereof.

Prior Art

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of specific serine, threonine, or tyrosine in cellular proteins. Post-translational modifications of these substrate proteins act as molecular switches that play key roles in various biological processes such as the control of cell growth, metabolism, tumor microenvironment (eg, VEGFR), differentiation and apoptosis. Abnormal, excessive or inappropriate PC activity has been observed in several pathological conditions, including malignant proliferative diseases such as functional mutations in medullary thyroid cancer (MTC) and other human malignancies, ITD mutation in FLT3 in acute myeloid leukemia ( AML), c-Kit mutation in gastrointestinal stromal tumor (GIST), and RET derived from BCR-ABL rearrangement in chronic myeloid leukemia (CML). In addition, activation and/or overexpression of tyrosine kinases (eg, TrkA, TrkB, TrkC, and RET) causes cancer. Many tyrosine kinases are homologous to each other: inhibition of one tyrosine kinase may also have some inhibitory effect on other tyrosine kinases. Several targets for cancer therapy and associated challenges are briefly described below.

RET

RET (rearranged during transfection) belongs to the receptor tyrosine kinase protein family and is a cell surface molecule that signals cell growth and differentiation. RET gene mutation or RET gene fusion have been identified as a driving factor for some cancers. The frequency of RET gene fusions in non-small cell lung cancer is about 2%, and the frequency of RET gene fusions in papillary thyroid cancer (PTC) is 10-20%. The most common fusion partners are KIF5B, TRIM33, CCDC6 and NCOA4. The frequency of RET gene mutation in medullary thyroid cancer (MTC) is approximately 60%, and the most common site of mutation is M918T. RET inhibitor resistance mutations include, but are not limited to, amino acid position 804 (V804M, V804L, V804E), amino acid position 805 (E805K), and amino acid position 806 (Y806C, Y806E).

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Trk (tropomyosin-related kinase) is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophin (NT). The Trk receptor family consists of three members, namely TrkA, TrkB and TrkC. Neurotrophin includes (1) neural growth factor (NGF), which can activate TrkA, (2) brain-derived neurotrophic factor (BDNF) and NT4/5, which can activate TrkB, and (3) NT3, which can activate TrkC. Trk is widely expressed in neural tissues and is involved in the maintenance, signaling, and survival of nerve cells. Overexpression, activation, amplification and/or mutation of Trk are associated with many types of cancer, including neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, astrocytoma and medulloblastoma, glioma, melanoma, thyroid cancer, cancer pancreas, large cell neuroendocrine tumor and colorectal cancer. In addition, inhibitors of the Trk/neurotrophin pathway have been shown to be effective in various preclinical animal models for the treatment of pain and inflammatory diseases.

FLT3

FLT3 (FMS-like tyrosine kinase 3) belongs to the class III receptor tyrosine kinase family of protein kinases. FLT3 is a receptor tyrosine kinase that plays a role in regulating normal hematopoietic cell production and is overexpressed in fetal leukemic cells. Mutations in the FLT3 gene are characteristic of 30% of AML cases. The internal tandem duplication (ITD) mutation (accounting for about 23% of AML cases) in FLT3 is associated with a particularly poor prognosis. It is preferable to inhibit FLT3 and its mutations.

c-KIT

c-KIT (also known as CD117) is a type of transmembrane receptor protein with tyrosine kinase activity encoded by the retroviral proto-oncogene c-kit. c-KIT kinase consists of an extracellular domain, a transmembrane domain, and an intracellular domain. The c-KIT ligand is stem cell factor (SCF), which binds to the extracellular domain of c-KIT, inducing dimerization of the receptor and activating downstream signal transduction pathways. c-KIT mutations typically occur in the DNA (exon 11) encoding the juxtamembrane region domain. They also occur in exons 7, 8, 9, 13, 14, 17, and 18 at lower frequencies. Mutations render c-KIT function independent of SCF activation, resulting in high rates of cell division and possible genomic instability. c-KIT mutations are implicated in the pathogenesis of a number of diseases and conditions, including systemic mastocytosis (SM), gastrointestinal stromal tumor (GIST), acute myeloid (myelocytic) leukemia (AML), melanoma, and seminoma. Therefore, there is a need to develop therapeutic agents that inhibit c-KIT, and in particular, drugs that inhibit mutant c-KIT.

PDGFR

PDGFR (platelet-derived growth factor receptor) is a cell surface tyrosine kinase receptor that is a member of the platelet-derived growth factor (PDGF) family. PDGF subunits PDGFα and PDGFβ are vital factors in the regulation of cell proliferation, cell differentiation, cell growth, development and various diseases, including cancer. The D842V PDGFRα mutation has been found in various gastrointestinal stromal tumor (GIST) isoforms, usually from the stomach. The D842V mutation is known to be associated with resistance to tyrosine kinase inhibitors.

VEGFR

VEGFR (Vascular Endothelial Growth Factor) is a vital signaling protein involved in angiogenesis and vasculogenesis. As its name suggests, VEGFR activity is primarily limited to vascular endothelial cells, although VEGFR also affects a limited number of other cell types. In vitro, VEGFR has been confirmed to stimulate mitogenesis and migration of endothelial cells. VEGFR also promotes microvascular permeability and is sometimes referred to as a vascular permeability factor. VEGFR kinase has been used as a target for solid tumors such as highly vascularized malignancies such as kidney cancer, glioblastoma and liver cancer.

The essence of the invention

The present invention relates to a new aromatic derivative with fused rings, to a composition containing the compound, and to its use. The aromatic derivative with fused rings has better inhibitory activity and selectivity against several wild-type and mutant RET kinases, KIF5B-RET, CCDC6-RET, TrkA, TrkB, TrkC, FLT3, FLT3-ITD, c-Kit, PDGFR and VEGFR , and has better pharmacodynamic and/or pharmacokinetic properties. The aromatic derivative with fused rings allows the treatment of diseases mediated by protein kinases.

In this regard, the present invention uses the following technical solutions.

In one aspect, the present invention provides a compound of formula (I):

(I)

Where

● ring A is a 5-membered heteroaryl group containing from 1 to 3 heteroatoms selected from N, O and S;

R ¹ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are each independently selected from H, D, halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl and -O- 3-7 membered heterocyclyl, where C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl and -O- 3-7 membered heterocyclyl are optionally substituted one or more R;

R ₂ is each independently H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O) R _a , -OC(O)OR _a or -OC(O)NR _b R _c ;

m is selected from 0, 1, 2 and 3;

● L ₁ selected from connection, O, S, NR _L1 and C(R _L1 ) ₂ ,

● L ₂ is selected from the connection, O, S, NR _L2 and C(R _L2 ) ₂ ,

wherein each example of R _L1 and R _L2 is independently selected from H, D, halogen, C _1-6 alkyl and C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

each of Y ₁ , Y ₂ , Y ₃ and Y ₄ independently selected from CR _Y and N;

where R _Y is independently selected from H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , and -OC(O)NR _b R _c ;

● ring B and ring C form an aromatic fused ring;

each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

Z ₁ is selected from CR _Z1 and N;

Z ₂ is selected from CR _Z2 and N;

each of Z ₃ and Z ₄ is independently selected from an N atom and a C atom;

Z ₅ is selected from an N atom and a C atom, which are optionally substituted with R _Z5 ;

Z ₆ is selected from an N atom and a C atom, which are optionally substituted with R _Z6 ;

where each of R _Z1 , R _Z2 , R _Z5 and R _Z6 is independently selected from H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O) OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , and -OC(O)NR _b R _c ;

● each of R _a , R _b and R _c is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, or R _b and R _c together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl or 5-10 membered heteroaryl group, where the group is optionally substituted by one or more R;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, -R _d , -C(O)R _d , -C(O)OR _d , -C(O)NR _e R _f , -NR _e R _f , -NR _d C(O)R _e , -NR _d C(O)OR _e , -NR _d C(O)NR _e R _f , -OR _d , -OC(O)R _d , -OC(O)OR _d , and -OC(O)NR _e R _f , or two R groups on the same atom or on adjacent atoms can together form a C _3-7 cycloalkyl, 3-7 membered heterocyclyl, a C _6-10 aryl or 5-10 membered heteroaryl group, wherein each group in the definition of R is optionally substituted with one or more Ds until complete deuteration;

each of R _d , R _e and R _f is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, or R _e and R _f together with a nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl or 5-10 membered heteroaryl group, where each group in the definition of R _d , R _e and R _f is optionally substituted with one or more D until complete deuteration;

or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

In another aspect, the present invention provides a pharmaceutical composition that contains a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and pharmaceutically acceptable excipient(s). In a specific embodiment, a compound disclosed herein is provided in a therapeutically effective amount. In a specific embodiment, a compound disclosed herein is provided in a prophylactically effective amount.

In another aspect, the present invention provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of protein kinase-mediated diseases.

In another aspect, the present invention provides a method of treating diseases, such as protein kinase-mediated diseases, in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition described herein.

In another aspect, the present invention provides a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein, for the treatment of diseases, such as protein kinase-mediated diseases.

In a specific embodiment, the diseases are mediated by at least one of the wild-type wild-type or mutant RET, KIF5B-RET, CCDC6-RET, Trk, FLT3, c-Kit, PDGFR or VEGFR kinases. In a specific embodiment, the RET, KIF5B-RET, and CCDC6-RET mutants are selected from V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y, C634W, and G810R. In a specific embodiment, Trk is selected from TrkA, TrkB and TrkC; in a specific embodiment, the TrkA mutant is G595R. In a specific embodiment, the mutant FLT3 and FLT3-ITD are selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842D, Y842H, Y842N, and Y842S. In a specific embodiment, the c-Kit mutant is selected from D816V, D816Y, D816F, D816K, D816A, and D816G. In a specific embodiment, the mutant PDGFR is D842V.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the following specific embodiments, examples, and claims.

Definitions

Chemical definitions

Definitions of specific functional groups and chemical terms are described in more detail below.

When a range of values is specified, it is intended to cover every value and subrange within the range. For example, "C _1-6 alkyl" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C 3-5 , C _3-4 , C _4-6 , _{C 4-5} , and C _5-6 alkyl.

"C _1-6 alkyl" refers to a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms, and is also referred to herein as "lower alkyl". In some embodiments, C _1-4 alkyl is an alternative. Examples of alkyl include methyl ( _C1 ), ethyl ( _C2 ), n-propyl ( _C3 ), isopropyl ( _C3 ), n-butyl (C4), t-butyl ( _{C4 )} , sec-butyl (C ₄ ), isobutyl ( _C4 ), n-pentyl ( _C5 ), 3-pentyl ( _C5 ), pentyl ( _C5 ), neopentyl ( _C5 ), 3-methyl-2-butyl ( _C5 ), t -pentyl (C ₅ ) and n-hexyl (C ₆ ), but are not limited to them. Regardless of whether the alkyl group is modified by the word "substituted", each alkyl group is independently substituted as necessary, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are defined as follows.

"C _2-6 alkenyl" refers to a straight or branched hydrocarbon group having 2-6 carbon atoms and one or more carbon-carbon double bonds (eg, 1, 2 or 3 carbon-carbon double bonds). The one or more carbon-carbon double bonds may be internal (eg, in 2-butenyl) or terminal (eg, in 1-butenyl). In some embodiments, C _2-4 alkenyl is an alternative. Examples of alkenyl include vinyl ( _C2 ), 1-propenyl ( _C3 ), 2-propenyl ( _C3 ), 1-butenyl ( _C4 ), 2-butenyl ( _C4 ), butadienyl ( _C4 ), pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), etc., but are not limited to them. Regardless of whether the alkenyl group is modified by the word "substituted", each alkenyl group is independently substituted as necessary, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are determined as follows.

"C _2-6 alkynyl" refers to a straight or branched hydrocarbon group containing 2-6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, or 3 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (for example, 1, 2 or 3 carbon-carbon double bonds). In some embodiments, C _2-4 -alkynyl is an alternative. In some embodiments, the alkynyl does not contain double bonds. One or more carbon-carbon triple bonds may be internal (eg, in 2-butynyl) or terminal (eg, in 1-butynyl). Examples of alkynyl include ethynyl ( _C2 ), 1-propynyl ( _C3 ), 2-propynyl ( _C3 ), 1-butynyl ( _C4 ), 2-butynyl ( _C4 ), pentynyl ( _C5 ), hexynyl (C ₆ ) etc., but are not limited to them. Regardless of whether the alkynyl group is modified by the word "substituted", each alkynyl group is independently substituted as necessary, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are defined as follows.

"C _1-6 alkoxy" refers to the group -OR, where R represents a substituted or unsubstituted C _1-6 alkyl. In some embodiments, C _1-4 alkoxy is an alternative. In particular, alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Thus, "C _1-6 haloalkyl" and "C _1-6 haloalkoxy" refer to the above "C _1-6 alkyl" and "C _1-6 alkoxy" substituted with one or more halogen groups. In some embodiments, C _1-4 haloalkyl is an alternative, and C _1-2 haloalkyl is another alternative. In some embodiments, C _1-4 haloalkoxy is an alternative, and C _1-2 haloalkoxy is another alternative. Examples of haloalkyl include -CF ₃ , -CH ₂ F , -CHF ₂ , -CHFCH ₂ F , -CH ₂ CHF ₂ , -CF ₂ CF ₃ , -CCl ₃ , -CH ₂ Cl , -CHCl ₂ , 2,2, 2-trifluoro-1,1-dimethylethyl, etc., but not limited to them. Examples of haloalkoxy include, but are not limited to -OCH ₂ F, -OCHF ₂ , -OCF ₃ etc.

"C _3-10 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3-10 ring carbon atoms and zero heteroatoms. In some embodiments, C _3-7 cycloalkyl is an alternative, C _3-6 cycloalkyl is an alternative, and C _5-6 cycloalkyl is another alternative. Cycloalkyl also includes a ring system in which the above cycloalkyl ring is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the cycloalkyl system. Examples of cycloalkyl include cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl ( _C6 ), cyclohexenyl ( _C6 ) , cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C _{7 ), cycloheptatrienyl (C 7 )} , cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptyl ( _C7 ), bicyclo[2.2.2]octyl ( _C8 ), cyclononyl ( _C9 ), cyclononenyl ( _C9 ), cyclodecyl ( _C10 ), cyclodecenyl ( _C10 ), octahydro-1H-indenyl ( _C9 ) , decahydronaphthyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), etc., but are not limited to them. Regardless of whether or not the cycloalkyl group is modified by the term "substituted", each cycloalkyl group is independently optionally substituted, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are defined as follows.

