WO2018068739A1

WO2018068739A1 - Alkynyl heterocyclic compound for inhibiting protein kinase activity

Info

Publication number: WO2018068739A1
Application number: PCT/CN2017/105789
Authority: WO
Inventors: 王义汉; 邢青峰
Original assignee: 深圳市塔吉瑞生物医药有限公司
Priority date: 2016-10-13
Filing date: 2017-10-12
Publication date: 2018-04-19
Also published as: CN108473476B; CN108473476A

Abstract

The present invention relates to alkynyl heterocyclic compounds having inhibitory effects on the protein kinase activity, and to the preparation and use thereof. In particular, disclosed are alkynyl heterocyclic compounds as shown in formula (I) and a pharmaceutical composition comprising the compounds, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug, or an isotope variant thereof. The compounds of the present invention can serve as protein kinase inhibitors for preparing anti-tumour drugs.

Description

Alkynyl heterocyclic compounds for inhibiting protein kinase activity

Technical field

The invention belongs to the field of medicine. Specifically, the present invention relates to alkynyl heterocyclic compounds which have an inhibitory effect on protein kinase activity, pharmaceutical compositions containing them, and processes for their preparation and use.

Background technique

Protein tyrosine kinases (PTKs) are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues, which are activated by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues. A proteinase system that functions as a functional protein. Protein tyrosine kinases play an important role in the signaling pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis. In addition, the abnormal expression of protein tyrosine kinase is also closely related to tumor invasion and metastasis, tumor angiogenesis, and chemotherapy resistance of tumors.

The tyrosine kinase expressed by the Bcr-Abl fusion gene can cause changes in cell proliferation, adhesion and survival properties, leading to the production of various tumors. For example, the oncogene c-Abl on human chromosome 9 is linked to the breakpoint cluster region (Bcr) on chromosome 22, forming the p210Bcr-Abl fusion gene and the p185Bcr-Abl fusion gene, which make the corresponding fusion genes Bcr-Abl tyrosine kinase is continuously activated, causing changes in cell proliferation, adhesion, and survival properties, resulting in the production of chronic myeloid leukemia (CML) and acute myeloid leukemia (ALL), respectively. Inhibition of Bcr-Abl tyrosine kinase is effective in inhibiting tumor growth.

Over the past 20 years, researchers have found that Bcr-Abl kinase plays an important role in cell signal transduction and transformation by promoting phosphorylation and activation of a series of downstream substrates that promote the infinite proliferation of CML mature granulocytes. Bcr-Abl is not expressed in normal cells, so it is an ideal drug target for the treatment of CML. In the early 1990s, researchers expected to inhibit the Bcr-Abl fusion gene through the RNA pathway, but failed to effectively treat CML. With the clarification of the fusion gene structure and expression products, the researchers turned their attention to the design and development of small molecule drugs that can directly act on Bcr-Abl protein.

The most commonly used small molecule inhibitors (TKI) against Bcr-Abl tyrosine kinase in clinical practice include: the first generation drug Imatinib; the second generation drug Dasatinib, Nile Nilotinib and Bosutinib; the third generation of punatinib (Ponatinib). Imatinib is an oral anti-chronic granulocyte leukemia small molecule tyrosine kinase inhibitor developed by Novartis AG. It pioneered a new era of treatment of diseases with kinases. Imatinib binds to the ATP site of the Bcr-Abl kinase domain, prevents phosphorylation of amino acid residues, thereby blocking signaling pathways and inhibiting cell proliferation. Relieve CML. After treatment, the patient's 5-year survival rate can reach 90%, and it can specifically act on CML cancer cells, while it has almost no damage to normal cells, and the side effects are greatly reduced. With the use of imatinib, mutations in the Bcr-Abl gene led to the emergence of drug resistance, which greatly reduced the efficacy of imatinib. Dasatinib is a multi-targeted oral kinase inhibitor targeting multiple kinases such as Bcr-Abl tyrosine kinase, Src kinase family (Src, Lck, Fyn), c-Kit and PDGFR-B. On June 28, 2006, Bristol-Myers Squibb developed and obtained FDA approval for listing. Like imatinib, it competitively binds to the ATP site of the Bcr-Abl kinase domain, but inhibits the activity of Bcr-Abl kinase by a factor of 300 that of imatinib. Although it can overcome the resistance of many imatinib, Ineffective for the T315I mutation. Nilotinib, a novel aniline pyrimidine derivative, was approved by the US FDA on October 29, 2007. It has a 20-fold higher affinity for Bcr-Abl kinase than imatinib and is widely active in patients with imatinib resistance (except for the T315I mutation). Most patients who use nilotinib to treat CML have common side effects such as gastrointestinal reactions, myelosuppression, and hyperbilirubinemia. For the resistance of imatinib, dasatinib and nilotinib, Wyeth Pharmaceuticals has developed 4-substituted aniline-3-quinoline plus carbonitrile drug Bosutinib for treatment CML was approved by the FDA on September 4, 2012. Bosutinib can inhibit the autophosphorylation of Src protein in a variety of human tumor cells, and also inhibit the autophosphorylation of Bcr-Abl protein, and is resistant to KU812 and K562 cells (Bcr-Abl-containing CML cells). In the proliferation test, bosutinib activity was significantly higher than imatinib, and its oral bioavailability was higher, but patients treated with bosuzinib often had abdominal pain, diarrhea, thrombocytopenia, fever and fatigue. Bad hair should be. Punatinib is an oral multi-target inhibitor that acts on Abl, PDGFRα, VEGFR2, FGFR1 and Src kinases. Due to its unique mechanism of action, administration can inhibit Bcr-Abl kinase activity, including the T315I mutation. However, according to the FDA's latest report, patients taking Ponatinib have serious cardiovascular problems.

Therefore, it is necessary to further develop new Bcr-Abl inhibitors and to effectively inhibit Bcr-Abl kinase activity against T315I mutation while reducing its side effects.

Summary of the invention

The present invention provides a novel alkynyl heterocyclic compound and a composition comprising the same and use thereof, which have better Bcr-Abl kinase inhibitory activity and/or have better pharmacodynamics/pharmacokinetics It has low toxicity and can be used for the preparation of drugs mediated by Bcr-Abl kinase.

In this regard, the technical solution adopted by the present invention is as follows:

In a first aspect of the invention, there is provided an alkynyl heterocyclic compound of the formula (I),

Wherein ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring; wherein the heteroaryl ring or heterocyclic ring contains 1-3 heteroatoms selected from N, O and S, and the ring It may be selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, carboxy, oxo, C _3- C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocycloalkyl, C ₃ -C ₇ heterocycloalkenyl Substituted with a substituent in a C ₁ -C ₆ alkylthio group, a C ₁ -C ₆ alkylamino group or a C ₁ -C ₆ alkanoyl group;

K is selected from CH, NH or S;

M is selected from CH, C or N;

X ¹ , X ² , X ³ , X ⁴ and X ^{5 are} independently N or CR ¹ , and R ^{1 is} independently H, hydroxy, halogen, silane, nitrile, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl , C _3-7 heterocycloalkyl or C _3-7 heterocycloalkenyl;

L is selected from O, S, NR ² , CR ² R ² , C(=O), C(=O)NR ² , NR ² C(=O), NR ² C(=O)NR ² , OC(= O) NR ² , NR ² C(=O)O, S(=O), S(=O) ₂ , S(=O)NR ² , S(=O) ₂ NR ² , NR ² S(=O ), NR ² S(=O) ₂ , NR ² S(=O)NR ² , NR ² S(=O) ₂ NR ² , OP(=O)R ² , P(=O)OR ² , where R ² independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 olefin a group, a C _2-6 alkynyl group, a C _6-10 aryl group, a C _3-7 heterocycloalkyl group or a C _3-7 heterocycloalkenyl group;

Ring C is a 5-6 membered aromatic ring having 1 to 5 substituents or a 5-6 membered heteroaryl ring having 1 to 5 substituents, which may be selected from halogen, -R, -CN, - COOH, -OH, -SH, -OR, -C(=O)R, -C(=O)OR, -OC(=O)R, -S(=O)R, -S(=O) ₂ R, -NR ₂ , -NHC(=O)R, -NHC(=O)OR, -C(=O)NHR, -C(=O)ONHR, where R is independently H, C _1-6 alkane , C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{6- 10} aryl, C _3-7 heterocycloalkyl or C _3-7 heterocycloalkenyl; two adjacent R and the carbon atom on ring C to which they are attached may together form an optionally substituted C ₅ - ₈ carbon a cyclo group, an optionally substituted 5 to 8 membered heterocyclic group, an optionally substituted C ₆ _-14 aryl group or an optionally substituted 5 to 10 membered heteroaryl group;

Or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a particular embodiment, a compound of the invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compounds of the invention are provided in a therapeutically effective amount. In a particular embodiment, the compounds of the invention are provided in a prophylactically effective amount.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.

In another aspect, the invention provides a compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a hydrate, a crystal form, a prodrug or an isotopic variant thereof, and other therapeutic agents, and a pharmaceutically acceptable compound, A kit of acceptable carriers, adjuvants or vehicles.

In another aspect, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of an anti-tumor or other disease, in a particular embodiment, the disease being a proliferative disorder caused by Bcr-Abl.

In a specific embodiment, the disease may be selected from the group consisting of: solid tumor, sarcoma, chronic myelogenous leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, acute myeloid leukemia, thyroid cancer, gastric cancer, rectal cancer, multiple Myeloma, neoplasia, and other proliferative or proliferative diseases.

In a specific embodiment, the condition caused by the Bcr-Abl is chronic myeloid leukemia, gastrointestinal stromal tumor, acute myeloid leukemia, thyroid cancer, or a combination thereof.

In a specific embodiment, the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the <RTIgt;

Definition

Chemical definition

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

When a range of values is recited, each value and sub-range within the range are intended to be included. For example, "C _1- C ₆ alkyl" includes _{_{_{C 1, C 2, C 3}}} , C 4, C 5, C 6, C 1- C 6, C 1- C 5, C 1- C 4, C 1- C ₃ , C _{1 -} C ₂ , C _{2 -} C ₆ , C _{2 -} C ₅ , C _{2 -} C ₄ , C _{2 -} C ₃ , C _{3 -} C ₆ , C _{3 -} C ₅ , C _{3 -} C ₄ , C _4- C ₆ , C _4- C ₅ and C _5- C ₆ alkyl.