“3-10 membered heterocyclyl” refers to a 3-10 membered non-aromatic ring system radical having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, depending on the valency. In some embodiments, the alternative is a 3-7 membered heterocyclyl and is a 3-7 membered non-aromatic ring system containing ring carbon atoms and 1-3 ring heteroatoms. In some embodiments, the alternative is a 3-6 membered heterocyclyl and is a 3-6 membered non-aromatic ring system containing ring carbon atoms and 1-3 ring heteroatoms. Another alternative is the 5-6 membered heterocyclyl, which is a 5-6 membered non-aromatic ring system containing ring carbon atoms and 1-3 ring heteroatoms. "Heterocyclyl" also includes ring systems in which the heterocyclyl, as defined above, is fused to one or more cycloalkyl, aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring. ring system. Regardless of whether or not the heterocyclyl group is modified by the term "substituted", each heterocyclyl group is independently optionally substituted, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are defined below.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl and tyanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and tiepanil. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

"C _6-14 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system radical (e.g., having 6, 10, or 14 pi electrons shared in the cyclic array) having 6-14 ring atoms carbon and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms (C ₆ -aryl, e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C ₁₀ -aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C ₁₄ -aryl"; eg, anthracyl). In some embodiments, C _6-10 aryl is an alternative, and C ₆ aryl is another alternative. "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, where the point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to denote the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is modified by the term "substituted", each aryl group is independently substituted as needed, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are defined below.

"5-10 membered heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system radical (e.g. having 6 or 10 pi electrons shared in the cyclic array) having ring carbon atoms and 1- 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, depending on the valency. Heteroaryl bicyclic ring systems may include one or more heteroatoms on one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, the alternative is 5-6 membered heteroaryl, and is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system containing ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is modified by the term "substituted", each heteroaryl group is independently optionally substituted, for example, with 1-5 substituents, 1-3 substituents, or 1 substituent. Suitable substituents are defined as follows.

Examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Examples of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl and purinyl , but are not limited to them. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of substituents on carbon atoms include halogen, -CN, _-NO2 , _-N3 , -SO2H, _{-SO3H ,} -OH, -OR ^aa , -ON( ^Rbb ) ₂ , -N( ^Rbb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , -OC(=O)R ^aa , -OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -OC(=O)N( R ^bb ) ₂ , -NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , - C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb ) N(R ^bb ) ₂ , -NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO ₂ R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , -OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi (R ^aa ) ₃ , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(= O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa , -P(=O) ₂ R ^aa , -OP(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P(=O) ₂ N(R ^bb ) ₂ , -OP(=O) ₂ N(R ^bb ) ₂ , -P(=O)(NR ^bb ) ₂ , -OP(=O)(NR ^bb ) ₂ , -NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(NR ^bb ) ₂ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ , -OP(R ^cc ) ₂ , -OP(R ^cc ) ₃ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), but not limited to, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

or two geminal hydrogen atoms on a carbon atom are replaced by the group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb or =NOR ^cc ;

each R ^{aa is} independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^aa groups are linked to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

each R ^bb is independently selected from hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl , aryl and heteroaryl, or two R ^bb groups are linked to form a heterocyclyl or heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

each R ^cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ^cc groups are linked to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

each R ^dd is independently selected from halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N(R ^ff ) ₂ ,, -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)R ^ee , -CO ₂ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , -NR ^ff C( =O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff )R ^ee , - OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , -SO ₂ OR ^ee , -OSO ₂ R ^ee , -S(=O)R ^ee , -Si (R ^ee ) ₃ , -OSi(R ^ee ) ₃ , -C(=S)N(R ^ff ) ₂ , -C(=O)SR ^ee , -C(=S)SR ^ee , -SC(=S )SR ^ee , -P(=O) ₂ R ^ee , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee ) ₂ , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal substituents R ^dd can be linked to form =O or =S;

each R ^ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

each ^Rff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two ^Rff groups are linked to form a heterocyclyl or heteroaryl ring, wherein each of alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

each R ^gg is independently halogen, CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl) ₂ , - N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- , -NH ₂ (C _1-6 alkyl) ⁺ X ^- , -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O )(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(=O )NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl), -NHCO ₂ ( C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , -NHC(=O)NH(C _1-6 alkyl), -NHC(=O)NH ₂ , -C( =NH)O(C _1-6 alkyl), -OC(=NH)(C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH (C _1-6 alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl) , -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ , -C(=S)N(C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _{1- 6} alkyl, -SC(=S)SC _1-6 alkyl, -P(=O) ₂ (C _1-6 alkyl), -P(=O)(C _1-6 alkyl) ₂ , -OP(=O )(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl , C ₃ -C ₇ carbocyclyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocyclyl, or C ₅ -C ₁₀ heteroaryl; or two geminal R ^gg substituents can be coupled to form =O or =S, where X- is the counterion.

Examples of substituents on the nitrogen atom include hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O) ₂ R ^aa , -P(=O)(R ^aa ) ₂ , -P(=O) ₂ N(R ^cc ) ₂ , -P(=O)(NR ^cc ) ₂ , alkyl , haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, but are not limited to; or two R ^cc groups bonded to a nitrogen atom are linked to form a heterocyclyl or heteroaryl ring wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are each independently substituted with 0, 1, 2, 3, 4 or 5 R groups ^dd , and where R ^aa , R ^bb , R ^cc and R ^dd are as defined above.

"Deuterated", "deuterated" or "D" means that one or more hydrogen atoms in a compound or group have been replaced by deuterium. Deuteration can be mono-, di-, poly- or fully substituted. The term "substituted with one or more deuteriums" can be used interchangeably with "deuterated one or more times."

"Non-deuterated compound" refers to a compound in which the content of deuterium atoms does not exceed the natural abundance (0.015%) of the deuterium isotope.

The deuterium isotope content at the deuterated position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, or more preferably greater than 99%.

The term "pharmaceutically acceptable salt" refers to those salts which, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit/risk ratio . Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid acid, citric acid, succinic acid or malonic acid. Salts prepared using conventional methods in the art, such as ion exchange, are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycero phosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate , picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

The “subject” in which use is intended includes a human (i.e., male or female of any age group, such as a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and/or a non-human animal, for example a mammal such as primates (e.g. cynomolgus, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and/or dogs, but not limited to them. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably in this application.

The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat” and “treatment” imply an action that occurs when a subject is suffering from a specified disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows the progression a disease, disorder or condition (“therapeutic treatment”), and also involves an action that occurs before the subject begins to suffer from said disease, disorder or condition (“preventative treatment”).

"Combination", "combined" and related terms refer to simultaneous or sequential administration of the therapeutic agents of the present invention. For example, a compound disclosed herein may be administered with another therapeutic agent concurrently or sequentially in separate unit dosage forms or together in a single unit dosage form.

Brief description of drawings

Fig. 1 is a tumor volume growth curve of each group of mice using the Ba/F3 KIF5B-RET tumor cell line model.

Fig. 2 is a curve of changes in body weight of each group of mice depending on treatment time using the Ba/F3 KIF5B-RET tumor cell line model.

Fig. 3 is a curve of the percentage change in body weight of each group of mice as a function of treatment time using the Ba/F3 KIF5B-RET tumor cell line model.

Fig. 4 is a tumor volume growth curve of each group of mice using the Ba/F3 KIF5B-RET ^G810R tumor cell line model.

Fig. 5 is a curve of changes in body weight of each group of mice depending on treatment time using the Ba/F3 KIF5B-RET ^G810R tumor cell line model.

Fig. 6 is a curve of the percentage change in body weight of each group of mice depending on the treatment time using the Ba/F3 KIF5B-RET ^G810R tumor cell line model.

Detailed Description of the Invention

Compound

As used herein, the term “compound of the present invention” refers to the following compound of formula (I) (including subsets of each formula) or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In one embodiment, the present invention provides a compound of formula (I):

(I)

Where

● ring A is a 5-membered heteroaryl group containing from 1 to 3 heteroatoms selected from N, O and S;

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are each independently selected from H, D, halogen, C _1-6 alkyl, C _1-6 haloalkyl , C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl and -O-3-7 membered heterocyclyl, where C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl and -O- 3-7 membered heterocyclyl are optionally substituted one or more R;

in each case, R ₂ is independently H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O )R _a , -OC(O)OR _a , or -OC(O)NR _b R _c ;

m is selected from 0, 1, 2 and 3;

● L1 is selected from the connection, O, S, N _RL1 and C(R _L1 ) ₂ ,

● L2 is selected from the connection, O, S, NR _L2 and C(R _L2 ) ₂ ,

wherein each example of R _L1 and R _L2 is independently selected from H, D, halogen, C _1-6 alkyl and C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

each of Y ₁ , Y ₂ , Y ₃ and Y ₄ is independently selected from CR _Y and N;

where R _Y is independently selected from H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , and -OC(O)NR _b R _c ;

● ring B and ring C form an aromatic fused ring;

each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

Z ₁ is selected from CR _Z1 and N;

Z ₂ is selected from CR _Z2 and N;

Z ₃ and Z ₄ are independently selected from an N atom and a C atom;

Z ₅ is selected from an N atom and a C atom, which are optionally substituted with R _Z5 ;

Z ₆ is selected from an N atom and a C atom, which are optionally substituted with R _Z6 ;

where each of R _Z1 , R _Z2 , R _Z5 and R _Z6 is independently selected from H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O) OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O)R _a , -OC(O)OR _a , and -OC(O)NR _b R _c ;

● each of R _a , R _b and R _c is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, or R _b and R _c together with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl or 5-10 membered heteroaryl group, where the group is optionally substituted by one or more R;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, -R _d , -C(O)R _d , -C(O)OR _d , -C(O)NR _e R _f , -NR _e R _f , -NR _d C(O)R _e , -NR _d C(O)OR _e , -NR _d C(O)NR _e R _f , -OR _d , -OC(O)R _d , -OC(O)OR _d , and -OC(O)NR _e R _f , or two R groups on the same atom or neighboring atoms can together form a C _3-7 -cycloalkyl, 3-7-membered heterocyclyl, a C _6-10 aryl or 5-10 membered heteroaryl group, wherein each group in the definition of R is optionally substituted with one or more Ds until complete deuteration;

each of R _d , R _e and R _f is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl, or R _e and R _f together with a nitrogen atom to which they are attached to form a 3-7 membered heterocyclyl or 5-10 membered heteroaryl group, where each group in the definition of R _d , R _e and R _f is optionally substituted with one or more D until complete deuteration;

or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

Ring A

In a specific embodiment, ring A is a 5-6 membered heteroaryl group containing from 1 to 3 heteroatoms selected from N, O and S; in another specific embodiment, ring A is selected from pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl and isothiazolyl; in another specific embodiment, ring A is selected from imidazolyl, isoxazolyl and isothiazolyl; in another specific embodiment, ring A is selected from isoxazolyl and isothiazolyl.

In a specific embodiment, ring A is selected from , , , , And ; in another specific embodiment, ring A is selected from , And ; in another specific embodiment, ring A is .

R ₁

In a specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently selected from H, D, halogen, C _1-6 alkyl, C _{1- 6} haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl and -O- 3-7 membered heterocyclyl, where C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -OC _3-7 cycloalkyl and -O- 3-7 -membered heterocyclyl is optionally substituted with one or more R.

In another specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _{a2 ,} and R _a3 are each independently selected from H, D, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl and 3-7 membered heterocyclyl, where C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl and 3-7 membered heterocyclyl are optionally substituted by one or more R.

In another specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _{a2 ,} and R _a3 are each independently selected from H, D, halogen, C _1-6 alkyl, and C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R.

In another specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are each independently selected from C _1-4 alkyl and C _1-4 haloalkyl, where C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R.

In another specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are each independently selected from methyl and halomethyl.

In another specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 , and R _a3 are each independently selected from H, D, F, Cl, methyl, -CD ₃ and trifluoromethyl.

In another specific embodiment, R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein at least one of R _a1 , R _a2 and R _a3 is a haloalkyl.

R ₂

In a specific embodiment, each example of R ₂ is independently H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O)OR _a , -C( O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , - OC(O)R _a , -OC(O)OR _a , or -OC(O)NR _b R _c .

In another specific embodiment, each example of R ₂ is independently H, D, halogen, C _1-6 alkyl, or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R's.

In another specific embodiment, each example of R ₂ is independently H, D, F, methyl or -CD ₃ .

In another specific embodiment, each group in the definition of R ₂ is optionally replaced with one or more Ds until complete deuteration.

m

In a specific embodiment, m is selected from 0, 1, and 2. In another specific embodiment, m is selected from 0 and 1. In another specific embodiment, m is 0. In another specific embodiment, m is 1. In another specific embodiment, m is 2 .

L ₁ and L ₂

In a specific embodiment, L ₁ represents a link. In another specific embodiment, L ₁ is O. In another specific embodiment, L ₁ is S. In another specific embodiment, L ₁ is NR _L1 . In another specific embodiment, L ₁ is C(R _L1 ) ₂ .

In a specific embodiment, L ₂ represents a link. In another specific embodiment, L ₂ is O. In another specific embodiment, L ₂ is S. In another specific embodiment, L ₂ is NR _L2 . In another specific embodiment, L ₂ is C(R _L2 ) ₂ .

In another specific embodiment, L ₁ is selected from the bond, O, S, NH and CH ₂ and L ₂ is selected from the bond, O, S, NH and CH ₂ . In another specific embodiment, L ₁ is selected from O, S, NH and CH ₂ and L ₂ is selected from bond, O, S and NH. In another specific embodiment, L ₁ is selected from NH and CH ₂ and L ₂ is NH.

Y ₁ , Y ₂ , Y ₃ and Y ₄

In a specific embodiment, Y ₁ , Y ₂ , Y ₃ and Y ₄ are each independently selected from CR _Y and N. In another specific embodiment, Y ₁ , Y ₂ , Y ₃ and Y ₄ are CR _Y. In another specific embodiment, Y ₁ , Y ₂ and Y ₃ are CR _Y and Y ₄ is N. In another specific embodiment, Y ₂ and Y ₃ are CR _Y and Y ₁ and Y ₄ are N.

In a specific embodiment selected from , , And .

R _Y

In a specific embodiment, R _Y is selected from H, D, -OH, halogen, -CN, -NO ₂ , -R _a , -C(O)R _a , -C(O)OR _a , -C(O)NR _b R _c , -NR _b R _c , -NR _a C(O)R _b , -NR _a C(O)OR _b , -NR _a C(O)NR _b R _c , -OR _a , -OC(O )R _a , -OC(O)OR _a , and -OC(O)NR _b R _c .

In another specific embodiment, R _Y is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl, 3-7 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl groups, where the groups optionally substituted with one or more R. In another specific embodiment, R _Y is selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-7 cycloalkyl and 3-7 membered heterocyclyl groups, where the groups are optionally substituted with one or more several R. In another specific embodiment, R _Y is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, pyrrolidinyl, and piperidinyl groups, where the groups are optionally substituted with one or more R. In another specific embodiment, each group in the definition of R _Y is optionally substituted one or more D until complete deuteration.

Z ₁ , Z ₂ , Z ₃ , Z ₄ , Z ₅ , and Z ₆

In a specific embodiment, Z ₁ is N. In another specific embodiment, Z ₁ is CR _Z1 . In another specific embodiment, Z ₁ represents CH.

In a specific embodiment, Z ₂ is N. In another specific embodiment, Z ₂ is CR _Z2 . In another specific embodiment, Z ₂ represents CH.

In a specific embodiment, Z ₃ is an N atom. In another specific embodiment, Z ₃ is a C atom.

In a specific embodiment, Z ₄ is an N atom. In another specific embodiment, Z ₄ is a C atom.

In a particular embodiment, Z ₅ represents an N atom, which is optionally substituted with R _{Z 5} . In another specific embodiment, Z ₅ represents a C atom, which is optionally substituted with R _{Z 5} .

In a particular embodiment _{, Z6} is an N atom which is optionally substituted with _RZ6 . In another specific embodiment, Z ₆ represents a C atom which is optionally substituted with R _{Z 6} . In a specific embodiment, R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl. In another specific embodiment, R _Z6 is C _1-6 alkyl. In another specific embodiment, R _Z6 is isopropyl.

In another specific embodiment represents . In another specific embodiment selected from , , And . In another specific embodiment selected from And .

In another specific embodiment represents . In another specific embodiment selected from And . In another specific embodiment selected from , , , , , , And . In another specific embodiment selected from , , And . In another specific embodiment selected from And .

_Rn1 and _Rn2

In a specific embodiment, R _n1 and R _n2 are each independently H. In another specific embodiment, R _n1 and R _n2 are each independently D. In another specific embodiment, R _n1 and R _n2 are each independently C _{1 -6} alkyl. In another specific embodiment, R _n1 and R _n2 are each independently C _1-6 haloalkyl. In another specific embodiment, R _n1 and R _n2 are each independently C _2-6 alkenyl. In another specific embodiment, R _n1 and R _n2 are each independently C _2-6 alkynyl.

Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in another specific embodiment. For example, any technical solution or any combination thereof of ring A can be combined with any technical solution or any combination thereof R ₁ , R ₂ , m, L ₁ , L ₂ , Y ₁ - Y ₄ , R _n1 , R _n2 , and Z ₁ - Z ₆ . The present invention is intended to include all combinations of these technical solutions that are not listed one after another due to space limitations.

In a more specific embodiment, the present invention provides a compound of formula (II) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(II)

Where

Ring A is pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl;

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

m is selected from 0, 1, 2 and 3;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

R _Y is H, D or halogen, alternatively fluorine;

Y ₄ represents CH, CD or N;

Z ₂ represents N or CR _Z2 where R _Z2 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

Z ₃ represents N or C;

Z ₅ is N, NR _Z5 or CR _Z5 , where R _Z5 is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted one or more R;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (II-1) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(II-1)

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

R _Y is H, D or halogen, alternatively fluorine;

Y ₄ represents CH, CD or N;

Z ₂ represents N or CR _Z2 where R _Z2 represents H, D, halogen, C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R;

Z ₃ represents N or C;

Z ₅ is N, NR _Z5 or CR _Z5 , where R _Z5 is H, D, halogen, C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted one or more R;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, no more than one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (II-2) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(II-2)

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R _Y is H, D or halogen, alternatively fluorine;

Y ₄ represents CH, CD or N;

Z ₂ represents N, CH or CD;

Z ₃ represents N or C;

Z ₅ represents N, NH, CH or CD;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl.

In another embodiment, no more than one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (II-3) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(II-3)

Where

R _Y is H, D or halogen, alternatively fluorine;

Y ₄ represents CH, CD or N;

Z ₂ represents N, CH or CD;

Z ₃ represents N or C;

Z ₅ represents N, CH or CD;

Z ₆ represents N or C.

In another embodiment, no more than one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (II-4-1) or formula (II-4-2), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(II-4-1) or (II-4-2)

Where

R _Y is H or halogen, alternatively fluorine;

Y ₄ represents CH or N;

Z ₂ represents CH or N;

Z ₅ represents CH or N.

In another more specific embodiment, the present invention provides a compound of formula (III) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(III)

Where

Ring A is pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl;

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

m is selected from 0, 1, 2 and 3;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

Z ₂ represents N or CR _Z2 where R _Z2 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

Z ₃ represents N or C;

Z ₅ is N, NR _Z5 or CR _Z5 , where R _Z5 is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted one or more R;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl;

wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted nitrogen atom.

In another more specific embodiment, the present invention provides a compound of formula (III-1) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(III-1)

Where

Z ₂ represents N or CH;

Z ₃ represents N or C;

Z ₅ represents N, NH or CH;

Z ₆ represents N or C;

where at most one of Z ₅ and Z ₆ represents a nitrogen atom.

In another more specific embodiment, the present invention provides a compound of formula (IV) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(IV)

Where

Ring A is pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl;

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

m is selected from 0, 1, 2 or 3;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

Y ₄ represents CH, CD or N;

Z ₂ represents N or CR _Z2 where R _Z2 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

Z ₃ represents N or C;

Z ₅ is N, NR _Z5 or CR _Z5 , where R _Z5 is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted one or more R;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl or C _2-6 alkynyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl;

wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N.

In another embodiment, only one of Z ₅ and Z ₆ is a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (IV-1) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(IV-1)

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C 1 _-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

Y ₄ represents CH, CD or N;

Z ₂ represents N or CR _Z2 where R _Z2 represents H, D, halogen, C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R;

Z ₃ represents N or C;

Z ₅ is N, NR _Z5 or CR _Z5 , where R _Z5 is H, D, halogen, C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted one or more R;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl;

wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N.

In another embodiment, only one of Z ₅ and Z ₆ is a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (IV-2) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(IV-2)

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

Y ₄ represents CH, CD or N;

Z ₂ represents N or CH;

Z ₃ represents N or C;

Z ₅ represents N, NH or CH;

Z ₆ is NR _Z6 or CR _Z6 , where R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl or C _1-6 haloalkyl;

wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N.

In another embodiment, only one of Z ₅ and Z ₆ is a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (IV-3) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(IV-3)

Where

Y ₄ represents CH, CD or N;

Z ₂ represents N or CH;

Z ₃ represents N or C;

Z ₅ represents N, NH or CH;

Z ₆ represents N or C;

wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N.

In another embodiment, only one of Z ₅ and Z ₆ is a substituted or unsubstituted carbon atom.

In another more specific embodiment, the present invention provides a compound of formula (V) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(V)

Where

Ring A is pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl;

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

m is selected from 0, 1, 2 and 3;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

Y ₄ represents N or CR _Y ,

R _Y is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Y is H or halogen; or alternatively fluorine;

each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Z ₅ represents N or CR _Z5 where R _Z5 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (V-1) or (V-1'), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(V-1) or (V-1')

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

Y ₄ represents N or CR _Y ,

R _Y is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively R _Y is H or halogen; in an additional alternative, fluorine;

R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Z ₅ represents N or CR _Z5 where R _Z5 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (V-2) or (V-2'), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(V-2) or (V-2')

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

L ₁ represents NH, ND, CHD, CD ₂ or CH ₂ ;

Y ₄ represents N, CD or CH;

R _Y is H, D or halogen, alternatively fluorine;

R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Z ₅ represents N, CD or CH;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (V-3) or (V-3'), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(V-3) or (V-3')

Where

L ₁ represents NH or CH ₂ ;

Y ₄ represents N or CH;

R _Y is H or halogen, alternatively fluorine;

₅ represents N or CH.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention relates to a compound of formula (VI) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(VI)

Where

Ring A is pyrrolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, thienyl, thiazolyl or isothiazolyl;

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

m is selected from 0, 1, 2 and 3;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

R _Y is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Y is H or halogen; in an additional alternative, fluorine;

each of R _n1 and R _n2 is independently selected from H, D, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl and C _2-6 alkynyl;

R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Z ₅ represents N or CR _Z5 where R _Z5 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (VI-1) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(VI-1)

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

R ₂ represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

L ₁ is O, S, NH, ND, CHD, CD ₂ or CH ₂ ;

R _Y is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively R _Y is H or halogen; in an additional alternative, fluorine;

R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Z ₅ represents N or CR _Z5 where R _Z5 represents H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (VI-2) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(VI-2)

Where

R ₁ is -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 are independently H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, where C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl, wherein C _1-4 alkyl and C _1-4 haloalkyl are optionally substituted by one or more R; alternatively, R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; alternatively, at least one of R _a1 , R _a2 and R _a3 is haloalkyl;

L ₁ represents NH, ND, CHD, CD ₂ or CH ₂ ;

R _Y is H, D, halogen, C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively R _Y is H or halogen; in an additional alternative, fluorine;

R _Z6 is C _1-6 alkyl or C _1-6 haloalkyl, wherein C _1-6 alkyl and C _1-6 haloalkyl are optionally substituted by one or more R; alternatively, R _Z6 is C _1-4 alkyl or C _1-4 haloalkyl;

Z ₅ represents N, CD or CH;

each R is independently selected from H, D, -OH, -NH ₂ , halogen, -CN, C _1-6 alkyl and C _1-6 haloalkyl.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (VI-3) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

(VI-3)

Where

L ₁ represents NH or CH ₂ ;

R _Y is H or halogen, alternatively fluorine;

Z ₅ represents N or CH.

In another embodiment, Z ₅ is N.

In another more specific embodiment, the present invention provides a compound of formula (II-3) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof.

In another more specific embodiment, the present invention relates to the following compounds or their tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates:

The compounds disclosed herein may include one or more asymmetric centers and thus may exist in various stereoisomeric forms, for example, as enantiomers and/or diastereomers. For example, the compounds disclosed herein may be in the form of a single enantiomer, diastereomer, or geometric isomer (eg, cis and trans isomers) or may be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture enriched in one or more stereoisomers. Isomers can be isolated from a mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or alternative isomers can be prepared by asymmetric synthesis.

"Tautomer" refers to an isomer in which one functional group in a compound changes its structure to another functional group, and the compound and isomer can rapidly convert into each other, thus being in dynamic equilibrium; these two isomers are called tautomers.

Those skilled in the art will appreciate that organic compounds can form complexes with the solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates". If the solvent is water, the complex is known as a "hydrate". The present invention covers all solvates of the compounds disclosed in this application.

The term "solvate" refers to forms of a compound or its salt that are bound to a solvent, usually by solvolysis. This physical association may involve hydrogen bonds. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be obtained, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, solvates can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. “Solvate” includes both solution phase solvates and liberated solvates. Typical solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that is associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a certain ratio to the number of molecules of the compound in the hydrate. Therefore, hydrates of a compound can be represented, for example, by the general formula _R⋅xH2O , where R is a compound and x is a number greater than 0. These compounds can form more than one type of hydrate, including, for example, monohydrates ( x is 1), lower hydrates (x means a number greater than 0 and less than 1, e.g. hemihydrates (R⋅0.5H ₂ O)) and polyhydrates (x means a number greater than 1, e.g. dihydrates (R⋅2H ₂ O) and hexahydrates (R⋅6H ₂ O)).

The compounds disclosed herein may be in amorphous or crystalline form (crystalline or polymorph). In addition, the compounds disclosed herein may exist in one or more crystalline forms. Thus, the present description includes all amorphous or crystalline forms of the compounds disclosed in this application, within the scope thereof. The term "polymorph" refers to the crystalline form of a compound (or its salt, hydrate or solvate) in a particular crystalline package. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Different polymorphs of the compound can be prepared by crystallization under different conditions.

The present invention also includes compounds labeled with isotopes that are equivalent to the isotopes described in formula (I), but one or more atoms are replaced by atoms having an atomic mass or mass number that differs from the mass of atoms that are common in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. All compounds described herein that contain the above isotopes and/or other isotopes of other atoms, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or prodrugs are within the scope of the present invention. Certain isotope-labeled compounds disclosed herein, such as those containing radioactive isotopes (eg, ³ H and ¹⁴ C), can be used to measure drug and/or substrate distribution in tissue. Alternatives are tritium, which is ^3H , and carbon-14, an isotope of ^14C , because they are easy to prepare and detect. Additionally, replacement with heavier isotopes such as deuterium, which is ^2H , may provide therapeutic benefits due to higher metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be an alternative in in some cases. The isotope-labeled compounds of formula (I) of the present invention and their prodrugs can be prepared generally using readily available isotope-labeled reagents to replace the non-isotope-labeled reagents in the following schemes and/or procedures disclosed in the examples and preparation examples.

In addition, prodrugs are also included in the context of the present invention. As used herein, the term “prodrug” refers to a compound that is converted in vivo to an active form that produces a therapeutic effect, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs,” Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which is incorporated herein by reference.

Prodrugs are any covalently linked compounds disclosed herein that release the parent compound in vivo upon administration of the prodrug to a patient. Prodrugs are typically prepared by modifying functional groups so that the modifications can be cleaved either by conventional manipulation or degraded in vivo to form the parent compound. Prodrugs include, for example, compounds disclosed herein in which hydroxyl, amino or sulfhydryl groups are linked to any group that, when administered to a patient, is cleaved to form hydroxyl, amino or sulfhydryl groups. Thus, typical examples of prodrugs include, but are not limited to, acetate/acetamide, formate/formamide and benzoate/benzamide derivatives of the hydroxy, amino or sulfhydryl functional groups of the compounds of formula (I). Moreover, in the case of carboxylic acid (-COOH), esters such as methyl esters and ethyl esters, etc. can be used. The ester itself may be active in itself and/or hydrolyzed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that can be readily cleaved in the human body to release the parent acids or salts thereof.