It will be understood that any of the moieties defined below may be substituted by a number of substituents, as described herein, and the corresponding definitions are within the scope of their inclusion, including such substitutions. Unless otherwise stated, the term "substituted" is as defined below.

"C _1- C ₆ alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl." In some embodiments, a C _1-4 alkyl group is particularly preferred. Examples of the alkyl group include, but are not limited to, methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), isopropyl (C ₃ ), n-butyl (C ₄ ), uncle Butyl (C ₄ ), sec-butyl (C ₄ ), isobutyl (C ₄ ), n-pentyl (C ₅ ), 3-pentyl (C ₅ ), pentyl (C ₅ ), neopentyl (C _5), 3- methyl-2-butyl (C _5), tert-pentyl (C ₅₎ and n-hexyl (C _6). Unless otherwise stated, each alkyl group is independently optionally substituted, ie, unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl") For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent. In some embodiments, the alkyl group is unsubstituted C _1- C ₆ alkyl (e.g., -CH _3). In some embodiments, the alkyl group is a substituted C _1- C ₆ alkyl.

"C _1- C ₆ alkoxy" refers to the group -OR, wherein, R is a substituted or unsubstituted C _1- C ₆ alkyl. In some embodiments, a C _1-4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-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 halo group is F, Cl or Br. In some embodiments, the halogen group is F or Cl. In some embodiments, the halogen group is F.

Therefore, "C _1- C ₆ haloalkyl" and "C _1- C ₆ haloalkoxy" mean the above-mentioned "C _1- C ₆ alkyl group" and "C _1- C ₆ alkoxy group" which are one or Multiple halogen groups are substituted. In some embodiments, C _1- C ₄ haloalkyl groups are particularly preferred, more preferably C _1- C ₂ haloalkyl. In some embodiments, a C _1-4 haloalkoxy group is particularly preferred, more preferably a C ₁ -C ₂ haloalkoxy group. Exemplary haloalkyl groups include, but the are not limited _{_{to: -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-dimethyl-ethyl, and the like. Exemplary haloalkoxy groups include, but are not limited to, -OCH ₂ F, -OCHF ₂ , -OCF ₃ , and the like.

"C3 _- _C10 carbocyclyl" means a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C _3- C ₆ carbocyclic group is particularly preferred, more preferably C _5- C ₆ carbocyclyl. Carbocyclyl also includes ring systems wherein the above carbocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and in such cases, the number of carbons continues to be represented The number of carbons in the carbocyclic system. Exemplary such carbocyclic groups include, but are not limited to, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl ( C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ), cycloheptyl (C ₇ ), cycloheptene (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo [2.2.1] Heptyl (C ₇ ), bicyclo [2.2.2] octyl (C ₈ ), cyclodecyl (C ₉ ), cyclodecenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthyl (C ₁₀ ), spiro[4.5]decyl (C ₁₀ ), and the like. Unless otherwise specified, each of the carbocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclic ring"base"). In some embodiments, the carbocyclic group is an unsubstituted C3 _- _C10 carbocyclic group. In some embodiments, a carbocyclyl is a substituted C3 _- _C10 carbocyclyl.

"3 to 10 membered heterocyclic group" or a group of a 3 to 10 membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring hetero atoms, wherein each hetero atom is independently selected from nitrogen and oxygen. , sulfur, boron, phosphorus and silicon. In the heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. In some embodiments, a 3- to 6-membered heterocyclic group is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclic ring. a group which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring hetero atoms. Unless otherwise stated, each of the heterocyclic groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heterocyclic") or substituted with one or more substituents ("substituted hetero Ring base"). In some embodiments, the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In some embodiments, a heterocyclic group is a substituted 3-10 membered heterocyclyl. The heterocyclic group further includes a ring system in which the above heterocyclic ring is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic ring, or wherein the above heterocyclic ring is bonded to one or more aryl groups or A heteroaryl fused ring system wherein the point of attachment is on a heterocyclyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thiorenyl. Exemplary 4-membered heterocyclic groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane. Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxalanyl, oxasulfuranyl, disulfuranyl, and Azolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl. Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxoalkyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one hetero atom include, but are not limited to, azepanyl, oxaheptyl, and thiaheptanyl. Exemplary 8-membered heterocyclic groups containing one hetero atom include, but are not limited to, azacyclooctyl, oxacyclooctyl, and thicyclooctyl. Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a _C6 aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to a C ₆ aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.

"C _6- C ₁₄ aryl" means a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms (eg, having A group of 6, 10 or 14 π electrons shared in a ring arrangement. In some embodiments, an aryl group having six ring carbon atoms ( "C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (" _C10 aryl"; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (" _C14 aryl"; for example, fluorenyl). In some embodiments, a C _6-10 aryl group is particularly preferred, more preferably a C ₆ aryl group. The aryl group also includes a ring system in which the above aryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be represented. The number of carbon atoms in the aryl ring system. Unless otherwise stated, each of the aryl groups is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In some embodiments, the aryl group is an unsubstituted C _6-14 aryl group. In some embodiments, the aryl group is a substituted C _6-14 aryl group.

"C ₅ -C ₁₀ heteroaryl" means a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms (for example, having a ring-shaped arrangement) a group of 6 or 10 π electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur. In a heteroaryl group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system. In some embodiments, a _C5-6 heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms. Unless otherwise stated, each of the heteroaryl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"base"). In some embodiments, the heteroaryl is an unsubstituted 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a substituted 5-10 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .

Other definitions

The term "pharmaceutically acceptable salt" means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids, such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or a salt formed using methods used in the art, for example, an ion exchange method. Other pharmaceutically acceptable salts include: adipic acid salts, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin ester, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Further pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed using counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.

"Subjects" for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "person," "patient," and "subject" are used interchangeably herein.

"Disease," "disorder," and "disorder" are used interchangeably herein.

The term "treatment" as used herein, unless otherwise indicated, includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition ("prophylactic treatment").

Generally, an "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As will be understood by one of ordinary skill in the art, an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.

Unless otherwise indicated, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. Delay or minimize. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.

A "prophylactically effective amount" of a compound, as used herein, is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.

"Combination" and related terms mean the simultaneous or sequential administration of a therapeutic agent of the invention. For example, a compound of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together with another therapeutic agent in a single unit dosage form.

The agents of the invention are also useful in the treatment of diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcers Colitis, Crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor, thyroid Cancer, systemic mastocytosis, eosinophilic granules Cytomegaly, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, seminoma, asexual Cell tumor, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular parathyroid hyperplasia/adenomas, colon cancer, colon Rectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, renal cancer, liver cancer, adrenal cancer, Bladder cancer, gastric cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, cervical and head tumors, neoplasia, and other proliferative or proliferative diseases, or a combination thereof.

detailed description

Compound

As used herein, "a compound of the invention" refers to a compound of formula (I) below, a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.

In one embodiment, the invention relates to a compound of formula (I):

K is selected from CH, NH or S;

M is selected from CH, C or N;

L is selected from O, S, NR ² , CR ² R ² , C(=O), C(=O)NR ² , NR ² C(=O), NR ² C(=O)NR ² , OC(= O) NR ² , NR ² C(=O)O, S(=O), S(=O) ₂ , S(=O)NR ² , S(=O) ₂ NR ² , NR ² S(=O ), NR ² S(=O) ₂ , NR ² S(=O)NR ² , NR ² S(=O) ₂ NR ² , OP(=O)R ² , P(=O)OR ² , where R ² independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 olefin a C _2-6 alkynyl group, a C _6-10 aryl group, a C _3-7 heterocycloalkyl group or a C _3-7 heterocycloalkenyl group;

In some embodiments, the ring comprising Ring A and Ring B has the structure:

Wherein M is C or N, ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring; and R ^{a is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, carboxy, oxo, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocycloalkyl, C ₃ -C ₇ heterocycloalkenyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino or C ₁ -C ₆ Alkanoyl, and m is 0, 1, 2, 3 or 4.

More preferably, the parallel ring composed of ring A and ring B has the following structure:

Wherein X ⁶ , X ⁷ and X ^{8 are} independently C(R ^a ) ₂ , CR ^a , NR ^a , N, O or S, and R ^{a is} selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, carboxy, oxo, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₆ -C ₁₀ aryl, C ₃ -C ₇ heterocycloalkyl, C ₃ -C ₇ heterocycloalkenyl, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino Or a C ₁ -C ₆ alkanoyl group; where chemistry permits, the bond between X ⁶ , X ⁷ and X ⁸ may be selected from a single bond or a double bond.

Preferably, the ring comprising ring A and ring B is selected from the group consisting of:

Wherein X ⁵ , X ⁶ , X ⁷ and X ^{8 are} as defined above;

Wherein X ⁵ and R ^{a are} as defined above.

In some embodiments, X ¹ , X ² , X ³ , X ^{4 ,} and X ^{5 are} independently N or CR ¹ , and R ^{1 is} independently H, hydroxy, halo, silane, nitrile, nitro, C _{1 -6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 heterocycloalkyl or C _3-7 heterocycloalkenyl.

Preferably, X ¹ , X ² , X ³ , X ⁴ are CR ¹ , and X ⁵ is N or CR ¹ , and R ^{1 is} independently H, hydroxy, halogen, silane, nitrile, nitro, C _{1- 6} alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 heterocycloalkyl or C _3-7 heterocycloalkenyl.

In some embodiments, L is selected from the group consisting of O, S, NR ² , CR ² R ² , C(=O), C(=O)NR ² , NR ² C(=O), NR ² C(=O) NR ² , OC(=O)NR ² , NR ² C(=O)O, S(=O), S(=O) ₂ , S(=O)NR ² , S(=O) ₂ NR ² , NR ² S(=O), NR ² S(=O) ₂ , NR ² S(=O)NR ² , NR ² S(=O) ₂ NR ² , OP(=O)R ² , P(=O And OR ² , wherein R ^{2 is} independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 heterocycloalkyl or C _3-7 heterocycloalkenyl.