Pharmaceutical composition, composition and kit

In another aspect, the disclosure relates to a pharmaceutical composition containing a compound disclosed herein (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains an effective amount of an active ingredient. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of an active ingredient. In some embodiments, the pharmaceutical composition contains a prophylactically effective amount of an active ingredient.

A pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or excipient that does not interfere with the pharmacological activity of the compound present with it. Pharmaceutically acceptable carriers, adjuvants or excipients that can be used in the compositions of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, whey proteins (eg, human serum albumin), buffers (such as phosphate), glycine, sorbic acid , potassium sorbate, mixture of partial glycerides of saturated vegetable fatty acids, water, salt or electrolyte (e.g. protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin, but are not limited to.

The present invention also includes kits (eg, pharmaceutical packages). Kits provided may include a compound disclosed herein, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials) containing the compound disclosed herein or other therapeutic agents. In some embodiments, the kits provided may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound and/or other therapeutic agent described herein. In some embodiments, a compound described herein provided in a first container and other therapeutic agents provided in a second container are combined to form a unit dosage form.

The pharmaceutical composition provided in the present invention can be administered by various routes, including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other means of administration. . For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.

Typically, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will generally be determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, body weight and response of the individual patient, the severity of the patient's symptoms, and the like.

When used to prevent a disorder disclosed herein, the compounds provided herein will be administered to a subject at risk of developing the condition, typically under the advice and supervision of a physician, at the dosages described above. Subjects at risk for developing a particular condition usually include those who have a family history of the condition or those who have been identified by genetic testing or screening as being particularly susceptible to developing the condition.

The pharmaceutical compositions provided herein can also be administered continuously (“chronic administration”). Chronic administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, for 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely. , for example, for the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant blood level of the compound, eg, within a therapeutic range, over an extended period of time.

The pharmaceutical compositions of the present invention can further be delivered using various dosage methods. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, for example, to rapidly increase the concentration of a compound in the blood to an effective level. The placement of the bolus dose depends on the required systemic levels of the active ingredient, for example, an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, while a bolus dose delivered directly into the veins (for example, through an intravenous drip) provides a much faster delivery that quickly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, such as an intravenous drip, to maintain a constant concentration of the active ingredient in the subject. Additionally, in yet other embodiments, the pharmaceutical composition may be administered initially as a bolus dose followed by a continuous infusion.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More often, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "single-dose dosage forms" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions or pills, tablets, capsules and the like. in the case of solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to 50% by weight, or alternatively, about 1 to 40% by weight), with the remainder being various carriers or fillers and processing aids useful in forming the desired dosage form.

For oral administration, one to five and especially two to four and usually three oral doses per day are typical regimens. Using these dosage regimens, each dose provides from about 0.01 to 20 mg/kg of the compound provided herein, with alternative doses each providing from about 0.1 to 10 mg/kg, and especially from about 1 to 5 mg/kg.

Transdermal doses are generally selected to provide the same or lower blood levels than injectable doses, typically in amounts of about 0.01 to 20% by weight, alternatively about 0.1 to 20% by weight , alternatively from about 0.1 to 10% by weight, and alternatively from about 0.5 to 15% by weight.

Dose levels for injections range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all over about 1 to 120 hours and especially 24 to 96 hours. A pre-bolus of approximately 0.1 mg/kg to 10 mg/kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed approximately 2 g/day for a patient weighing 40 to 80 kg.

Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier with buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: a binding agent such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose, a disintegrant such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as fumed silica; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injection excipients known in the art. As before, the active compound in such compositions is typically a minor component, often comprising about 0.05 to 10% by weight, with the remainder being an injection excipient or the like.

Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients are typically combined with either a paraffin or water-miscible ointment base. Alternatively, the active ingredients may be formulated into a cream, for example an oil-in-water cream. Such transdermal formulations are well known in the art and typically include additional ingredients to improve skin penetration or stability of the active ingredients or formulation. All such known transdermal compositions and ingredients are included within the scope of this application.

The compounds provided herein can also be administered via a transdermal device. Accordingly, transdermal administration can be accomplished using a reservoir or porous membrane type patch, or a solid matrix patch.

The above-described components for orally administered, injectable or topically administered compositions are merely exemplary. Other materials, as well as processing methods, etc. set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, incorporated herein by reference.

The compounds disclosed herein may also be administered in sustained release forms or from sustained release drug delivery systems. Descriptions of exemplary sustained release materials can be found in Remington's Pharmaceutical Sciences.

The present invention also relates to pharmaceutically acceptable formulations of the compound disclosed herein. In one embodiment, the composition contains water. In another embodiment, the composition contains a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, consisting of 6, 7 and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moieties, which include methylated, hydroxyalkyl , acylated and sulfoalkyl ether substitutions, but not limited to. In some embodiments, the cyclodextrin is a sulfoalkyl ester of β-cyclodextrin, such as, for example, sulfobutyl ester of β-cyclodextrin, also known as captisol. See, for example, US Patent 5,376,645. In some embodiments, the composition contains hexapropyl-β-cyclodextrin (eg, 10-50% in water).

Indications

This application provides a method of treating, preventing, or ameliorating diseases or disorders modulated or otherwise mediated by one or more RET, Trk, FLT3, c-Kit, PDGFR, and VEGFR kinases (including one or more wild-type and/or mutant RET kinases , Trk, FLT3, c-Kit, PDGFR and VEGFR), or one or more of their symptoms or causes.

The present invention provides a method of treating protein kinase-mediated diseases in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition disclosed herein.

As used herein, the term “wild type” refers to the most common genes or alleles found in organisms. In some specific embodiments, “wild type” refers to a gene or allele that does not have a mutation.

As used herein, the term “cancer” refers to the abnormal growth of cells that proliferate in an uncontrolled manner and, under some circumstances, metastasize. Types of cancer include solid tumors such as bladder tumor, bowel tumor, brain tumor, breast tumor, endometrial tumor, heart tumor, kidney tumor, lung tumor, lymphoid tissue tumor (lymphoma), ovarian tumor, pancreatic tumor or tumor another endocrine organ (thyroid gland), prostate tumor, skin tumor (melanoma) or hematological malignancy (for example, leukemia) and so on, but are not limited to them.

RET

In a specific embodiment, the compounds disclosed herein are RET kinase inhibitors and can be used for the treatment, prevention, or amelioration of diseases or disorders that are modulated or otherwise mediated by one or more of wild-type RET kinase and RET kinase domain mutants, or one or several of their symptoms or causes. Such diseases or disorders include, but are not limited to, proliferative conditions (eg, cancer, including hematological malignancies and solid tumors) and gastrointestinal diseases (IBS), which can be treated, prevented or controlled by modulating various kinase activities (including dimerization, ligand binding and phosphotransferase activity) or by modulating kinase expression.

As used herein, the term “RET kinase domain mutants” refers to one or more mutants of a RET kinase domain or, alternatively, refers to a RET (the protein itself becomes a “RET kinase domain mutant”) containing one or more mutations. Mutations in the RET kinase domain can be insertions, deletions, or point mutations. In a specific embodiment, the RET kinase domain mutations include at least one point mutation in the RET kinase domain. In another specific embodiment, the RET kinase domain mutations include at least one point mutation in the RET kinase domain. In another specific embodiment, the point mutation in the RET kinase domain is selected from S32L, D34S, L40P, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, A510V, E511K, C515S, C531R, G533 C,G533S , G550E, V591I, G593E, I602V, R600Q, K603Q, K603E, Y606C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, C6 18S, C618Y, C618R, C618Y, C618G , C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, D631N, D631Y, D631A, D6 31G, D631V, D631E, E632K, E632G , C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641S, A641T, V648I, S649L, A664D, H665Q, K666E, K6 66M, K666N, S686N, G691S, R694Q , M700L, V706M, V706A, E713K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, L790F, Y791F, V8 04L, V804M, V804E, E805K, Y806E , Y806F, Y806S, Y806G, Y806C, E818K, S819I, G823E, Y826M, R833C, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, A866W, R873W, A876V, L8 81V, A883F, A883S, A883T, E884K , R886W, S891A, R897Q, D898V, E901K, S904F, S904C, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T9 30M, F961L, R972G, R982C, M1009V , D1017N, V1041G and M1064T. In another specific embodiment, the point mutation in the RET kinase domain is selected from V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y, and C634W. In another specific embodiment, mutations in the RET kinase domain further involve a RET gene fusion. In another specific embodiment, the RET fusion gene is selected from BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, ELKS-RET, RET-ELKS, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PCM1, RET-PPKAR1A, RET-TRIM24, RET-RFG9, RFP-RET, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15- RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, PPKAR1A-RET, RFG8/RET, RET/RFG8, H4-RET, ACBD5-RET, PTCex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET and MPRIP-RET; in another specific embodiment, the RET fusion gene is selected from KIF5B-RET and CCDC6-RET; in another specific embodiment, the point mutation in the KIF5B-RET and CCDC6-RET kinase domains is selected from V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y, C634W, and G810R.

TRK

In a specific embodiment, the compounds disclosed herein are Trk kinase inhibitors and can be used for the treatment, prevention, or amelioration of diseases or disorders that are modulated or otherwise mediated by one or more of wild-type Trk kinase and Trk kinase domain mutants, or one or more of their symptoms or causes. Such diseases or disorders include, but are not limited to, proliferative conditions (eg, cancer, including hematologic malignancies and solid tumors), pain, inflammation, and certain infectious diseases, which can be treated, prevented, or controlled by modulating various kinase activities. (including dimerization, ligand binding and phosphotransferase activity) or by modulating kinase expression. In a specific embodiment, the cancer may be selected from non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer, colon cancer, acute myeloid leukemia, sarcoma, childhood glioma, intrahepatic cholangiocarcinoma, hairy cell astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast cancer, fibrosarcoma, nephroma and breast cancer.

In a specific embodiment, the Trk kinase is selected from TrkA, TrkB and TrkC.

Point mutations in the NTRK1 gene, NTRK2 gene, and NTRK3 gene have been found in cancer cells resistant to Trk inhibitors. Point mutations in the NTRK1/2/3 genes can produce TrkA/B/C proteins, including wild-type TrkA/B/C proteins whose amino acids have been replaced by other amino acids.

The compounds of the present invention can be used to treat diseases mediated by at least one point mutation in the NTRK genes resulting in expression of the Trk protein.

The compounds of the present invention can be used in the manufacture of medicaments for the treatment of diseases mediated by at least one point mutation in the NTRK genes resulting in expression of the Trk protein.

In another specific embodiment, the at least one point mutation in the NTRK genes that results in expression of the Trk protein (which includes mutations at one or more amino acid positions) may be selected from (i) at least one point mutation in the NTRK1 gene, which results in the expression of a mutant TrkA protein at one or more amino acid positions selected from the group consisting of 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656, 657, 667 and 676, and/ or (ii) at least one point mutation in the NTRK2 gene that results in the expression of a mutant TrkB protein at one or more amino acid positions selected from the group consisting of 545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693 and 702, and/or (iii) at least one point mutation in the NTRK3 gene that results in the expression of a mutant TrkC protein at one or more amino acid positions selected from the group consisting of 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and 705. In another specific embodiment, the TrkA protein includes one or more amino acid substitutions from G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C and Y676S. In another specific embodiment, the TrkB protein includes one or more amino acid substitutions from G545R, A570V, Q596E, Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S, and G713S. In another specific embodiment, the TrkC protein includes one or more amino acid substitutions from G545R, A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A.

FLT3

In a specific embodiment, the compounds disclosed herein are FLT3 kinase inhibitors and can be used for the treatment, prevention, or amelioration of diseases or disorders that are modulated or otherwise mediated by one or more of wild-type FLT3, FLT3-ITD, and kinase domain mutants FLT3, or one or more of its symptoms or causes. Such diseases or disorders include hematologic malignancies, including, but not limited to, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS); which can be treated, prevented or controlled by modulating various kinase activities (including dimerization, ligand binding and phosphotransferase activities) or by modulating the expression of kinases, where the method includes administering a therapeutically or prophylactically effective amount of a compound provided herein to a subject, such as a human, in need of such treatment, prevention or control.

As used herein, the term “FLT3 kinase domain mutants” refers to one or more mutants of the FLT3 kinase domain or, alternatively, refers to FLT3 (the protein itself becomes a “FLT3 kinase domain mutant”) containing one or more mutations. Mutations in the FLT3 kinase domain can be insertions, deletions, or point mutations. In a specific embodiment, the FLT3 kinase domain mutations include at least one point mutation in the FLT3 kinase domain. In another specific embodiment, the FLT3 kinase domain mutations include at least one point mutation in the FLT3 kinase domain. In another specific embodiment, the point mutation in the FLT3 kinase domain is at position E608, N676, F691, C828, D835, D839, N841, Y842, or M855. In another specific embodiment, the point mutation in the FLT3 kinase domain is selected from E608K, N676D, N676I, N676S, F691I, F691L, C828S, D835Y, D835V, D835H, D835F, D835E, D839G, D839H, N841C, Y842C, Y842 H, Y842N, Y842S and M855T. In another specific embodiment, the term “FLT3 kinase domain mutants” refers to point mutations at positions F691, D835, or Y842, or refers to FLT3 containing at least one point mutation at these positions. In another specific embodiment, the term "FLT3 kinase domain mutants" refers to one or more point mutations selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842H, Y842N, and Y842S, or refers to FLT3 containing at least at least one of the point mutations. In another specific embodiment, the FLT3 kinase domain mutants further comprise one or more additional FLT3-ITD mutants. In another specific embodiment, the FLT3 kinase domain mutants further comprise one or more additional FLT3-ITD mutants. However, when FLT3 kinase domain mutants contain more than one point mutation, additional point mutations or mutations may appear in the same FLT3 receptor, or additional point mutations or mutations may appear in separate alleles or in different pure leukemia lines; in this case the mutation is polyclonal.

The term "juxtamembrane region" or "juxtamembrane domain" of FLT3 refers to the region of FLT3 that connects the transmembrane helices to the tyrosine kinase domains.

In another specific embodiment, “wild-type FLT3” refers to the FTL3 gene or allele, including allelic variants and mutations other than FLT3 kinase domain mutations and FLT3-ITD mutations.

c-KIT

In a specific embodiment, the compounds disclosed herein are c-Kit kinase inhibitors and can be used to treat symptoms associated with abnormal c-KIT activity. Activating mutations in c-KIT exist in a variety of indications, including systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, and mediastinal B-cell lymphoma.

In another specific embodiment, the compounds disclosed herein can be used to treat one or more c-Kit mutations in exon 17 (e.g., D816V, D816Y, D816F, D816K, D816A, D816G, D820A, D820E, D820G, N822K, N822H, Y823D and A829P) and have activity against mutations, but have much lower activity against wild-type c-Kit.

In the method of treatment of the present invention, "effective amount" means an amount or dose sufficient to produce the desired therapeutic effect in persons in need thereof. The effective amount or dose of a compound of the present invention can be determined by conventional methods (eg, modeling, dose escalation, or clinical trials) and conventional factors (eg, mode or route of drug delivery, drug pharmacokinetics, severity and infection process, health status, and weight human body, as well as a doctor’s opinion). An exemplary dose ranges from about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. The total dose may be a single dose unit or individual dose units (eg, twice daily, three times daily, or four times daily).

Once the patient's condition improves, the dose may be adjusted for prophylactic or maintenance therapy. For example, the dose or frequency of administration, or both, can be reduced to an amount that maintains the desired therapeutic or prophylactic effect depending on the symptoms. Of course, if symptoms have decreased to an appropriate extent, treatment can be stopped. However, patients may require long-term intermittent treatment if symptoms recur. Patients may also require long-term, slow treatment.

Combination of drugs

The compound of the present invention can be used in combination with one or more other active ingredients in pharmaceutical compositions or methods for treating the diseases and conditions described herein. Other additional active ingredients include other therapeutic agents or drugs that mitigate the adverse effects of the therapeutic agent on the intended disease target. The combination may be used to increase effectiveness, improve symptoms of other diseases, reduce one or more negative effects, or reduce the required dose of a compound of the present invention. The additional active ingredient may be included in the pharmaceutical composition separately from the compound of the present invention, or may be included in a single pharmaceutical composition with the compound of the present invention. The additional active ingredient may be administered simultaneously, before or after administration of the compound of the present invention.

Combination agents include those additional active ingredients that are known or have been observed to be effective in treating the diseases and conditions described herein, including those that are effective against another target associated with the disease. For example, the compositions and compositions of the present invention, as well as methods of treatment, may further include other drugs or medicaments, such as other active agents, that can be used to treat or alleviate the target disease or related symptoms or conditions. For oncology indications, other such agents include kinase inhibitors, for example, EGFR inhibitors (such as erlotinib, gefitinib); Raf inhibitors (such as vemurafenib), VEGFR inhibitors (such as sunitinib); standard chemotherapeutic agents such as, but not limited to, alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormonal therapy or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory drugs such as NSAIDs. The pharmaceutical composition of the present invention may further include one or more active agents, and the method of treatment may further include administering an effective amount of one or more active agents.

EXAMPLES

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are used only to illustrate the present disclosure and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples generally follow normal conditions, or the conditions recommended by the manufacturer. Unless otherwise noted, parts and percentages are parts or percentages by weight.

Typically, during preparation, each reaction is carried out in an inert solvent at room temperature to reflux temperature (eg, 0°C to 100°C or alternatively 0°C to 80°C). The reaction time is typically 0.1-60 hours or alternatively 0.5-24 hours.

The abbreviations used in this application have the following meanings:

Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)

B2pin2: bis(pinacolato)dibor

NBS: N-bromosuccinimide

DMAP: 4-dimethylaminopyridine

HATU: 2-(7-oxidobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

TEA: triethylamine

DIEA: N,N-diisopropylethylamine

Na ₂ CO ₃ : sodium carbonate

K ₂ CO ₃ : potassium carbonate

MeOH: methanol

EtOH: ethanol

DCM: dichloromethane

THF: tetrahydrofuran

ACN: Acetonitrile

DME: 1,2-dimethoxyethane

DMF: N,N-dimethylformamide

EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

Intermediate A-1: Preparation of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A-1

The following route was used for synthesis:

3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.6 g; 17.6 mmol) and potassium carbonate (4.86 g; 35.2 mmol) were dissolved in 50 ml DMF, and 2-iodopropane (3.3 g; 19.4 mmol) was added dropwise slowly in an ice bath. The ice bath was removed after addition was complete, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with 150 ml of water and extracted with ethyl acetate (100 ml*3). The organic phase was washed with 50 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 3.2 g of a pale yellow solid in 60% yield. ERI-MS:304[M ⁺ +1].

Intermediate A-2: Preparation of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

A-2

The following route was used for synthesis:

5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.6 g; 17.6 mmol) and potassium carbonate (4.86 g; 35.2 mmol) were dissolved in 50 ml DMF, and 2-iodopropane (3.3 g; 19.4 mmol) was added dropwise slowly in an ice bath. The ice bath was removed after addition was complete, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with 150 ml of water and extracted with ethyl acetate (100 ml*3). The organic phase was washed with 50 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 2.8 g of a pale yellow solid in 52% yield. ERI-MS:303[M ⁺ +1].

Intermediate A-3: Preparation of 1-bromo-3-isopropylimidazo[1,5-a]pyrazin-8-amine

A-3

The following route was used for synthesis:

Step 1. Synthesis of (3-chloropyrazin-2-yl)methylamine compound

2-cyano-3-chloropyrazine (1.5 g; 10.8 mmol) and Raney-Ni (50% slurry in water, 0.5 g) were added to 15 ml of glacial acetic acid under nitrogen, and the atmosphere was changed 3 times hydrogen gas. The reaction mixture was stirred at 50°C in a hydrogen atmosphere at 3 atm. during the night. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.82 g of a light yellow oil in 53% yield. ERI-MS:144[M ⁺ +1].

Step 2. Synthesis of N-((3-chloropyrazin-2-yl)methyl)isobutyramide compound

(3-chloropyrazin-2-yl)methylamine (0.82 g; 5.7 mmol) and triethylamine (0.86 g; 8.5 mmol) were dissolved in 10 ml dichloromethane and isobutyryl chloride (0.72 g; 6.8 mmol). drop by drop in an ice bath. The ice bath was removed after addition was complete and the reaction mixture was stirred at room temperature overnight. The reaction was completed according to TLC. The reaction solution was washed with 1N hydrochloric acid, 5% NaHCO ₃ solution and saturated saline solution, respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.7 g of a light yellow oil in 58% yield. ERI-MS:214[M ⁺ +1].

Step 3. Synthesis of the compound 8-chloro-3-isopropylimidazo[1,5-a]pyrazine

N-((3-chloropyrazin-2-yl)methyl)isobutyramide (0.7 g, 3.3 mmol) was dissolved in 15 ml anhydrous acetonitrile and phosphorus oxychloride (2.1 g, 14 mmol) was added. The mixture was heated to 60°C and reacted overnight. After completion of the reaction, the solvent was evaporated. The residue was slowly added to ice water, and the mixture was extracted with ethyl acetate (10 ml*3). The organic phase was washed with saturated sodium bicarbonate and brine, respectively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.51 g of a light yellow solid in 80% yield. ERI-MS:196[M ⁺ +1].

Step 4. Synthesis of the compound 1-bromo-8-chloro-3-isopropylimidazo[1,5-a]pyrazine

8-chloro-3-isopropylimidazo[1,5-a]pyrazine (0.51 g, 2.6 mmol) was dissolved in 10 ml DMF and NBS (0.51 g, 2.9 mmol) was added portionwise in an ice bath . The mixture was allowed to naturally warm to room temperature and reacted overnight. After completion of the reaction, 20 ml of water was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.51 g of a light yellow solid in 72% yield. ERI-MS:276[M ⁺ +2].

Step 5. Synthesis of 1-bromo-3-isopropylimidazo[1,5-a]pyrazin-8-amine (intermediate A-3)

1-bromo-8-chloro-3-isopropylimidazo[1,5-a]pyrazine (0.51 g, 1.8 mmol) and 10 ml of concentrated ammonia were added to a 50 ml sealed tube. The mixture was heated to 120°C in an oil bath and reacted overnight. After completion of the reaction, the reaction solution was allowed to cool to room temperature. The solvent was removed by rotary evaporation to obtain 0.4 g of a white powdery solid with a yield of 87%. ERI-MS:257[M ⁺ +2].

Intermediate A-4: Preparation of 5-bromo-7-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine

A-4

The following route was used for synthesis:

Step 1. Synthesis of the compound 7-(prop-1-en-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine

4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (0.94 g; 4.4 mmol), isopropenylboronic acid pinacol ester (0.89 g; 5.3 mmol), Pd(dppf)Cl ₂ (165 mg; 0.22 mmol) and Na ₂ CO ₃ (1.4 g; 13.2 mmol) were added to 20 ml DME and 5 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 40 ml of water was added. The mixture was extracted with ethyl acetate (30 ml*3). The organic phase was washed with 20 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.54 g of a light yellow solid in 70% yield. ERI-MS: 175[M ⁺ +1].

Step 2. Synthesis of the compound 7-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine

7-(prop-1-en-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.54 g, 3.1 mmol) was dissolved in 20 ml ethanol and 100 mg of 10% palladium on carbon was added. The atmosphere was replaced with hydrogen gas 3 times, and the reaction mixture was stirred under a hydrogen atmosphere at 1 atm at room temperature overnight. After completion of the reaction, palladium on carbon was separated by filtration. The filtrate was concentrated and dried to obtain 0.49 g of a white solid with a yield of 90%. ERI-MS: 177[M ⁺ +1].

Step 3. Synthesis of 5-bromo-7-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (intermediate A-4)

7-isopropylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.49 g, 2.8 mmol) was dissolved in 10 ml DMF, and NBS (0.55 g, 3.1 mmol) is added in portions in an ice bath. The mixture was allowed to naturally warm to room temperature and reacted overnight. After completion of the reaction, 20 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.5 g of a light yellow solid in 70% yield. ERI-MS: 257[M ⁺ +2].

Intermediate A-5: Preparation of 5-iodo-7-isopropylimidazo[5,1-f][1,2,4]triazin-4-amine

A-5

The following route was used for synthesis:

Stage 1. Synthesis of the compound 2,5-dioxopyrrolidine-1-ylisobutyrate.

Isobutyric acid (2.67 g; 30.4 mmol), 1-hydroxypyrrolidine-2,5-dione (4.26 g; 37 mmol) and triethylamine (6.14 g; 60.8 mmol) were dissolved in dichloromethane (50 ml) and EDCI (8.68 g; 45.3 mmol) were added in an ice bath. The mixture was reacted at room temperature overnight. The reaction solution was diluted with DCM (150 ml) and washed with water (200 ml×3). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness to give 4.6 g of a pale yellow oil in 81.8% yield. ERI-MS: 186.1[M ⁺ +1].

Step 2. Synthesis of the compound N-((3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)isobutyramide

2,5-dioxopyrrolidin-1-yl isobutyrate (1.8 g; 10.0 mmol) and 3-amino-6-(aminomethyl)-1,2,4-triazin-5(4H)-one (2.0 g; 10.0 mmol). mmol) was dissolved in acetonitrile (30 ml) and triethylamine (3.0 g; 30 mmol) was added. The mixture was heated to 50°C and the reaction was carried out for 2 hours. A large amount of white solid precipitated. The reaction mixture was allowed to cool to room temperature, diluted with water (150 ml) and stirred for 10 minutes. The mixture was then filtered and washed with water (30 ml). The filter cake was dried in an oven to give 1.7 g of a whitish solid with a yield of 80.6%. ERI-MS: 212.1[M ⁺ +1].

Step 3. Synthesis of the compound 2-amino-7-isopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Phosphorus oxychloride (2.45 g, 16.2 mmol) was added slowly dropwise to acetonitrile (30 ml) under a nitrogen atmosphere. The mixture was heated to 80°C and the reaction was carried out for 4 hours while maintaining the temperature. The reaction mixture was cooled to room temperature and quenched by adding water (20 ml). Saturated aqueous sodium bicarbonate (30 ml) was added and the mixture was extracted with ethyl acetate (60 ml*3). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.6 g of an off-white solid in 38.6% yield. ERI-MS: 194.1[M ⁺ +1].

Step 4. Synthesis of the compound 2-amino-5-iodo-7-isopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

2-amino-7-isopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.6 g, 3.1 mmol) was dissolved in DMF (8 ml) and NIS. (0.70 g; 3.1 mmol) was added in portions over an ice bath. The mixture was allowed to naturally warm to room temperature and the reaction was carried out overnight. After completion of the reaction, 50 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml*3). The organic phase was washed with brine (150 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.62 g of a light yellow solid in 62.5% yield. ERI-MS: 320.0[M ⁺ +2].

Step 5. Synthesis of the compound 5-iodo-7-isopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

2-amino-5-iodo-7-isopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.62 g, 1.94 mmol) was dissolved in tetrahydrofuran (8 ml ) and DMF (2 ml), and tert-butyl nitrite (1.0 g; 9.7 mmol) were slowly added dropwise under nitrogen atmosphere. The reaction was carried out under a nitrogen atmosphere at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (30 ml*3). The organic phase was washed with brine (50 ml x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.46 g of a light yellow solid in 77.8% yield. ERI-MS: 305[M ⁺ +1].

Step 6. Synthesis of the compound 5-iodo-7-isopropylimidazo[5,1-f][1,2,4]triazin-4-amine.

Under a nitrogen atmosphere, phosphorus oxychloride (0.67 g; 4.5 mmol) was slowly added dropwise to a bath-cooled solution of 1,2,4-triazole (0.93 g; 13.5 mmol) in pyridine (6 mL). with ice water to obtain a white solid. The reaction mixture was stirred at room temperature for 20 minutes. 5-iodo-7-isopropylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (0.45 g, 1.5 mmol) was dissolved in pyridine (3 ml), and the resulting the solution was slowly added dropwise to the above mixture of phosphorus chloroxide solution. After addition was completed, the reaction was carried out under stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was added dropwise to ammonia water (40 ml) in ice-water (150 g), and the reaction was carried out for half an hour. The reaction mixture was extracted with ethyl acetate (60 ml x 3) and the organic phases were combined. The combined organic phase was washed with brine (30 ml), dried with anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 0.32 g of a light yellow solid in 70.2% yield. ERI-MS: 304.1[M ⁺ +2].