Preferably, L is selected from the group consisting of C(=O)NR ² , NR ² C(=O), NR ² C(=O)NR ² , OC(=O)NR ² , NR ² C(=O)O, S (=O), S(=O) ₂ , S(=O)NR ² , S(=O) ₂ NR ² , NR ² S(=O), NR ² S(=O) ₂ , NR ² S( =O)NR ² , NR ² S(=O) ₂ NR ² , OP(=O)R ² , P(=O)OR ² , wherein R ^{2 is} independently selected from H or C _1-6 alkyl.

In some embodiments, Ring C is a 5-6 membered aromatic ring containing 1-5 substituents or a 5-6 membered heteroaryl ring containing 1-5 substituents, which may be selected from halogen, - R, -CN, -COOH, -OH, -SH, -OR, -C(=O)R, -C(=O)OR, -OC(=O)R, -S(=O)R, - S(=O) ₂ R, -NR ₂ , -NHC(=O)R, -C(=O)NHR, -NHC(=O)OR, -C(=O)ONHR, where R is independently H , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _6-10 aryl, C _3-7 heterocycloalkyl or C _3-7 heterocycloalkenyl, two adjacent R and the carbon atom on ring C to which they are attached may together form an optional substitution the C ₅ - ₈ carbocyclyl, optionally substituted 5- to 8-membered heterocyclic group, optionally substituted C ₆ - ₁₄ aryl group or an optionally substituted 5- to 10-membered heteroaryl group.

Preferably, ring C is a 5-6 membered aromatic ring containing 1-5 substituents, which may be selected from the group consisting of halogen, -R, -CN, -COOH, -OH, -SH, -OR, -C (=O)R, -C(=O)OR, -OC(=O)R, -S(=O)R, -S(=O)2R, -NR2, -NHC(=O)R, - NHC(=O)OR, -C(=O)NHR, -C(=O)ONHR, wherein R is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy , C _1-6 haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 heterocycloalkyl or C _{3 -7} heterocycloalkenyl, two adjacent carbon atoms on the ring C R which they are attached may form an optionally substituted C ₅ - ₈ carbocyclyl, optionally substituted 5- to 8-membered heterocyclic group, Optionally substituted C ₆ _-14 aryl or optionally substituted 5 to 10 membered heteroaryl.

More preferably, ring C is a benzene ring of 1 to 5 substituents, which may be selected from the group consisting of halogen, -R, -CN, -COOH, -OH, -SH, -OR, -C(=O) R, -C(=O)OR, -OC(=O)R, -S(=O)R, -S(=O)2R, -NR2, -NHC(=O)R, -NHC(=O OR, -C(=O)NHR, -C(=O)ONHR, wherein R is independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1 -6} haloalkoxy, C _3-7 cycloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 heterocycloalkyl or C _3-7 heterocycle alkenyl group, two adjacent carbon atoms on the ring C R which they are attached may form an optionally substituted C ₅ - ₈ carbocyclyl, optionally substituted 5- to 8-membered heterocyclic group, optionally substituted C ₆ _-14 aryl or optionally substituted 5 to 10 membered heteroaryl.

Preferably, ring C is:

Wherein R is as defined in claim 8 or 9, and L ¹ is substituted or unsubstituted (CH ₂ ) _x , O(CH ₂ ) _x , NR(CH ₂ ) _x , S(CH ₂ ) _x , or (CH ₂ ) _x NRC(O)(CH ₂ ) _x , x is 1, ₂ , 3 or 4.

Preferably, ring C is selected from:

In some embodiments, the compounds of the invention may be selected from the group consisting of:

The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of a compound of the invention is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, respectively. ¹⁸ F, ³¹ P, ³² P, ³⁵ S and ³⁶ Cl. Some isotopic variations of the compounds of the invention, such as those in which a radioisotope such as ³ H or ¹⁴ C is incorporated, are useful in drug and/or substrate tissue distribution studies. Deuterated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with isotopes (e.g., hydrazine, i.e., ² H) can provide some therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. . Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures, for example by illustrative methods or by the preparations described in the Examples below, using appropriate isotopic variations of the appropriate reagents.

The compound of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline form. Furthermore, the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.

Those skilled in the art will appreciate that many organic compounds can form complexes with solvents in which they react or precipitate or crystallize from the solvent. These complexes are referred to as "solvates." When the solvent is water, the complex is referred to as a "hydrate." The present invention encompasses all solvates of the compounds of the invention.

In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium 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 This article is incorporated herein by reference.

A prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group. Thus, representative examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I). Further, in the case of a carboxylic acid (-COOH), an ester such as a methyl ester, an ethyl ester or the like can be used. The ester itself may be active and/or may hydrolyze under conditions in humans. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.

Pharmaceutical compositions, formulations and kits

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the active component. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active component. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active component.

A pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block polymers, polyethylene glycol and lanolin.

The invention also includes kits (e.g., pharmaceutical packs). Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container). In some embodiments, provided kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent. In some embodiments, a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.

The following formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention. However, the invention is not limited to the following pharmaceutical compositions.

Exemplary Formulation 1 - Tablet: The compound of the invention in dry powder form can be dried with a gel adhesive at about 1:2 The weight ratio is mixed. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2 - Tablet: The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 3 - Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 4-Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 5 - Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 6-Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.

Exemplary Formulation 7-Tablet: The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 8-Capsule: The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).

Exemplary Formulation 9-Liquid: The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.

Exemplary Formulation 10 - Injection: The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.

Administration

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

Generally, an effective amount of a compound provided herein is administered. Depending on the circumstances, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. The amount of the compound actually administered can be determined by a physician.

When used to prevent a condition of the invention, the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above. Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.

The pharmaceutical compositions provided herein ("long-term administration") can also be administered chronically. Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.

The pharmaceutical composition of the present invention can be further delivered using various methods of administration. For example, in some embodiments, a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body. Moreover, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.

Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration. A carrier or excipient and a processing aid.

For oral doses, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.

In order to provide a blood level similar to the use of an injectable dose, or a lower blood level than the injectable dose, a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

The injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours. In order to obtain a sufficient level of steady state, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered. For a human patient of 40 to 80 kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. The solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, E.g, Alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silica; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, peppermint, salicylic acid Methyl or orange flavoring.

Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

The transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.

The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.

The above components of the composition for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, etc., are set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, part 8 of which is incorporated herein by reference.

The compounds of the invention may also be administered in sustained release form or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

The invention further relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation comprises hexapropyl-β-cyclodextrin (eg, 10-50% in water).

treatment

The agents of the invention are also useful in the treatment of diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcers Colitis, Crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor, thyroid Cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, rheumatoid arthritis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Al Alzheimer's disease, seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular thyroid Paragonadin / adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, evil Pleural mesothelioma, hemangioblastoma, hemangioma, renal cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, cervical and head tumors , neoplasia, and other proliferative or proliferative diseases, or a combination thereof.

The invention thus provides compounds (I) and salts, solvates, physiologically functional compounds thereof for use in therapy, particularly in the treatment of diseases and conditions mediated by inappropriate Bcr-Abl activity.

Inappropriate Bcr-Abl activity as referred to herein is any Bcr-Abl activity that deviates from the expected normal Bcr-Abl activity in a particular mammalian subject. Inappropriate Bcr-Abl activity can be, for example, in the form of an abnormal increase in activity, or a timing and/or controlled aberration of Bcr-Abl activity. Such inappropriate activity can result, for example, from overexpression or mutation of an activated protein kinase that results in inappropriate or uncontrolled.

In another embodiment, the invention relates to a method of modulating, modulating or inhibiting Bcr-Abl for the prevention and/or treatment of a disorder associated with dysregulated or inappropriate Bcr-Abl activity.

In another embodiment, the condition mediated by Bcr-Abl activity is a respiratory disease. In another embodiment, the condition is a proliferative disorder. In yet another embodiment, the condition is cancer. In another embodiment, the condition is leukemia.

In another embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, prepared for use in therapy for mediated by Bcr-Abl activity Use of the drug for the illness.

A further aspect of the invention resides in the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a Bcr-Abl mediated disease or a Bcr-Abl mediated condition.

In another embodiment, the invention provides a method of treating a mammal having a condition mediated by Bcr-Abl activity, the method comprising: administering to the mammal an effective amount of Formula (I) a compound or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.

An effective amount of a compound of the invention will generally be administered in a single or multiple doses at an average daily dose of from 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight. In general, the compounds of the invention may be administered to a patient in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg. For example, the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. It can be administered one or more times daily, weekly (or several days apart) or on an intermittent schedule. For example, the compound can be administered one or more times per day on a weekly basis (e.g., every Monday), continually or for several weeks, such as 4-10 weeks. Alternatively, the administration may be continued for several days (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) without administration of the compound, and the cycle may be repeated indefinitely or repeated for a given number of times, such as 4-10 Cycles. For example, the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days, then intermittent for 9 days, and so on, optionally repeating the cycle or repeating 4-10 times.

Combination therapy

The compounds of the present invention, their salts and solvates and physiologically functional derivatives thereof may be used alone or in combination with other treatments for the treatment of Bcr-Abl mediated diseases and conditions associated with inappropriate Bcr-Abl activity. The agents are used in combination. Combination therapies according to the invention thus comprise the administration of at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other pharmaceutically active agent. One or more compounds of formula (I) and one or more other pharmaceutically active agents may be administered together or separately, and when administered separately, may be carried out simultaneously or sequentially in any order. The amount and relative timing of administration of one or more compounds of formula (I) and one or more other pharmaceutically active agents will be selected to achieve the desired combined therapeutic effect.