Intermediate B-1: Preparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(5-(1,1,1- trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide

IN 1

The following route was used for synthesis:

4-(Carboxymethyl)phenylboronic acid pinacol ester (3.85 g; 14.7 mmol), 5-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-3-amine (2.85 g ; 14.7 mmol) and triethylamine (3.0 g; 29.4 mmol) were dissolved in 50 ml dichloromethane and HATU (8.4 g; 22 mmol) was added in an ice bath. The mixture was reacted at room temperature overnight. The reaction solution was diluted with 50 ml of dichloromethane and washed with water. The organic phase was washed with 30 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 4.5 g of a light yellow solid in 70% yield. ERI-MS: 439[M ⁺ +1].

Intermediate B-2: Preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(5-(1,1,1- trifluoro-2-methylprop-2-yl)isoxazol-3-yl)urea

AT 2

The following route was used for synthesis:

4-Aminophenylboronic acid pinacol ester (0.79 g, 3.6 mmol) was dissolved in 15 ml of tetrahydrofuran and bis(trichloromethyl)carbonate (0.38 g, 1.3 mmol) was added slowly. The mixture was heated to reflux and reacted for 1 hour. The solvent was removed using a rotary evaporator. The residue was dissolved in 20 ml of tetrahydrofuran and DMAP (49 mg; 0.4 mmol), triethylamine (0.73 g; 7.2 mmol) and then 5-(1,1,1-trifluoro-2-methylprop- 2-yl)isoxazol-3-amine (0.7 g; 3.6 mmol). The mixture was reacted under reflux overnight. The reaction solution was cooled to room temperature and 40 ml of water was added. The mixture was extracted with ethyl acetate (30 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 1.2 g of a light yellow solid in 76% yield. ERI-MS: 440[M ⁺ +1].

Intermediate B-3: Preparation of 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-N-(5-(1, 1,1-Trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide

AT 3

The following route was used for synthesis:

Step 1: Synthesis of the compound 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)acetic acid

2-(6-bromopyridin-3-yl)acetic acid (4.23 g; 19.6 mmol), bis(pinacolato)diboron (5.97 g; 23.5 mmol), Pd(dppf)Cl2 (0. 44 g; 0.6 mmol) and potassium acetate (5.88 g; 60 mmol) were added to 80 ml of dioxane and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out for 3 hours. The reaction solution was cooled to room temperature and 150 ml of water was added. The mixture was extracted with ethyl acetate (100 ml*3). The organic phase was washed with 50 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 3.87 g of a light yellow solid in 75% yield. ERI-MS: 264[M ⁺ +1].

Step 2: Synthesis of the compound 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-N-(5-(1,1, 1-Trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (intermediate B-3)

2-(-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)acetic acid (3.87 g; 14.7 mmol), 5-( 1,1,1-Trifluoro-2-methylprop-2-yl)isoxazol-3-amine (2.85 g; 14.7 mmol) and triethylamine (3.0 g; 29.4 mmol) were dissolved in 20 ml of dichloromethane , and HATU (8.4 g; 22 mmol) was added in an ice bath. The mixture was reacted at room temperature overnight. The reaction solution was diluted with 20 ml of dichloromethane and washed with water. The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 3.55 g of a light yellow solid in 55% yield. ERI-MS: 440[M ⁺ +1].

Intermediate B-4: Preparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1,1,1- trifluoro-2-methylprop-2-yl)isoxazol-5-yl)acetamide

AT 4

The following route was used for synthesis:

4-(Carboxymethyl)phenylboronic acid pinacol ester (3.85 g; 14.7 mmol), 3-(1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-5-amine (2.85 g ; 14.7 mmol)) and triethylamine (3.0 g; 29.4 mmol) were dissolved in 50 ml dichloromethane and HATU (8.4 g; 22 mmol) was added in an ice bath. The mixture was reacted at room temperature overnight. The reaction solution was diluted with 50 ml of dichloromethane and washed with water. The organic phase was washed with 30 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 4.5 g of a light yellow solid in 70% yield. ERI-MS: 439[M ⁺ +1].

Intermediate B-5: Preparation of 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-N-(3-(1, 1,1-Trifluoro-2-methylprop-2-yl)isoxazol-5-yl)acetamide

AT 5

The following route was used for synthesis:

2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)acetic acid (3.87 g; 14.7 mmol), 3- (1,1,1-trifluoro-2-methylprop-2-yl)isoxazol-5-amine (2.85 g; 14.7 mmol) and triethylamine (3.0 g; 29.4 mmol) were dissolved in 20 ml dichloromethane, and HATU (8.4 g; 22 mmol) was added in an ice bath. The mixture was reacted at room temperature overnight. The reaction solution was diluted with 20 ml of dichloromethane and washed with water. The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 3.55 g of a light yellow solid in 55% yield. ERI-MS: 440[M ⁺ +1].

Example 1. Preparation of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(5-(1,1,1-trifluoro) -2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-1).

T-1

The following route was used for synthesis:

Intermediate A-1 (96 mg; 0.32 mmol), Intermediate B-1 (166 mg; 0.38 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (102 mg; 0.96 mmol) was added to 12 ml DME and 4 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 100 mg of a light yellow solid in 65% yield. ERI-MS: 488[M ⁺ +1]. ^1H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1H); 8.24 (s, 1H); 7.63 (d, J = 8.1 Hz, 2H); 7.49 (d, J = 7.9 Hz, 2H); 6.97 (s, 1H); 5.15-4.96 (m, 1H); 3.78 (s, 2H); 1.53 (s, 6H); 1.48 (d, J = 6.7 Hz, 6H).

Example 2. Preparation of 1-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(5-(1,1,1-trifluoro) -2-methylprop-2-yl)isoxazol-3-yl)urea (Compound T-2).

T-2

The following route was used for synthesis:

Intermediate A-1 (106 mg; 0.35 mmol), Intermediate B-2 (184 mg; 0.42 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (110 mg; 1.05 mmol) was added to 12 ml DME and 4 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 110 mg of a light yellow solid in 64% yield. ERI-MS: 489[M ⁺ +1]. ^1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H); 9.06 (s, 1H); 8.23 (s, 1H); 7.71 - 7.56 (m, 4H); 6.93 (s, 1H); 5.11 - 5.00 (m, 1H); 1.56 (s, 6H); 1.48 (d, J = 6.7 Hz, 6H).

Example 3. Preparation of 2-(4-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-N-(5-(1,1,1-trifluoro) -2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-3).

T-3

The following route was used for synthesis:

Intermediate A-2 (94 mg; 0.31 mmol), Intermediate B-1 (162 mg; 0.37 mmol), Pd(dppf)Cl2 (15 mg; 0.02 mmol) and Na ₂ CO ₃ ( 131 mg; 1.24 mmol) was added to 12 ml DME and 4 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 90 mg of a light yellow solid in 60% yield. ERI-MS: 487[M ⁺ +1]. ^1H NMR (500 MHz, DMSO-d6) δ 11.39 (s, 1H); 8.14 (s, 1H); 7.46 - 7.39 (m, 5H); 6.97 (s, 1H); 6.04 (s, 2H), 4.97 (s p, J = 6.8 Hz, 1H); 3.74 (s, 2H); 1.54 (s, 6H); 1.46 (d, J = 6.8 Hz, 6H).

Example 4. Preparation of 2-(4-(8-amino-3-isopropylimidazo[1,5-a]pyrazin-1-yl)phenyl)-N-(5-(1,1,1-trifluoro-2-methylprop) -2-yl)isoxazol-3-yl)acetamide (Compound T-4).

T-4

The following route was used for synthesis:

Intermediate A-3 (80 mg; 0.31 mmol), Intermediate B-1 (162 mg; 0.37 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (131 mg; 1.24 mmol) was added to 12 ml DME and 4 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 93 mg of a light yellow solid in 62% yield. ERI-MS: 487[M ⁺ +1]. ^1H NMR (500 MHz, DMSO-d6) δ 11.41 (s, 1H); 7.64 - 7.53 (m, 3H); 7.44 (d, J = 7.8 Hz, 2H); 7.02 (d, J = 5.0 Hz, 1H); 6.97 (s, 1H); 5.98 (s, 2H); 3.76 (s, 2H); 3.48-3.38 (m, 1H); 1.53 (s, 6H); 1.32 (d, J = 6.8 Hz, 6H).

Example 5. Preparation of 2-(4-(4-amino-7-isopropylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl)-N-(5-(1,1, 1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-5).

T-5

The following route was used for synthesis:

Intermediate A-4 (76 mg; 0.3 mmol), Intermediate B-1 (158 mg; 0.36 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (127 mg; 1.2 mmol) was added to 10 ml DME and 2 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 89 mg of a light yellow solid in 61% yield. ERI-MS: 487[M ⁺ +1]. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.01 (s, 1H); 7.94 (s, 1H); 7.48 (d, J = 8.0 Hz, 2H); 7.40 (d, J = 7.8 Hz, 2H); 7.04 (s, 1H); 6.49 (d, J = 3.5 Hz, 1H); 5.47 (s, 1H); 3.82 (s, 2H); 3.58 - 3.46 (m, 1H); 1.57 (s, 6H); 1.38 (d, J = 6.9 Hz, 6H).

Example 6. Preparation of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(5-(1,1, 1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-6).

T-6

The following route was used for synthesis:

Step 1. Synthesis of the compound ethyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

Ethyl 2-(4-bromo-2-fluorophenyl)acetate (2.7 g; 10.3 mmol), bis(pinacolato)diboron (3.15 g; 12.4 mmol), Pd(dppf)Cl ₂ ( 0.23 g; 0.3 mmol) and potassium acetate (3.04 g; 31 mmol) were added to 50 ml of dioxane and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out for 3 hours. The reaction solution was cooled to room temperature and 100 ml of water was added. The mixture was extracted with ethyl acetate (50 ml*3). The organic phase was washed with 40 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 2.21 g of a light yellow solid in 70% yield. ERI-MS: 309[M ⁺ +1].

Step 2. Synthesis of the compound ethyl 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetate

Intermediate A-1 (2.21 g; 7.3 mmol), ethyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl)acetate (2.71 g; 8.8 mmol), Pd(dppf)Cl ₂ (0.27 g; 0.36 mmol) and Na ₂ CO ₃ (2.32 g; 21.9 mmol) were added to 30 ml DME and 6 ml water, and replaced the atmosphere 3 times with nitrogen. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 50 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 1.43 g of a light yellow solid in 55% yield. ERI-MS: 358[M ⁺ +1].

Step 3. Synthesis of the compound 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetic acid

Ethyl 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetate (1.43 g, 4.0 mmol) was dissolved in 20 ml ethanol and 10 ml water and sodium hydroxide (0.4 g; 10 mmol) was added. The mixture was reacted at room temperature overnight. The reaction solution was diluted with 30 ml of water and adjusted to pH 3 to 4 with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate (30 ml*3). The organic phase was washed with 20 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 1.2 g of a light yellow solid in 90% yield. ERI-MS: 330[M ⁺ +1].

Step 4. Synthesis of the compound 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)-N-(5-(1,1 ,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-6)

2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl)acetic acid (112 mg; 0.34 mmol), (1, 1,1-Trifluoro-2-methylprop-2-yl)isoxazol-3-amine (66 mg; 0.34 mmol) and triethylamine (70 mg; 0.68 mmol) were dissolved in 10 ml dichloromethane and HATU (194 mg; 0.51 mmol) in an ice bath. The mixture was reacted at room temperature overnight. The reaction solution was diluted with 20 ml of dichloromethane and washed with water. The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 120 mg of a light yellow solid in 70% yield. ERI-MS: 506 [M ⁺ +1]. ^1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H); 8.25 (s, 1H); 7.63 - 7.35 (m, 3H); 6.96 (s, 1H); 5.17 - 4.92 (m, 1H); 3.86 (s, 2H); 1.54 (s, 6H); 1.48 (d, J = 6.7 Hz, 6H).

Example 7. Preparation of 2-(6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-yl)-N-(5-(1,1 ,1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-7).

T-7

The following route was used for synthesis:

Intermediate A-1 (121 mg; 0.4 mmol), Intermediate B-3 (210 mg; 0.48 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (127 mg; 1.2 mmol) was added to 10 ml DME and 2 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 110 mg of a light yellow solid in 56% yield. ERI-MS: 489[M ⁺ +1]. ^1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H); 8.26 (s, 1H); 7.95 (s, 1H); 7.52 (d, J = 7.9 Hz, 2H); 6.93 (s, 1H); 5.12-4.94 (m, 1H); 3.76 (s, 2H); 1.54 (s, 6H); 1.48 (d, J = 6.7 Hz, 6H).

Example 8. Preparation of 2-(4-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-N-(3-(1,1,1-trifluoro) -2-methylprop-2-yl)isoxazol-5-yl)acetamide (Compound T-8).

T-8

The following route was used for synthesis:

Intermediate A-1 (96 mg; 0.32 mmol), Intermediate B-4 (166 mg; 0.38 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (102 mg; 0.96 mmol) was added to 12 ml DME and 4 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 100 mg of a light yellow solid in 65% yield. ERI-MS: 488[M ⁺ +1]. ^1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H); 8.27 (s, 1H); 7.68 (d, J = 8.1 Hz, 2H); 7.42 (d, J = 7.9 Hz, 2H); 5.97 (s, 1H); 5.17-4.94 (m, 1H); 3.78 (s, 2H); 1.54 (s, 6H); 1.48 (d, J = 6.7 Hz, 6H).

Example 9. Preparation of 2-(6-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)pyridin-3-yl)-N-(3-(1,1 ,1-trifluoro-2-methylprop-2-yl)isoxazol-5-yl)acetamide (Compound T-9).