For cancer treatment, the compound of formula (I) can be combined with one or more anticancer agents. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (ed.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art will be able to identify which combination of agents can be used based on the drug and the particular characteristics of the cancer involved. Such anticancer agents include, but are not limited to: (1) estrogen receptor modulators such as diethyltibestral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluorotestosterone, and SH646; (2) Other hormonal agents include aromatase inhibitors (eg, aminoglutethimide, tetrazoranazol, letrozole, and exemestane), luteinizing hormone releasing hormone (LHRH) analogs, ketoconazole, Goserelin acetate, leuprolide, megestrol acetate and mifepristone; (3) androgen receptor modulators such as finasteride and other 5α-reductase inhibitors, nilutamide, Flutamide, bicalutamide, liazodazole, and abiraterone acetate; (4) retinoid receptor modulators such as bexarotene, retinoic acid, 13-cis-retinoic acid, 9- Cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) cresol amide, and N-4-carboxyphenyl cresol Amide; (5) anti-proliferative agents such as antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enesitabine, carmofur, fluridine, whistles Heding, Oxyfluorouridine, trimethoate, fludarabine, capecitabine, galoxibine, cytarabine, fosteabine sodium hydrate, raltitrexed, paltitrexid, ethifluzine, thiazole Carboplatin nucleoside (tiazofurin), decitabine, lorazepam, pemetrexed, naribine, 2'-deoxy-2'-methylidene cytidine, 2'-fluoromethylene- 2'-deoxycytidine, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-propane trioxide --BL-mannose-pyranose-glycosyl]adenine, aplidine, ascidin, trastazin, aminopterin, 5-fluorouracil, fluorouridine, methotrexate, leucovorin, hydroxyurea, sulfur Guanine (6-TG), 巯嘌呤(6-MP), cytarabine, pentastatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine, alano New, swainsonine, lometripsol, dextromethionine, methioninase, and 3-aminopyridine-2-formaldehyde phenylthiourea; (6) isoprenyl-protein transferase inhibitors including Base-protein transferase (FPTase), geranyl geranyl-protein transferase type I (GGPTase-I), and geranyl geranyl- White transferase-type II (GGPTase-II, also known as Rab GGPTase); (7) HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin and Rosuvastatin; (8) angiogenesis inhibitors such as tyrosine kinase receptor Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2) inhibitors, epidermal-derived, fibroblast-derived or platelet Inhibitors of derived growth factors, MMP (matrix metalloproteinase) inhibitors, integrin blockers, interferon-α, interleukin-12, erythropoietin (erythropoietin-α), granulocyte-CSF Siting), granulocytes, macrophages-CSF (saxstatin), pentosan polysulfate, cyclooxygenase inhibitor, steroidal anti-inflammatory agent, carboxyamidotriazole, Comprising A- 4, squalamine, 6-O-chloroacetyl-carbonyl)-nicotin, salitonide, angiostatin, troponin-1, angiotensin II antagonist, heparin, carboxypeptidase U inhibition Agent, and antibodies to: VEGF, endostatin, ukrain, leopard frog enzyme, IM862, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4) -Chlorobenzoyl Phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, Compris, RPI4610, NX31838, sulfated mannose pentasaccharide, and 3- [(2,4-Dimethylpyrrole-5-yl)methylene]-2-indololinone (SU5416); (9) PPAR-γ agonist, PPAR-δ agonist, thiazolidinedione ( Such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, xylene oxyheptanoic acid, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555 , GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazole- 6-yloxy]-2-methylpropionic acid (in USSN 09/782,856) (), and (2R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchroman-2-carboxylic acid (in USSN60/ (9) Intrinsic multidrug resistance inhibitors include p-glycoprotein (P-gp) inhibitors such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar); (10) Cell proliferation and survival signaling inhibitors such as EGFR inhibitors (eg gefitinib, erlotinib, ectinib and oxistatinib (AZD9291)), ERB-2 inhibitors (eg trastone) Anti-), IGF1R inhibitors such as MK-0646 (dalotuzumab), CD20 inhibitor (rituximab), cytokine receptor inhibitors, MET inhibitors, PI3K family kinase inhibitors (eg LY294002), serine/threonine Acid kinases (including but not limited to Akt inhibitors such as in WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02 Inhibitors of Raf kinase (eg BAY-43-9006), MEK inhibitors (eg CI-1040 and PD-098059) and mTOR inhibitors (eg Wyeth CCI-779 and Ariad AP23573); (11) Bisphosphonates such as etidronate, pamidronate , alendronate, risedronate, zoledronate, ibandronate, incadinate or cicadronate, clodronate, EB-1053, rice Nodronate, nacredronate, piridronate and tiludronate; (12) γ-secretase inhibitor, (13) interference with receptor tyrosine kinase (RTK) Agents, including c-Kit, Eph, PDGF, Flt3 and c-Met inhibitors; (14) Agents that interfere with cell cycle checkpoints include ATR, ATM, Chk1 and Chk2 kinase and CDK inhibitors and CDC kinase inhibitors and In particular, for example, 7-hydroxystaurosporin, flurazipine, CYC202 (Cyclacel) and BMS-387032; (15) BCR-ABL inhibitors such as PCI32765, AVL-292 and AVL-101; PARP inhibitors include iniparib, olaparib, AGO14699, ABT888 and MK4827; (16) ERK inhibitors; (17) mTOR inhibitors such as rapamycin, 42-(dimethylphosphinyl) rapamycin , temsirolimus, everolimus; (18) cytotoxicity/cytostatics.

"Cytotoxicity/cytostatic" refers to compounds that primarily cause cell death or inhibit cell proliferation or inhibit or interfere with cell mitosis by direct interference with cellular functionalization, including alkylating agents, tumor necrosis factors, intercalators, hypoxia-activated compounds. Compounds, microtubule inhibitors/microtubule stabilizers, inhibitors of mitotic kinesins, inhibitors of histone deacetylases, inhibitors of kinases involved in mitotic processes, antimetabolites, biological response modifiers, hormones/antibiotics Hormone therapeutics, hematopoietic growth factors, monoclonal antibody-targeted therapeutics, topoisomerase inhibitors, proteasome inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef, cachexia, cyclamate, cyclophosphamide, ifosfamide, nitrogen mustard, melphalan, uracil mustard, thiotepa, busulfan, carmustine , cyclohexyl nitrosourea, streptozotocin, tastatin, chloridamine, carboplatin, hexamethylene melamine, dacarbazine, procarbazine, prednisolone, dibromodusol, thunder Mistin, formoterol, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, mesalamine, trlophosphamide, nimustine, dibromospirochloramine, Pyridoxine, lobaplatin, celecoxime, porphyrin, cisplatin, ilofufen, dexfosfamide, cis-amine dichloro(2-methyl-pyridine)platinum, benzyl Base guanine, glufos amide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)] double [ Diamine (chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7 - dimethylxanthine, zolubicin, doxorubicin, daunorubicin, idabe , guanidine, bleomycin, mitomycin C, dactinomycin, plicatomycin, specific group, mitoxantrone, pirarubicin, pyrofibine, pentrube, amrubicin, anti- Ketosterone, 3'-desamino-3'-morpholino-13-deoxy-10-hydroxyerythromycin, kanamycin, galarubicin, ilinavird, MEN10755, and 4 -desmethoxy-3-desamino-3-azepine-4- Methylsulfonyl-danomycin.

Examples of proteasome inhibitors include, but are not limited to, lactacystin and bortezomib.

Examples of microtubule inhibitor/microtubule stabilizing agents include vincristine, vinblastine, vindesine, vinorelbine, vinorelbine, vindesine sulfate, 3', 4'-didehydro-4' - deoxy-8'-norvinine ditartrate, podophyllotoxin (eg etoposide (VP-16) and teniposide (VM-26)), paclitaxel, docetaxel, rhizomycin , tail sea rabbit, mivobulin isethionate, auristatin, simatin, RPR109881, BMS184476, vinflunine, cryptophycin, anhydrovinblastine, N, N-dimethyl-L-prolyl-L-prolyl- N-methyl-L-prolyl-L-prolyl-L-valine-tert-butylamide, TDX258, epothilone (see, e.g., U.S. Patent Nos. 6,284,781 and 6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitatecan, 6-ethoxypropionyl-3', 4'-O-exo-benzylidene-teaching bacteria , letoticon, 7-[2-(N-isopropylamino)ethyl]-(20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, cable Buzool, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl- 6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo [c]-phenanthridine, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1 -de] acridine-6-one, N-[1-[2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthene-4-yl Methyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy- 7H-indolo[2,1-c]quinolin-7-one, and dimesima.

Examples of histone deacetylase inhibitors include, but are not limited to, vorinostat, trichostatin A, oxamflatin, PXD101, MG98, valproic acid, and scriptaid.

"Inhibitors of kinases involved in mitotic processes" include, but are not limited to, Aurora kinase inhibitors, Polo-like kinase inhibitors (PLK; in particular inhibitors of PLK-1), Bub-1 inhibitors and Bub-R1 inhibitors. An example of an "Aurora kinase inhibitor" is VX-680.

"Anti-proliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enesitabine, carmofur, fluridine, pentastatin, deoxygenation Fluorouridine, trimethoate, fludarabine, capecitabine, gallotine, cytarabine, fosteabine sodium hydrate, raltitrexed, paltitrexid, ethidium fluoride, thiazole carboxylate Amine nucleoside, decitabine, loratrix, pemetrexed, naribine, 2'-deoxy-2'-methylidene cytidine, 2'-fluoromethylene-2'- Oxycytidine, N6-[4-deoxy-4-[N2-[2,4-tetradecadienoyl]glycylamino]-L-propanetrioxy-BL-mannose-pyran Glycosyl] adenine, aplidine, ascidin, troxacitabine, aminopterin, 5-fluorouracil, fluorouridine, methotrexate, leucovorin, hydroxyurea, thioguanine (6-TG), 巯嘌呤(6-MP), cytarabine, pentastatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine, alanoxin, swainsonine, lomel Cord, dextromethionine, methioninase, and 3-aminopyridine-2-formaldehyde phenylthiourea.

Non-limiting examples of suitable agents for use in combination with a compound of formula (I) for use in the treatment of cancer include, but are not limited to, abarelix; aldileukin; alemtuzumab; alibretin; allopurinol; Hexamethyl melamine; amifostine; anastrozole; arsenic trioxide; asparaginase; azacitidine; bendamustine; bevacizumab; bexarotene; spectabilin; bortezomib; Ans; captopril; capecitabine; carboplatin; carmustine; cetuximab; tumanning; cisplatin; cladribine; clofarabine; cyclophosphamide; Carbazine; dactinomycin, actinomycin D; dalteparin sodium; erythropoietin; dasatinib; daunorubicin; degarelix; dinisin; dextromethamine; docetaxel A Rhinomycin; trastrolone propionate; eculizumab; Elliott's B solution; itrapox; epirubicin; recombinant human erythropoietin; erlotinib; estramustine; Glycosides; etoposide; everolimus; exemestane; feigestatin; fluorouridine; fludarabine; fluorouracil; fulvestrant; Iressa; Tarceva; Osilo; Gytozumab; goserelin acetate; histamine acetate; hydroxyurea; temimumab; idarubicin; ifosfamide; imatinib mesylate; interferon alpha-2a; Interferon alpha-2b; irinotecan; isepipron; lapatinib; lenalidomide; letrozole; leucovorin; leuprolide acetate; levamisole; lomustine; meclorethamine, nitrogen mustard Megestrol acetate; melphalan, L-PAM; guanidine; mesit; methotrexate; methoxysarsin; mitomycin C; mitoxantrone; mitoxantrone; phenylpropionic acid Nallon; naribinib; nilotinib; nofetumomab; ofatumumab; opal interleukin; oxaliplatin; paclitaxel; palyfamine; Disodium phosphonate; panitumumab; pazopanib; pergase; pemillonase; pegfilgrastim; pemetrexed disodium; pentastatin; Alkane; Puleshafu; pucamycin, mithramycin; phenanthrene sodium; pralatrexate; procarbazine; quinacrine; labrase; raloxifene hydrochloride; Rituximab; romidetin; romitastine; saxstatin; saxstatin; sateplatin; sorafenib; streptozotocin; sunitinib maleate; tamoxifen; temozolomide ; temsirolimus; teniposide; testosterone; thioguanine; thiotepa; topotecan; toremifene; tocilizumab; trastuzumab; retinoic acid; uracil Mustard; valrubicin; vinblastine; vincristine; vinorelbine; vorinostat; and zoledronic acid.

It will be apparent to those skilled in the art that, where appropriate, the other therapeutic component or ingredients may be added as a salt, such as an alkali metal or amine salt or an acid, or a prodrug, or an ester such as a lower alkyl ester. Or in the form of a solvate such as a hydrate to optimize the activity and/or stability and/or physical properties of the therapeutic component, such as solubility. It is also clear that the therapeutic ingredients can be used in optically pure form, where appropriate.

The above combination may conveniently be used in the form of a pharmaceutical composition, and thus a pharmaceutical composition comprising the above combination and a pharmaceutically acceptable diluent or carrier represents a further aspect of the invention. These combinations are particularly useful for respiratory diseases and are suitable for inhalation or intranasal delivery.

The individual compounds of this combination may be administered sequentially or simultaneously in separate or combined pharmaceutical compositions. Preferably, each compound is administered simultaneously in the form of a combined pharmaceutical composition. Suitable dosages of known therapeutic agents are readily apparent to those skilled in the art.

Example

The following examples are provided to provide a person skilled in the art with a complete disclosure and description of how to make, prepare and evaluate the methods and compounds claimed herein, and are intended to be merely illustrative of the invention and not to limit the scope of the invention.

resolve resolution

The compounds of the present invention can be prepared according to conventional methods in the art and using suitable reagents, starting materials, and purification methods known to those skilled in the art.

The preparation of the structural compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.

Usually, in the preparation, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C). The reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.

Intermediate N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (Compound 3 )Synthesis

Compound 2 (1.05 g, 3.74 mmol) was dissolved in 10 mL of tetrahydrofuran, then compound 1 (1.03 g, 3.74 mmol), 4-dimethylaminopyridine (4-DMAP, 0.046 g, 0.374 mmol) and diisopropyl Ethylamine (1.3 mL, 7.49 mmol) was stirred at room temperature for 1 hour, then 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. LC-MS (APCI): m / z = 517 (M + 1) +.

Example 1 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxo-2,3) -dihydrogen -1H-imidazo[4,5-b]pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 8)

The specific synthesis steps are as follows:

Step 1. Synthesis of 5-bromo-1,3-dihydro-2Himidazo[4,5-b]pyrazin-2-one (Compound 5).

5-Bromopyrazine-2,3-diamine (0.75 g, 4 mmol) was added to 10 mL of tetrahydrofuran (THF) under nitrogen, and carbonyldiimidazole (CDI, 1.95 g, 12 mmol) was slowly added under ice-cooling, stirring 10 In minutes, the temperature was raised to reflux for overnight. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated to dryness. The solid was 0.7 g, and the yield was 82%. LC-MS (APCI): m / z = 216 (M + 1) +.

Step 2. Synthesis of 5-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (Compound 6).

5-Bromo-1,3-dihydro-2H imidazo[4,5-b]pyrazin-2-one (0.7 g, 3.27 mmol) and trimethylsilylacetylene (0.42 g, 4.25 mmol), Pd(PPh ₃ ) ₄ (173mg, 0.15mmol), CuI (49mg, 0.26mmol) and 1.2mL N,N-diisopropylethylamine (DIEA) were added to 5mL DMF, replaced three times with nitrogen, and heated to 90 °C , the reaction was 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. . LC-MS (APCI): m / z = 233 (M + 1) +.

Step 3. Synthesis of 5-ethynyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (Compound 7).

5-((Trimethylsilyl)ethynyl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (0.53 g, 2.3 mmol) was dissolved in 5 mL of tetrahydrofuran Tetrabutylammonium fluoride (TBAF, 1.2 g, 4.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 161 (M + 1) +.

Step 4. N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxo-2,3- Synthesis of dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 8).

5-Ethynyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (60 mg, 0.37 mmol) and Compound 3 (160 mg, 0.31 mmol), Pd (PPh ₃₎ ₄ (16 mg, 0.01 mmol), CuI (5 mg, 0.02 mmol) and 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc (EtOAc) was evaporated. LC-MS (APCI): m / z = 550 (M + 1) +; 1 H NMR (300MHz, DMSO-d 6) δ10.53 (s, 1H), 8.28-8.11 (m, 3H), 8.06 ( d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 3.56 (s, 2H), 2.55 (s, 3H), 2.37 (s, 8H), 2.16 (s, 3H).

Example 2 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-methyl-2-oxo) Generation-2,3- Dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 14).

The specific synthesis steps are as follows:

Step 1. Synthesis of 6-bromo-N ² -methylpyrazine-2,3-diamine (Compound 10).

3,5-dibromopyrazin-2-amine (Compound 9, 0.44 g, 1.75 mmol) was placed in a sealed tube, 10 mL of ethanol and 5 mL of 1 M aqueous methylamine solution were added, and the mixture was replaced with nitrogen once, and sealed in an oil bath. The reaction was heated to 100 ° C overnight. After the reaction was completed, the mixture was cooled to room temperature, and the residue was evaporated to dryness. 0.3 g, yield 85%. LC-MS (APCI): m / z = 204 (M + 1) +.

Step 2. Synthesis of 6-bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (Compound 11).

6-Bromo-N ² -methylpyrazine-2,3-diamine (0.29 g, 1.44 mmol) was added to 5 mL of tetrahydrofuran under nitrogen, and carbonyl diimidazole (CDI, 0.7 g, 4.32) was slowly added in an ice bath. Methyl), stirred for 10 minutes, warmed to reflux overnight. After the reaction was completed, it was cooled to room temperature, and then transferred to an ice-bath, and the mixture was evaporated to EtOAc (EtOAc). The solid was 0.26 g, and the yield was 80%. LC-MS (APCI): m / z = 230 (M + 1) +.

Step 3. 1-Methyl-6-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (Compound 12) Synthesis.

6-Bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (0.26 g, 1.14 mmol) and trimethylsilylacetylene (0.15) g, 1.48 mmol), Pd(PPh ₃ ) ₄ (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF and replaced with nitrogen three times. The reaction was carried out for 3 hours at 90 °C. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. . LC-MS (APCI): m / z = 247 (M + 1) +.

Step 4. Synthesis of 6-ethynyl-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (Compound 13).

1-Methyl-6-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (210 mg, 0.85 mmol) Dissolved in 5 mL of tetrahydrofuran, tetrabutylammonium fluoride (TBAF, 0.44 g, 1.7 mmol) was added and stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 175 (M + 1) +.

Step 5. N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-methyl-2-oxo) Synthesis of -2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 14).

6-ethynyl-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (65 mg, 0.37 mmol) and compound 3 (160 mg, 0.31 mmol) , Pd(PPh ₃ ) ₄ (16 mg, 0.01 mmol), CuI (5 mg, 0.02 mmol) and 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C. 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated. LC-MS (APCI): m / z = 564 (M + 1) +; 1 H NMR (300MHz, DMSO-d 6) δ10.56 (s, 1H), 8.22 (s, 3H), 8.13-8.03 ( m, 1H), 7.95 (dd, J = 8.0, 2.0 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 3.59 (s, 2H), 3.31 (s, 3H), 2.67 - 2.58 (m, 4H), 2.57 (s, 3H), 2.48 - 2.37 (m, 4H), 2.33 (s, 3H).

Example 3 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-methyl-2-oxo) Generation-2,3- Dihydro-1H-imidazo[4,5-b]pyridin-6-yl)ethynyl)-4-methylbenzamide (Compound 14)

The specific synthesis steps are as follows:

Step 1. Synthesis of benzyl (2-amino-5-bromopyridin-3-yl)carbamate (Compound 16).