T-9

The following route was used for synthesis:

Intermediate A-1 (121 mg; 0.4 mmol), Intermediate B-5 (210 mg; 0.48 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (127 mg; 1.2 mmol) was added to 10 ml DME and 2 ml water, and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 110 mg of a light yellow solid in 56% yield. ERI-MS: 489[M ⁺ +1]. ^1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H); 8.29 (s, 1H); 7.93 (s, 1H); 7.55 (d, J = 7.9 Hz, 2H); 5.98 (s, 1H); 5.14-4.92 (m, 1H); 3.75 (s, 2H); 1.54 (s, 6H); 1.46 (d, J = 6.7 Hz, 6H).

Example 10. Preparation of 2-(4-(4-amino-7-isopropylimidazo[5,1-f][1,2,4]triazin-5-yl)phenyl)-N-(5-(1,1, 1-trifluoro-2-methylprop-2-yl)isoxazol-3-yl)acetamide (Compound T-10).

T-10

The following route was used for synthesis:

Intermediate A-5 (96 mg; 0.32 mmol), Intermediate B-1 (166 mg; 0.38 mmol), Pd(dppf)Cl ₂ (15 mg; 0.02 mmol) and Na ₂ CO ₃ (102 mg; 0.96 mmol) was added to DME (12 ml) and water (4 ml), and the atmosphere was replaced with nitrogen gas 3 times. The mixture was heated to 90°C and the reaction was carried out overnight. The reaction solution was cooled to room temperature and 30 ml of water was added. The mixture was extracted with ethyl acetate (20 ml*3). The organic phase was washed with 10 ml brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by a silica gel column to give 80 mg of a light yellow solid in 51.2% yield. ERI-MS: 488.1[M ⁺ +1]. ¹ H NMR (400 MHz, DMSO-D6) δ (ppm); 11.38 (s, 1H); 7.90 (s, 1H); 7.58 (d, J=8.4 Hz, 2H); 7.44 (d, J=8.4 Hz, 2H); 6.95 (s, 1H); 3.75 (s, 2H); 3.51 (t, J=6.8 Hz, 1H); 1.53 (s, 6H); 1.33 (d, J=6.8 Hz, 6H).

Biological Activity Analysis

Biological Example 1: Kinase Inhibition

Reagents and materials:

Ret wt (Carna, cat. no. 08-159-10ug), RET (V804M), Active (Signalchem, cat. no. R02-12GG), HTRF KinEASE-TK kit (Cisbio, cat. no. 62TK0PEC), CEP-32496 ( MCE, Cat. No. HY-15200), ATP (Sigma, Cat. No. A7699), DMSO (Sigma, Cat. No. D8418-1L), DTT (Sigma, Cat. No. D0632), MgCl ₂ (Sigma, Cat. No. M1028), 384-well plate (Labcyte, Cat. No. P-05525-BC).

Specific analysis procedure:

Compound composition: Test compounds were dissolved in dimethyl sulfoxide to obtain 10 mM stock solutions, which were then serially diluted 3-fold in DMSO to obtain 10 concentrations. During addition, the compound was further diluted 10-fold with buffer.

Detection of Ret wt and RET V804M kinase:

In 5× kinase buffer A, Ret wt or RET V804M kinase was mixed with various concentrations of pre-diluted compounds for 10 minutes. Each concentration was tested twice. The appropriate substrate and ATP were added and the reaction was carried out at room temperature for 20 minutes (negative and positive controls were provided: the negative control was a blank and the positive control was CEP-32496 (Agerafenib)). After completion of the reaction, detection reagents (reagents from the HTRF KinEASE-TK kit) were added. After incubation for 30 minutes at room temperature, the enzymatic activity in the presence of various concentrations of the compounds of the present invention was determined using an Envision microplate reader, and the inhibitory activity of various concentrations of compounds on enzymatic activity was calculated. The inhibitory activity of different concentrations of compounds on enzyme activity was determined using Graphpad 5.0 software and the IC ₅₀ value was calculated.

The compounds disclosed herein were tested in the above kinase inhibition assay and were found to have potent activity against Ret wt and RET V804M. The results of typical connection examples are summarized in Table 1 below.

Table 1 Approximate connection Ret wt IC ₅₀ (nM) RET V804M IC ₅₀ (nM) T-1 A A T-2 A C T-3 A C T-4 A C T-6 A B T-7 C C

where A is IC ₅₀ ≤ 0.5 nM, B is 0.5 nM < IC ₅₀ ≤ 1 nM, C is 1 nM < IC ₅₀ ≤ 10 nM, D is 10 nM < IC ₅₀ ≤ 50 nM, and E represents IC ₅₀ > 50 nM

Biological Example 2: Cytotoxicity Assay

The inhibitory effect of the compounds of the example was determined in relation to the activity of the initial generation of cells Ba/F ₃ , Ba/F ₃ KIF5B-RET, Ba/F ₃ KIF5B-RET ^V804M , Ba/F ₃ KIF5B-RET ^V804L , Ba/F ₃ KIF5B-RET ^G810R , Ba/F ₃ FLT3-ITD, Ba/F ₃ FLT3-ITD ^D835Y , Ba/F ₃ FLT3-ITD ^F691L .

Materials and Reagents: FBS Fetal Bovine Serum (GIBCO, cat. no. 10099141), CellTiter-Glo® Fluorescent Cell Viability Assay Kit (Promega, cat. no. G7572), clear, flat-bottomed, black-walled 96-well plate (Corning®, cat. no. No. 3603).

Analysis procedure

Cell cultivation and seeding:

1. Cells in logarithmic growth phase were collected and counted using a platelet counter. Cell viability was determined by trypan blue exclusion, ensuring cell viability of 90% or more.

2. The cell concentration was adjusted to approximately 3000 cells/well. 90 μl of cell suspension was added to each well of a 96-well plate.

3. Cells in a 96-well plate were incubated overnight at 37°C, 5% CO ₂ and 95% humidity.

Dilution and addition of compounds.

1. A series of compound solutions were prepared by 3.16-fold serial dilution starting at a concentration of 10 µM, resulting in 9 concentrations. 10 μl of compound solutions were added to each well of a 96-well plate seeded with cells in triplicate for each compound concentration.

2. Cells in a 96-well plate with added compounds were further incubated at 37°C, 5% CO ₂ and 95% humidity for 72 hours, after which CTG analysis was performed.

Determining tablet readings at the end

1. The CTG reagent was thawed and the cell plate was equilibrated at room temperature for 30 minutes.

2. An equal volume (10 μL) of CTG solution was added to each well.

3. The plate with cells was shaken on an orbital shaker for 5 minutes to lyse the cells.

4. The plate was placed for 20 minutes at room temperature to stabilize the luminescence signal.

5. The luminescence value was determined.

Data processing

Data were analyzed using GraphPad Prism 5.0 software and fitted using non-linear S-curve regression to obtain a dose-response curve from which IC ₅₀ values were calculated.

Cell survival rate (%) = (luminescence value of the test drug - luminescence value of the culture medium control) / (luminescence value of the cell control - luminescence value of the culture medium control) × 100%.

The compounds disclosed herein were tested in the above cytotoxicity assay. It was found that the compounds described in this application have high activity and selectivity against the cell lines Ba/F ₃ KIF5B-RET, Ba/F ₃ KIF5B-RET ^V804M , Ba/F ₃ KIF5B-RET ^V804L , Ba/F ₃ KIF5B- RET ^G810R , Ba/F ₃ FLT3-ITD, and Ba/F ₃ FLT3-ITD ^D835Y . The results of typical connection examples are summarized in Tables 2 and 3 below, where the AD80 structure is as follows:

.

table 2

Table 3

Biological Example 3: Pharmacokinetic Analysis in Rats

Six male Sprague-Dawley rats (7-8 weeks old and approximately 210 g body weight) were divided into 2 groups, 3 rats in each group. A single dose of compounds (1 mg/kg IV, 10 mg/kg PO) was administered intravenously or orally to compare their pharmacokinetics.

The rats were fed standard food and water. Fasting began 16 hours before analysis. The drug was dissolved in 5% DMSO, 10% Solutol (polyethylene glycol-15 hydroxystearate) and 85% saline. Blood was taken from the eye socket. Blood collection points were 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration.

Rats were briefly anesthetized by diethyl ether inhalation, and 300 μl of blood sample was collected from the orbit into a tube containing 30 μl of 1% sodium heparin solution. Before use, the tube was dried in an oven overnight at 60°C. After the blood sample was collected at the last time point, the rats were anesthetized with diethyl ether and then sacrificed.

Immediately after collecting the blood sample, the tube was carefully inverted at least 5 times to ensure adequate mixing and then placed on ice. The blood sample was centrifuged at 6000 rpm at 4°C for 8 minutes to separate plasma from red blood cells. 100 µl of blood (about 50 µl of plasma can be obtained) was aspirated by pipette into a microtube with K ₂ EDTA and the name of the compound and the time point were noted. Plasma was stored at -20°C before analysis. The concentration of the compound of the present invention in plasma was determined using LC-MS/MS. Pharmacokinetic parameters were calculated based on the drug concentration in the blood of each animal at different time points.

The analysis shows that the compounds of the present invention have better pharmacokinetic properties in animals and thus have better pharmacodynamic and therapeutic effects.

Biological Example 4: Efficacy in Ba/F ₃ KIF5B-RET and Ba/F ₃ KIF5B-RET ^G810R Allograft Models in Female NPSG Mice

The efficacy of the compounds of the present invention was confirmed in allograft models of female NPSG mice of two B-cell lymphoma cell lines, Ba/F ₃ KIF5B-RET and Ba/F ₃ KIF5B-RET ^G810R .

Study animals: 6-8 week old female NPSG mice (mice's age at the time of tumor cell inoculation), weighing 18-20 g, 60 mice purchased from Shanghai Jihui Laboratory Animal Care Co., Ltd.

Environmental conditions in the breeding room of the test animals: All test animals were housed in individual animal cages (IVC). In the breeding room, the temperature was maintained at 20-26°C, humidity 30-70% and light regime 12h/12h day and night. Dry pelleted food, which had been sterilized by radiation, was supplied continuously and provided without restrictions. Drinking tap water (sterilized by acidification) was continuously supplied from a drinking bottle ad libitum. The bedding consisted of corn cobs and was changed once a week. There were 4-5 animals in each cage. On the cell card, the quantity, gender, strain, time of receipt, method of processing, item number, group number, animal number, time of start of use in animals were noted. Study animals were marked with ear tags.

Handling and feeding of animals in this analysis were in accordance with AAALAC guidelines, version 2011 (International Guidelines for the Care and Use of Laboratory Animals, National Research Council, 2011).

Assay methods: (1) Ba/F3 KIF5B-RET and Ba/F3 KIF5B-RET ^G810R cells, respectively, were recovered and cultured in vitro, and 3×10 ⁷ cells of each type were obtained. (2) 60 female NPSG mice, 6–8 weeks old, were adaptively bred for 1 week and then weighed. (3) The inoculation conditions are shown in Table 4. (4) After inoculation, tumor volume and body weight were measured once a week. When the average tumor volume reached approximately 75-110 mm ³ , mice inoculated with each type of Ba/F ₃ cells were randomly assigned to 7 groups based on tumor volume and body weight, 3 mice in each group. Administration began immediately after grouping. The start date of administration was considered day 0. Information about administration and grouping is presented in Tables 5 and 6. (5) After the start of administration, mice were measured twice a week for body weight and tumor volume. (6) After completion of the administration, the analysis was completed.

Table 4. Inoculation information

Table 5. Information on grouping and administration of Ba/F3 KIF5B-RET cells

Table 6. Grouping and injection information for Ba/F3 KIF5B-RET ^G810R cells.

Analysis monitoring and data collection: After tumor inoculation, animal morbidity and mortality were monitored every working day. Daily monitoring included tumor growth and drug effects on laboratory animals, such as changes in activity, changes in feeding and drinking, weight loss, changes in coat and eye appearance, death, and other clinical symptoms. The formula for calculating tumor volume is: tumor volume (mm ³ ) = 1/2 × (a × b ² ) (where “a” represents the longitudinal dimension and “b” represents the transverse dimension).

Relative tumor inhibition rate TGI (%): TGI% = (1-T/C) × 100%. T/C% represents the relative tumor proliferation rate, that is, the percentage of the relative tumor volume between the experimental group and the control group at a certain point in time. T and C represent the relative tumor volume (RTV, that is, the difference between the tumor volume at this time point and the tumor volume at day 0) of the experimental group and the control group at a certain time point, respectively.

Statistical analysis: T-analysis was used for pairwise comparisons, and one-way analysis of variance was used to compare three or more groups. Two-way analysis of variance was used to compare potential synergistic effects. SPSS 24.0 was used for all data. A p value of less than 0.05 was considered a significant difference.

Analysis results

1. Result and discussion of the analysis of the antitumor effect on the tumor model of the Ba/F3 KIF5B-RET cell line.

Mice in the vehicle control group had an average tumor volume of 1447 mm ³ on day 14 of administration. Mice in the positive control AD80 (10 mg/kg) group had a mean tumor volume of 821.7 mm ³ on day 14 of administration, and the relative TGI tumor inhibition rate (%) was 46.4%. Compared with the AD80 positive control group, the efficacy in the test drug group was significantly higher. Mice in the test drug groups T-1, T-2, T-3, T-6 and T-8 had average tumor volumes of 233 mm ³ , 588.7 mm ³ , 153.7 mm ³ , 108.7 mm ³ and 163.7 mm ³ , respectively, on the 14th day of administration, and the relative tumor inhibition rate TGI (%) was 90.3%, 63.9%, 96.3%, 99.7% and 95.4%, respectively. It can be seen that the efficacy in the test drug groups was significantly higher compared to the AD80 positive control group.

Tumor growth in each experimental group and control group is shown in Table 7 and Figure 1.

Table 7. Table of analysis of the effectiveness of drugs in each group on the model of the Ba/F3 KIF5B-RET tumor cell line.

Experimental group Day 0 of use Day 14 of use Tumor volume
( ±S) Tumor volume
( ±S) TGI (%) Group 1 control solvent 100±8.39 1447±242 -- Group 2 positive control AD80 (10 mg/kg) 100.3±4.33 821.7±54.5 46.4% Group 3 test drug T-1 (10 mg/kg) 102.7±6.06 233±65.74 90.3% Group 4 test drug T-2 (10 mg/kg) 102±5.51 588.7±25.3 63.9% Group 5 test drug T-3 (10 mg/kg) 104±10.44 153.7±13.22 96.3% Group 6 test drug T-6 (10 mg/kg) 104±3.61 108.7±31.33 99.7% Group 7 test drug T-8 (10 mg/kg) 101.3±4.33 163.7±19.74 95.4%

2. Result and discussion of safety analysis using the Ba/F3 KIF5B-RET tumor cell line model.

No significant weight loss, drug withdrawal, or significant drug toxicity was observed in any of the experimental groups, including test drug groups T-1, T-2, T-3, T-6 and T-8 and the positive control group AD80. The experimental groups tolerated the treatment well.