5-Bromopyridine-2,3-diamine (0.8 g, 4.25 mmol) and pyridine (0.67 g, 8.5 mmol) were dissolved in 10 mL of tetrahydrofuran, and benzyl chloroformate (0.87 g, 5.1 mmol) was slowly added dropwise in an ice bath. After the completion of the dropwise addition, the ice bath was removed, and the mixture was reacted at room temperature for 3 hours, and the reaction was confirmed to be complete by TLC. 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. LC-MS (APCI): m / z = 323 (M + 1) +.

Step 2. 5-Bromo -N ³ - Synthesis of Methyl-2,3-diamine (Compound 17).

Lithium aluminum hydride (0.24 g, 6.2 mmol) was added to 10 mL of tetrahydrofuran, and the mixture was cooled to -5 ° C, and benzyl (2-amino-5-bromopyridin-3-yl)carbamate was added dropwise. A solution of 1.1 g, 3.1 mmol) in 5 mL of tetrahydrofuran. After the completion of the dropwise addition, stirring was continued for 30 minutes, the ice bath was removed, and the reaction was carried out for 2 hours at room temperature. The reaction was completely detected by TLC. The reaction was quenched by slowly dropping 0.3 mL of water in an ice bath. Then, 0.6 mL of 15% sodium hydroxide solution and 2 mL of water were added in sequence, and the mixture was stirred at room temperature. After stirring for 15 minutes, the white precipitate was filtered off. Dry and column chromatography gave 0.3 g of pale yellow solid, yield 43%. LC-MS (APCI): m / z = 203 (M + 1) +.

Step 3. Synthesis of 6-bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 18).

5-Bromo-N ³ -methylpyridine-2,3-diamine (0.29 g, 1.44 mmol) was added to 5 mL of tetrahydrofuran under nitrogen, and carbonyldiimidazole (0.7 g, 4.32 mmol) was slowly added to the ice bath. Stir for 10 minutes and warm to reflux overnight. After the reaction was completed, it was cooled to room temperature, and then transferred to an ice-bath, and the mixture was evaporated to EtOAc (EtOAc). The solid was 0.26 g, and the yield was 80%. LC-MS (APCI): m / z = 229 (M + 1) +.

Step 4. 1-Methyl-6-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 19) synthesis.

6-Bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.26 g, 1.14 mmol) and trimethylsilylacetylene (0.15 g) , 1.48 mmol), Pd(PPh ₃ ) ₄ (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF and replaced with nitrogen three times. The reaction was carried out for 3 hours at 90 °C. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. . LC-MS (APCI): m / z = 246 (M + 1) +.

Step 5. Synthesis of 6-ethynyl-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (Compound 20).

Dissolving 1-methyl-6-((trimethylsilyl)ethynyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (210 mg, 0.85 mmol) To 5 mL of tetrahydrofuran, tetrabutylammonium fluoride (0.44 g, 1.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 174 (M + 1) +.

Step 6. N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((1-methyl-2-oxo) Synthesis of -2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)ethynyl)-4-methylbenzamide (Compound 21).

6-ethynyl-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (64 mg, 0.37 mmol) and compound 3 (160 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (16 mg, 0.01 mmol), CuI (5 mg, 0.02 mmol) and 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C, reaction 3 hour. After the reaction was completed, the mixture was cooled to room temperature. EtOAc (EtOAc) was evaporated. LC-MS (APCI): m / z = 563 (M + 1) +. ^{1 H NMR (400MHz, DMSO-} d 6) δ11.85 (s, 1H), 10.61 (s, 1H), 8.24 (d, J = 2.2Hz, 1H), 8.17 (dd, J = 4.7,1.9Hz, 2H), 8.13–8.08 (m, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.74–7.65 (m, 2H), 7.51 (d, J=8.1 Hz, 1H), 3.62 (s) , 2H), 3.33 (s, 6H), 2.87 (d, J = 12.5 Hz, 5H), 2.56 (s, 6H).

Example 4 Preparation of 4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxygen) Generation-2,3- Dihydrooxazolo[4,5-b]pyridin-6-yl)ethynyl)benzamide N-(4-((4-methylpiperazin-1-yl)methyl)-3-(three Fluoromethyl)benzene 3-((2-oxo-2,3-dihydrooxazolo[4,5-b]pyridin-6-yl)ethynyl)-4-methylbenzamide (Compound 26)

The specific synthesis steps are as follows:

Step 1. Synthesis of 6-bromooxazolo[4,5-b]pyridine-2(3H)-one (Compound 23).

The oxazolo[4,5-b]pyridine-2(3H)-one (0.39 g, 2.87 mmol) was dissolved in 5 mL of DMF, and liquid bromine (0.91 g, 5.7 mmol) was slowly added dropwise in an ice bath. The ice bath was removed and allowed to react at room temperature for 2 hours. The reaction was complete by TLC. The reaction was quenched by the addition of 20 mL of EtOAc EtOAc. LC-MS (APCI): m / z = 216 (M + 1) +.

Step 2. Synthesis of 6-((trimethylsilyl)ethynyl)oxazolo[4,5-b]pyridine-2(3H)-one (Compound 24).

6-Bromooxazolo[4,5-b]pyridine-2(3H)-one (0.25 g, 1.14 mmol) and trimethylsilylacetylene (0.15 g, 1.48 mmol), Pd(PPh ₃ ) ₄ (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, and then added with 20 mL of water, and the mixture was washed with ethyl acetate. . LC-MS (APCI): m / z = 233 (M + 1) +.

Step 3. Synthesis of the compound 6-ethynyloxazolo[4,5-b]pyridine-2(3H)-one (Compound 25).

6-((Trimethylsilyl)ethynyl)oxazolo[4,5-b]pyridine-2(3H)-one (197 mg, 0.85 mmol) was dissolved in 5 mL of tetrahydrofuran, and tetrabutylammonium fluoride was added. (0.44 g, 1.7 mmol) was stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 161 (M + 1) +.

Step 4. N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxo-2,3- Synthesis of dihydrooxazo[4,5-b]pyridin-6-yl)ethynyl)-4-methylbenzamide (Compound 26).

6-ethynyloxazolo[4,5-b]pyridine-2(3H)-one (60 mg, 0.37 mmol) and compound 3 (160 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (16 mg, 0.01 mmol CuI (5 mg, 0.02 mmol) and 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc was evaporated, evaporated, evaporated, evaporated. LC-MS (APCI): m / z = 550 (M + 1) +; 1 H NMR (400MHz, DMSO-d 6) δ10.57 (s, 1H), 8.22 (dd, J = 4.1,2.0Hz, 2H), 8.15 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.8, 2.2 Hz, 1H), 7.91 (dd, J = 7.9, 1.9 Hz, 1H), 7.73 - 7.66 (m, 2H) ), 7.50 (d, J = 8.1 Hz, 1H), 3.62 (s, 2H), 2.78 (s, 6H), 2.55 (s, 5H), 2.47 (s, 3H).

Example 5 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxo-2,3) -dihydrothiazide Zizo[4,5-b]pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 31)

The specific synthesis steps are as follows:

Step 1. Synthesis of 3-amino-6-bromopyrazine-2-thiol (Compound 27).

3,5-Dibromopyrazine-2-amine (0.6 g, 2.37 mmol) was dissolved in 10 mL of methanol, and sodium thiosulfate (0.38 g, 4.75 mmol) of 70% purity was added, and the reaction was refluxed overnight under nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was adjusted to pH = 7 with 1N hydrochloric acid, and a large solid precipitated. Filtration, the filter cake was washed with 5 mL of cold methanol and dried to give &lt The yield was 62%. LC-MS (APCI): m / z = 207 (M + 1) +.

Step 2. Synthesis of 6-bromothiazolo[4,5-b]pyrazine-2(3H)-one (Compound 28).

3-Amino-6-bromopyrazine-2-thiol (0.29 g, 1.44 mmol) was added to 5 mL of tetrahydrofuran under nitrogen, and carbonyldiimidazole (0.7 g, 4.32 mmol) was slowly added and stirred for 10 min. The temperature was raised to reflux reaction overnight. After the reaction was completed, it was cooled to room temperature, and then transferred to an ice-bath, and the mixture was evaporated to EtOAc (EtOAc). The solid was 0.26 g, and the yield was 80%. LC-MS (APCI): m / z = 233 (M + 1) +.

Step 3. Synthesis of 6-((trimethylsilyl)ethynyl)thiazolo[4,5-b]pyrazine-2(3H)-one (Compound 29).

6-Bromothiazolo[4,5-b]pyrazine-2(3H)-one (0.26 g, 1.14 mmol) and trimethylsilylacetylene (0.15 g, 1.48 mmol), Pd(PPh ₃ ) ₄ (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. . LC-MS (APCI): m / z = 250 (M + 1) +.

Step 4. Synthesis of 6-ethynylthiazolo[4,5-b]pyrazine-2(3H)-one (Compound 30).

6-((Trimethylsilyl)ethynyl)thiazolo[4,5-b]pyrazine-2(3H)-one (210 mg, 0.85 mmol) was dissolved in 5 mL of tetrahydrofuran, and tetrabutylammonium fluoride was added. (0.44 g, 1.7 mmol) was stirred at room temperature for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 178 (M + 1) +.

Step 5. N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxo-2,3- Synthesis of dihydrothiazolo[4,5-b]pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 31).

6-ethynylthiazolo[4,5-b]pyrazine-2(3H)-one (65 mg, 0.37 mmol) and compound 3 (160 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (16 mg, 0.01 mmol CuI (5 mg, 0.02 mmol) and 0.12 mL of N,N-diisopropylethylamine were added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. EtOAc (EtOAc) was evaporated. LC-MS (APCI): m / z = 567 (M + 1) +; 1 H NMR (500MHz, DMSO-d 6) δ10.58 (s, 1H), 8.31 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.11 (dd, J = 8.6, 2.2 Hz, 1H), 7.93 (dd, J = 8.0, 2.0 Hz, 1H), 7.71 ( d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 3.66 (s, 2H), 2.72 (s, 3H), 2.55 (s, 3H), 2.48 - 2.51 (s, 8H) ).

Example 6 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2,3-dihydro-1H) -pyrrole And [2,3-b]pyridin-5-yl)ethynyl)-4-methylbenzamide (Compound 34)

The specific synthesis steps are as follows:

Step 1. Synthesis of 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (Compound 33).

7-Azaporphyrin (0.37 g, 3.1 mmol) was dissolved in 5 mL of DMF, and liquid bromine (1.0 g, 6.2 mmol) was slowly added dropwise thereto under ice-cooling, and the ice bath was removed after the dropwise addition, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched with 20 mL of EtOAc EtOAc. LC-MS (APCI): m / z = 200 (M + 1) +.

The following procedure is identical to Steps 3-5 of Example 5, except that 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine is substituted for 6-bromothiazole [4,5 -b] pyrazine-2(3H)-one, the product compound 34 was finally obtained as a pale yellow solid, a total of 107 mg, yield 65%. LC-MS (APCI): m / z = 534 (M + 1) +; 1 H NMR (500MHz, DMSO-d 6) δ10.54 (s, 1H), 8.22 (d, J = 2.2Hz, 1H) , 8.13 - 8.03 (m, 2H), 7.95 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 8.0, 2.0 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.46 ( d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 6.98 (s, 1H), 3.62 (s, 2H), 3.54 (t, J = 8.5 Hz, 2H), 3.33 (s, 8H), 3.01 (t, J = 8.5 Hz, 2H), 2.84 (s, 3H), 2.58 (s, 3H).

Example 7 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((thieno[2,3-b] Pyridine -5-yl)ethynyl)-4-methylbenzamide (Compound 40)

The specific synthesis steps are as follows:

Step 1. Synthesis of 5-bromo-3-iodopyridin-2-ol (Compound 36).

5-Bromopyridin-2-ol (1.2 g, 6.9 mmol) and NIS (1.55 g, 6.9 mmol) were dissolved in 20 mL of toluene, reacted in an oil bath at 90 ° C for 30 minutes, cooled to room temperature, filtered, and filtered cake with methanol After washing and drying, 1.8 g of a pale pink solid was obtained in a yield of 86%. LC-MS (APCI): m / z = 301 (M + 1) +.

Step 2. Synthesis of 5-bromo-3-((trimethylsilyl)ethynyl)pyridine-2-ol (Compound 37).

5-Bromo-3-iodopyridin-2-ol (1.8 g, 6 mmol), trimethylsilylacetylene (1.1 g, 9 mmol), palladium acetate (14 mg, 0.06 mmol), cuprous iodide (23 mg, 0.12) Methyl), triphenylphosphine (32 mg, 0.12 mmol) and 2 mL of N,N-diisopropylethylamine were added to 10 mL of dry toluene, replaced with nitrogen three times, warmed to 90 ° C, and reacted for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. . LC-MS (APCI): m / z = 271 (M + 1) +.

Step 3. Synthesis of 5-bromo-2-(trimethylsilyl)thieno[2,3-b]pyridine (Compound 38).

5-Bromo-3-((trimethylsilyl)ethynyl)pyridine-2-ol (1.3 g, 4.8 mmol) was dissolved in 20 mL of toluene, and the Lawson reagent (LR, 0.97 g, 2.4 mmol) was added and the temperature was raised to The reaction was carried out at 120 ° C for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, The rate is 80%. LC-MS (APCI): m / z = 287 (M + 1) +.

Step 4. Synthesis of 5-bromothieno[2,3-b]pyridine (Compound 39).

5-Bromo-2-(trimethylsilyl)thieno[2,3-b]pyridine (1.06 g, 3.7 mmol) was dissolved in 10 mL of methanol and potassium carbonate (1.02 g, 7.4 mmol) was added at room temperature Stir for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 215 (M + 1) +.

The following procedure is identical to Steps 3-5 of Example 5, except that 5-bromothieno[2,3-b]pyridine is substituted for 6-bromothiazolo[4,5-b]pyrazine-2 (3H). The ketone finally gave the product compound 40 as a pale yellow solid (yield: 119 mg, yield: 65%). LC-MS (APCI): m / z = 549 (M + 1) +; 1 H NMR (400MHz, DMSO-d 6) δ10.60 (s, 1H), 8.78 (d, J = 2.0Hz, 1H) , 8.55 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 3.1 Hz, 2H), 8.10 (d, J = 8.6 Hz, 1H), 7.98 (dd, J = 19.1, 7.1 Hz, 2H) , 7.71 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 14.1, 7.0 Hz, 2H), 3.62 (s, 2H), 2.76 (s, 5H), 2.60 (s, 3H), 2.54 ( s, 3H), 2.46 (s, 3H).

Example 8 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(pyrrolo[1,2-a] Pyrimidine 3--3-ethynyl)-4-methylbenzamide (Compound 46)

The specific synthesis steps are as follows:

Step 1. Synthesis of 5-bromo-2-(prop-1-yn-1-yl)pyrimidine (Compound 42).

Add 2,5-dibromopyrimidine (2.07 g, 8.7 mmol), bistriphenylphosphine palladium chloride (1.22 g, 17.4 mmol) and tributylpropynestannane (3.73 g, 11.3 mmol) to 20 mL In the anhydrous dioxane, the nitrogen was replaced three times, and the temperature was raised to 90 ° C to react overnight. After the reaction was completed, the mixture was cooled to room temperature, then 40 mL of water was added, and ethyl acetate was evaporated, and the organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate and evaporated. LC-MS (APCI): m / z = 198 (M + 1) +.

Step 2. Synthesis of 3-bromopyrrolo[1,2-a]pyrimidine (Compound 43).

Add 5-bromo-2-(prop-1-yn-1-yl)pyrimidine (1.2 g, 6.1 mmol), cuprous chloride (120 mg, 1.21 mmol) and triethylamine (1.85 g, 18.3 mmol) In 20 mL of N,N-dimethylacetamide, nitrogen was replaced three times, and the temperature was raised to 140 ° C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and then evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 198 (M + 1) +.

Step 3. Synthesis of 3-((trimethylsilyl)ethynyl)pyrrolo[1,2-a]pyrimidine (Compound 44).

3-Bromopyrrolo[1,2-a]pyrimidine (0.23 g, 1.16 mmol) and trimethylsilylacetylene (0.15 g, 1.48 mmol), Pd(PPh ₃ ) ₄ (66 mg, 0.06 mmol), CuI (16 mg, 0.08 mmol) and 0.42 mL of N,N-diisopropylethylamine were added to 20 mL of DMF, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, 20 mL of water was added, and the mixture was washed with ethyl acetate. . LC-MS (APCI): m / z = 251 (M + 1) +.

Step 4. Synthesis of 3-ethynylpyrrolo[1,2-a]pyrimidine (Compound 45).

3-((Trimethylsilyl)ethynyl)pyrrolo[1,2-a]pyrimidine (182 mg, 0.85 mmol) was dissolved in 5 mL of tetrahydrofuran, and tetrabutylammonium fluoride (0.44 g, 1.7 mmol) was added. Stir at room temperature for 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. LC-MS (APCI): m / z = 143 (M + 1) +.

Step 5. N-(4-((4-Methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(pyrrolo[1,2-a]pyrimidine Synthesis of -3-ylethynyl)-4-methylbenzamide (Compound 46).

3-ethynylpyrrolo[1,2-a]pyrimidine (53 mg, 0.37 mmol) and Compound 3 (160 mg, 0.31 mmol), Pd(PPh ₃ ) ₄ (16 mg, 0.01 mmol), CuI (5 mg, 0.02 mmol) And 0.12 mL of N,N-diisopropylethylamine was added to 3 mL of DMF, replaced with nitrogen three times, and heated to 90 ° C for 3 hours. After the completion of the reaction, the mixture was cooled to room temperature, and then evaporated to ethyl ether. LC-MS (APCI): m / z = 532 (M + 1) +. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.57 (s, 1H), 9.12 (d, J = 2.1Hz, 1H), 8.22 (t, J = 2.7Hz, 2H), 8.17 (s, 1H) , 8.08 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.05 (t, J = 3.5 Hz, 1H), 6.60 (d, J = 4.0 Hz, 1H), 3.59 (s, 2H), 2.57 (s, 3H), 2.48 - 2.51 (s, 8H), 2.33 (s, 3H).

Example 9 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(isothiazolo[4,3-b Pyridine Pyridin-6-ylethynyl)-4-methylbenzamide (Compound 52)

The specific synthesis steps are as follows:

Step 1. Synthesis of 3-amino-5-bromopyridine-2-carbonitrile (Compound 48).

5-Bromo-2-cyano-3-nitropyridine (4.6 g, 20.2 mmol) was dissolved in 50 mL of glacial acetic acid, cooled to 15 ° C in an ice bath, and reduced iron powder (5.65 g, 101 mmol) was added in portions. The temperature of the reaction solution did not exceed 35 ° C. After the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction was completely monitored by TLC, filtered, and the filter cake was washed with 10 mL of toluene and then transferred to dichloromethane-methanol (100 mL - 10 mL) and stirred at room temperature 2 The filtrate was washed with 30 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated. LC-MS (APCI): m / z = 199 (M + 1) +.

Step 2. Synthesis of 3-amino-5-bromopyridine-2-thiocarboxamide (Compound 49).

3-Amino-5-bromopyridine-2-carbonitrile (2.4 g, 12.1 mmol) was dissolved in 30 mL of ethanol, and the Lawson reagent (2.5 g, 6.1 mmol) was added, and the mixture was warmed to reflux overnight. TLC (Thin-layer chromatography) was carried out, and the solvent was evaporated. The solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The solid was 2.4 g, and the yield was 85%. LC-MS (APCI): m / z = 233 (M + 1) +.

Step 3. Synthesis of 6-bromoisothiazolo[4,3-b]pyridin-3-amine (Compound 50).

3-Amino-5-bromopyridine-2-thioformamide (2.37 g, 10.2 mmol) was dissolved in 10 mL of methanol, and 3 mL of 30% hydrogen peroxide was slowly added dropwise in an ice bath. After the addition was completed, the mixture was transferred to room temperature. The reaction was overnight. The reaction was completely monitored by TLC, filtered, and the filter cake was washed with cold methanol and dried to give a pale yellow solid 1.88 g. LC-MS (APCI): m / z = 231 (M + 1) +.