The changes in body weight of mice in the experimental group and control group after administration are shown in Table 8, Figure 2 and Figure 3.

Table 8. Changes in body weight of mice in each group using the Ba/F3 KIF5B-RET tumor cell line model

Analysis group Number of animals at the beginning/end of the test Average body weight, g ( ±S) Mass change rate (%) Day 0 of use Day 14 of use Day 14 of use Group 1 control solvent 3/2* 20.1±1.12 23.6±0.25 11.1% Group 2 positive control AD80 (10 mg\kg) 3/3 20.1±0.81 22.6±0.87 12.7% Group 3 test drug T-1 (10 mg/kg) 3/3 20.9±1.06 21.6±1.05 3.4% Group 4 test drug T-2 (10 mg/kg) 3/3 20.1±0.56 21.7±0.59 8.1% Group 5 test drug T-3 (10 mg/kg) 3/3 19.6±0.84 21.5±0.7 9.8% Group 6 test drug T-6 (10 mg/kg) 3/3 19.3±0.57 21±0.91 8.8% Group 7 test drug T-1 (8 mg/kg) 3/3 20.5±1.07 21.7±0.82 6.0%

* One of the mice died.

3. Result and discussion of the analysis of the antitumor effect on the model of the Ba/F3 KIF5B-RET ^G810R tumor cell line.

Mice in the vehicle control group had an average tumor volume of 457 mm ³ on day 13 of treatment. Mice in the AD80 positive control group (25 mg/kg) had a mean tumor volume of 185.7 mm ³ on day 13 of administration, and the relative TGI tumor inhibition rate (%) was 75.2%. Mice in the test drug groups T-1, T-2, T-3, T-6 and T-8 had average tumor volumes of 63.7 mm ³ , 150.7 mm ³ , 132.7 mm ³ , 89.7 mm ³ and 90.7 mm ³ , respectively, on day 13 of application, and the relative TGI tumor inhibition levels (%) were 109.4%, 84.6%, 91.6%, 100.9% and 101.6%, respectively. It can be seen that the efficacy in the test drug groups was significantly higher compared to the AD80 positive control group.

Tumor growth in mice in each experimental group and control group is shown in Table 9 and Figure 4.

Table 9. Table of analysis of the effectiveness of drugs in each group on the model of the Ba/F3 KIF5B-RET ^G810R tumor cell line.

Analysis group Day 0 of use Day 13 of use Tumor volume
( ±S) Tumor volume
( ±S) TGI (%) Group 1 control solvent 90.3±6.89 457±91.13 -- Group 2 positive control AD80 (25 mg/kg) 94.7±5.24 185.7±33.65 75.2% Group 3 test drug T-1 (25 mg/kg) 98±3.61 63.7±16.19 109.4%# Group 4 test drug T-2 (25 mg/kg) 94.3±3.84 150.7±4.33 84.6% Group 5 test drug T-3 (25 mg/kg) 102±7.77 132.7±11.78 91.6% Group 6 test drug T-6 (25 mg/kg) 93±8.33 89.7±4.48 100.9%# Group 7 test drug T-8 (25 mg/kg) 96.7±6.74 90.7±8.41 101.6%#

# TGI more than 100% was manifested by a decrease in tumor volume.

4. Result and discussion of safety analysis using the Ba/F3 KIF5B-RET ^G810R tumor cell line model.

No significant weight loss, drug withdrawal, or significant drug toxicity was observed in any of the experimental groups, including test drug groups T-1, T-2, T-3, T-6 and T-8 and the positive control group AD80. The experimental groups tolerated the treatment well.

The changes in body weight of mice in the experimental group and control group after application are shown in Table 10, Figure 5 and Figure 6.

Table 10. Changes in body weight of mice in each group using the Ba/F3 KIF5B-RETG ^810R tumor cell line model Analysis group Number of animals at the beginning/end of the analysis Average body weight
G ( ±S) Body weight change rate (%) Day 0 of use Day 13 of use Day 13 of use Group 1 control solvent 3/3 20.4±1.21 22.5±0.89 10.43% Group 2 positive control AD80 (25 mg/kg) 3/3 19.9±0.44 20.7±1.53 4.14% Group 3 test drug T-1 (25 mg/kg) 3/3 20.3±1.32 21.3±1.19 4.90% Group 4 test drug T-2 (25 mg/kg) 3/3 19.6±0.47 21.7±0.74 11.05% Group 5 test drug T-3 (25 mg/kg) 3/3 19.9±1.18 23.1±1.49 16.01% Group 6 test drug T-6 (25 mg/kg) 3/3 19.4±0.66 22.4±0.46 15.75% Group 7 test drug T-8 (25 mg/kg) 3/3 19.6±0.32 22.5±0.73 14.40%

The foregoing constitutes further detailed description of the present invention in conjunction with specific alternative embodiments, and it is not intended that specific embodiments of the present invention be limited to these descriptions. For one of ordinary skill in the art to which the present invention relates, without deviating from the concept of the present invention, various simple conclusions or substitutions can be made that should be considered as falling within the scope of the present invention.

Claims (190)

1. Compound of formula (II) (II), wherein ring A is isoxazolyl; R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; m is selected from 0, 1, 2 and 3; L ₁ represents CH ₂ ; R _Y is H or halogen, alternatively fluorine; Y ₄ represents CH or N; Z ₂ represents N or CR _Z2 where R _Z2 represents H; Z ₃ represents N or C; Z ₅ represents N, NR _Z5 or CR _Z5 , where R _Z5 represents H; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; each of R _n1 and R _n2 is independently selected from H; or a pharmaceutically acceptable salt thereof; alternatively, wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II-1) (II-1), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; R _Y is H or halogen, alternatively fluorine; Y ₄ represents CH or N; Z ₂ represents N or CR _Z2 where R _Z2 represents H; Z ₃ represents N or C; Z ₅ represents N, NR _Z5 or CR _Z5 , where R _Z5 represents H; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; alternatively, wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II-2) (II-2), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R _Y is H or halogen, alternatively fluorine; Y ₄ represents CH or N; Z ₂ represents N or CH; Z ₃ represents N or C; Z ₅ represents N, NH or CH; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; alternatively, no more than one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom. 4. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II-3) (II-3), where R _Y represents H or halogen, alternatively fluorine; Y ₄ represents CH or N; Z ₂ represents N or CH; Z ₃ represents N or C; Z ₅ represents N or CH; Z ₆ represents N or C; alternatively, no more than one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom. 5. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (II-4-1) or formula (II-4-2): (II-4-1) or (II-4-2), where R _Y represents H or halogen, alternatively fluorine; Y ₄ represents CH or N; Z ₂ represents CH or N; Z ₅ represents CH or N. 6. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III) (III), wherein ring A is isoxazolyl; R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; m is selected from 0, 1, 2 and 3; L ₁ represents CH ₂ ; Z ₂ represents N or CR _Z2 where R _Z2 represents H; Z ₃ represents N or C; Z ₅ represents N, NR _Z5 or CR _Z5 , where R _Z5 represents H; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; each of R _n1 and R _n2 is independently selected from H; wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted nitrogen atom. 7. A compound or a pharmaceutically acceptable salt thereof according to claim 6, which is a compound of formula (III-1) (III-1), where Z ₂ represents N or CH; Z ₃ represents N or C; Z ₅ represents N, NH or CH; Z ₆ represents N or C; where at most one of Z ₅ and Z ₆ represents a nitrogen atom. 8. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (IV) (IV), where ring A is isoxazolyl; R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; m is selected from 0, 1, 2 or 3; L ₁ represents CH ₂ ; Y ₄ represents CH or N; Z ₂ represents N or CR _Z2 where R _Z2 represents H; Z ₃ represents N or C; Z ₅ represents N, NR _Z5 or CR _Z5 , where R _Z5 represents H; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; each of R _n1 and R _n2 is independently selected from H; wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and, when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N. 9. The compound or a pharmaceutically acceptable salt thereof according to claim 8, which is a compound of formula (IV-1) (IV-1), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; Y ₄ represents CH or N; Z ₂ represents N or CR _Z2 where R _Z2 represents H; Z ₃ represents N or C; Z ₅ represents N, NR _Z5 or CR _Z5 , where R _Z5 represents H; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and, when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N. 10. The compound or a pharmaceutically acceptable salt thereof according to claim 8, which is a compound of formula (IV-2) (IV-2), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; Y ₄ represents CH or N; Z ₂ represents N or CH; Z ₃ represents N or C; Z ₅ represents N, NH or CH; Z ₆ represents NR _Z6 or CR _Z6 , where R _Z6 represents C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and, when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N. 11. The compound or a pharmaceutically acceptable salt thereof according to claim 8, which is a compound of formula (IV-3) (IV-3), where Y ₄ represents CH or N; Z ₂ represents N or CH; Z ₃ represents N or C; Z ₅ represents N, NH or CH; Z ₆ represents N or C; wherein at most one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom; and, when both Z ₅ and Z ₆ represent a substituted or unsubstituted nitrogen atom, Y ₄ represents N. 12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 11, wherein only one of Z ₅ and Z ₆ represents a substituted or unsubstituted carbon atom. 13. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (V) (V), where ring A is isoxazolyl; R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; m is selected from 0, 1, 2 and 3; L ₁ represents CH ₂ ; Y ₄ represents N or CR _Y , R _Y is H or halogen; or alternatively fluorine; each of R _n1 and R _n2 is independently selected from H; R _Z6 is C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; Z ₅ represents N or CR _Z5 , where R _Z5 represents H. 14. The compound or a pharmaceutically acceptable salt thereof according to claim 13, which is a compound of formula (V-1) or (V-1’): (V-1) or (V-1'), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; L ₁ represents CH ₂ ; Y ₄ represents N or CR _Y , R _Y is H or halogen; in an additional alternative, fluorine; R _Z6 is C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; Z ₅ represents N or CR _Z5 , where R _Z5 represents H. 15. The compound or a pharmaceutically acceptable salt thereof according to claim 13, which is a compound of formula (V-2) or (V-2’): (V-2) or (V-2'), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; L ₁ represents CH ₂ ; Y ₄ represents N or CH; R _Y is H or halogen, alternatively fluorine; R _Z6 is C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; Z ₅ represents N or CH. 16. The compound or a pharmaceutically acceptable salt thereof according to claim 13, which is a compound of formula (V-3) or (V-3’): (V-3) or (V-3'), where L ₁ represents CH ₂ ; Y ₄ represents N or CH; R _Y is H or halogen, alternatively fluorine; Z ₅ represents N or CH. 17. A compound or pharmaceutically acceptable salt according to any one of claims 13 to 16, where Z ₅ represents N. 18. A compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (VI) (VI), wherein ring A is isoxazolyl; R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), wherein R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; m is selected from 0, 1, 2 and 3; L ₁ represents CH ₂ ; R _Y is H or halogen; in an additional alternative, fluorine; each of R _n1 and R _n2 is independently selected from H; R _Z6 is C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; Z ₅ represents N or CR _Z5 , where R _Z5 represents H. 19. The compound or a pharmaceutically acceptable salt thereof according to claim 18, which is a compound of formula (VI-1) (VI-1), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; R ₂ represents H; L ₁ represents CH ₂ ; R _Y is H or halogen; in an additional alternative, fluorine; R _Z6 is C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; Z ₅ represents N or CR _Z5 , where R _Z5 represents H. 20. The compound or a pharmaceutically acceptable salt thereof according to claim 18, which is a compound of formula (VI-2) (VI-2), where R ₁ represents -C(R _a1 )(R _a2 )(R _a3 ), where R _a1 , R _a2 and R _a3 independently represent H, C _1-6 alkyl or C _1-6 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently C _1-4 alkyl or C _1-4 haloalkyl; alternatively R _a1 , R _a2 and R _a3 are independently methyl or halomethyl; L ₁ represents CH ₂ ; R _Y is H or halogen; in an additional alternative, fluorine; R _Z6 is C _1-6 alkyl; alternatively R _Z6 is C _1-4 alkyl; Z ₅ represents N or CH. 21. The compound or a pharmaceutically acceptable salt thereof according to claim 18, which is a compound of formula (VI-3) (VI-3), where L ₁ represents CH ₂ ; R _Y is H or halogen, alternatively fluorine; Z ₅ represents N or CH. 22. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 18 to 21, where Z ₅ represents N. 23. A compound or a pharmaceutically acceptable salt thereof, where the compound is selected from: 24. A pharmaceutical composition used for inhibiting wild-type and mutant RET, KIF5B-RET, FLT3 and FLT3-ITD kinases, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 and a pharmaceutically acceptable excipient (substances). 25. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 in the manufacture of a medicament for the treatment and/or prevention of a disease, where the disease is a protein kinase-mediated disease, such as a protein kinase-mediated disease. one or more kinases selected from wild type and mutant RET, KIF5B-RET, FLT3 and FLT3-ITD kinases. 26. Use according to claim 25, wherein the mutant RET and KIF5B-RET kinases are selected from V804L, V804M, V804E, M918T, E805K, Y806C, Y806E, C634Y, C634W and G810R. 27. Use according to claim 25, wherein the mutant FLT3 and FLT3-ITD kinases are selected from F691L, D835Y, D835V, D835H, D835F, D835E, Y842C, Y842D, Y842H, Y842N and Y842S. 28. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 in the production of a medicinal product for the treatment and/or prevention of a disease, where the disease is mediated by one or more kinases selected from wild-type and mutant RET, KIF5B-RET, FLT3 and FLT3-ITD kinases, and the disease is selected from non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer, colon cancer, acute lymphoblastic leukemia, sarcoma, infantile glioma, intrahepatic bile duct cancer, pilocytic astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast cancer, fibrosarcoma, kidney cancer, breast cancer, myelodysplastic syndrome, gastrointestinal stromal tumor, melanoma , seminoma, intracranial germ cell tumor and mediastinal B-cell lymphoma.