Step 4. Synthesis of 6-bromoisothiazolo[4,3-b]pyridine (Compound 51).

6-Bromoisothiazolo[4,3-b]pyridin-3-amine (1.88g, 8.2mmol) was dissolved in 50mL of 85% phosphoric acid and 15mL concentrated nitric acid, cooled to -5 ° C in ice bath, slowly added 6mL An aqueous solution of sodium nitrite (0.6 g, 8.7 mmol) was added and the mixture was stirred at -5 ° C for 30 minutes. The reaction solution obtained above was added portionwise to 25 mL of 30% hypophosphorous acid, and after the completion of the addition, the reaction was carried out at room temperature for 1 hour, and the reaction solution was adjusted to pH = 13 with 20% aqueous sodium hydroxide solution, and extracted with methyl t-butyl ether. The mixture was washed with brine, dried over anhydrous sodium sulfate and evaporated. LC-MS (APCI): m / z = 216 (M + 1) +.

The following procedure is the same as Steps 3-5 of Example 8, except that 6-bromoisothiazolo[4,3-b]pyridine is substituted for 3-bromopyrrolo[1,2-a]pyrimidine to give the product compound. 52 was a pale yellow solid, a total of 105 mg, yield 62%. LC-MS (APCI): m / z = 550 (M + 1) +; 1 HNMR (400MHz, DMSO-d 6) δ10.57 (s, 1H), 10.05 (s, 1H), 8.96 (d, J =2.0 Hz, 1H), 8.58 - 8.51 (m, 1H), 8.23 (dd, J = 13.8, 2.2 Hz, 2H), 8.07 (dd, J = 8.5, 2.1 Hz, 1H), 7.97 (dd, J = 8.0, 2.0 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 3.57 (s, 2H), 2.62 (s, 3H), 2.38 (s, 8H), 2.18 (s, 3H).

Example 10 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((isothiazolo[5,4- b] Pyridin-5-yl)ethynyl)-4-methylbenzamide (Compound 58)

The specific synthesis steps are as follows:

Step 1. Synthesis of 2,5-dibromo-3-(dibromomethyl)pyridine (Compound 54).

2,5-Dibromo-3-methylpyridine (3.0 g, 12 mmol), benzoyl peroxide (BPO, 0.31 g, 1.3 mmol) and N-bromosuccinimide (NBS, 4.7 g, 26.4 mmol) was dissolved in 30 mL of carbon tetrachloride and allowed to warm to reflux overnight. The reaction was completely monitored by TLC, cooled to room temperature, filtered, and the filtrate was washed with 20 mL of water, dried over anhydrous sodium sulfate, and evaporated. LC-MS (APCI): m / z = 409 (M + 1) +.

Step 2. Synthesis of 2,5-dibromopyridine-3-carbaldehyde (Compound 55).

2,5-Dibromo-3-(dibromomethyl)pyridine (4.2 g, 10.3 mmol) was dissolved in 40 mL of ethanol and 10 mL of water, and silver nitrate (8.8 g, 51.5 mmol) was added, and the mixture was warmed to reflux overnight. The reaction was completed by TLC. EtOAc was evaporated to dryness. The oil was 2.5 g in a yield of 92%. LC-MS (APCI): m / z = 266 (M + 1) +.

Step 3. Synthesis of 5-bromo-2-thiocyanato-3-carbaldehyde (Compound 56).

2,5-Dibromopyridine-3-carbaldehyde (2.05 g, 7.7 mmol) was dissolved in 15 mL of formic acid, and potassium thiocyanate (0.78 g, 8.0 mmol) was added portionwise, and the mixture was warmed to room temperature overnight. The reaction was completed by TLC, EtOAc (EtOAc)EtOAc. LC-MS (APCI): m / z = 244 (M + 1) +.

Step 4. Synthesis of 5-bromoisothiazolo[5,4-b]pyridine (Compound 57).

5-Bromo-2-thiocyanato-3-carbaldehyde (0.93 g, 3.8 mmol) was dissolved in 10 mL of a 30% aqueous ammonia solution and stirred at room temperature overnight. The reaction was completed by TLC, EtOAc (EtOAc)EtOAc. LC-MS (APCI): m / z = 216 (M + 1) +.

The following procedure is the same as Step 3-5 of Example 8, except that 5-bromoisothiazolo[5,4-b]pyridine is substituted for 3-bromopyrrolo[1,2-a]pyrimidine to give the product compound. 58 is a pale yellow solid, a total of 110 mg, yield 65%. LC-MS (APCI): m / z = 550 (M + 1) +; 1 HNMR (500MHz, DMSO-d 6) δ10.57 (s, 1H), 9.26 (s, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 8.22 (dd, J = 9.8, 2.1 Hz, 2H), 8.10 - 8.04 (m, 1H), 7.97 (dd, J = 8.1, 1.9 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 3.57 (s, 2H), 2.61 (s, 3H), 2.38 (s, 8H) , 2.17 (s, 3H).

Example 11 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((2-oxo-1,2) -dihydrogen Thiazolo[5,4-b]pyridin-6-yl)ethynyl)-4-methylbenzamide (Compound 62)

The specific synthesis steps are as follows:

Step 1. Synthesis of 3-amino-5-bromopyridine-2-thiol (Compound 60).

2,5-Dibromopyridin-3-amine (0.61 g, 2.4 mmol) was dissolved in 10 mL of ethylene glycol, and sodium thiosulfate (0.38 g, 4.75 mmol) of 70% purity was added, and the reaction was refluxed overnight under nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was adjusted to pH = 7 with 1N hydrochloric acid, and a large solid precipitated. Filtration, the filter cake was washed with 5 mL of cold methanol and dried to give &lt The yield was 60%. LC-MS (APCI): m / z = 206 (M + 1) +.

Step 2. Synthesis of 6-bromothiazolo[5,4-b]pyridine-2(1H)-one (Compound 61).

3-Amino-5-bromopyridine-2-thiol (0.3 g, 1.46 mmol) was added to 5 mL of tetrahydrofuran under nitrogen, and carbonyldiimidazole (0.71 g, 4.38 mmol) was slowly added and stirred for 10 min. The temperature was raised to reflux overnight. After the reaction was completed, it was cooled to room temperature, and then transferred to an ice-bath, and the mixture was evaporated to EtOAc (EtOAc). The solid was 0.26 g, and the yield was 77%. LC-MS (APCI): m / z = 232 (M + 1) +.

The following procedure is identical to Steps 3-5 of Example 8, except that 6-bromothiazolo[5,4-b]pyridine-2(1H)-one is substituted for 3-bromopyrrolo[1,2-a]. The pyrimidine finally gave the product compound 62 as a pale yellow solid, a total of 105 mg, yield 60%. LC-MS (APCI): m / z = 566 (M + 1) +; 1 HNMR (500MHz, DMSO-d6) δ10.53 (s, 1H), 8.38 (d, J = 1.8Hz, 1H), 8.20 (dd, J = 10.2, 2.1 Hz, 2H), 8.13 - 8.00 (m, 1H), 7.93 (dd, J = 8.0, 2.0 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.57 - 7.45 (m, 2H), 3.58 (s, 2H), 2.56 (s, 3H), 2.45 (m, 8H), 2.30 (s, 3H).

Example 12 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((thieno[2,3-b] Pyridine Pyrazin-5-yl)ethynyl)-4-methylbenzamide (Compound 68).

The specific synthesis steps are as follows:

Step 1. Synthesis of 5-bromo-3-iodopyrazin-2-ol (Compound 64).

5-Bromopyrazin-2-ol (1.36 g, 7.8 mmol) and NIS (1.8 g, 8.0 mmol) were dissolved in 20 mL of toluene, reacted in an oil bath at 90 ° C for 30 minutes, cooled to room temperature, filtered, filter cake It was washed with methanol and dried to give 1.87 g of pale pink solid. LC-MS (APCI): m / z = 302 (M + 1) +.

Step 2. Synthesis of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-ol (Compound 65).

5-Bromo-3-iodopyrazin-2-ol (1.87 g, 6.2 mmol), trimethylsilylacetylene (1.1 g, 9 mmol), palladium acetate (14 mg, 0.06 mmol), cuprous iodide (23 mg) , 0.12 mmol), triphenylphosphine (32 mg, 0.12 mmol) and 2 mL of N,N-diisopropylethylamine were added to 10 mL of dry toluene, replaced with nitrogen three times, and warmed to 90 ° C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, and the mixture was evaporated. . LC-MS (APCI): m / z = 272 (M + 1) +.

Step 3. Synthesis of 5-bromo-2-(trimethylsilyl)thieno[2,3-b]pyrazine (Compound 66).

5-Bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-ol (1.32 g, 4.8 mmol) was dissolved in 20 mL of toluene, and Lawson's reagent (LR, 0.97 g, 2.4 mmol) was added and the temperature was raised. The reaction was carried out at 120 ° C for 1 hour. The reaction was cooled to room temperature, and the solvent was evaporated to dryness. EtOAc was evaporated, evaporated, evaporated. The rate is 81%. LC-MS (APCI): m / z = 288 (M + 1) +.

Step 4. Synthesis of 5-bromothieno[2,3-b]pyrazine (Compound 67).

Dissolve 5-bromo-2-(trimethylsilyl)thieno[2,3-b]pyrazine (1.14 g, 4 mmol) in 10 mL of methanol, add potassium carbonate (1.1 g, 8 mmol), stir at room temperature 1 hour. The solvent was evaporated, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated LC-MS (APCI): m / z = 216 (M + 1) +.

The following procedure is identical to Steps 3-5 of Example 5, except that 5-bromothieno[2,3-b]pyrazine is substituted for 6-bromothiazolo[4,5-b]pyrazine-2 (3H). The ketone finally gave the product compound 40 as a pale yellow solid, a total of 120 mg, yield 71%. LC-MS (APCI): m / z = 549 (M + 1) +; 1 H NMR (400MHz, DMSO-d 6) δ10.61 (s, 1H), 8.90 (s, 1H), 8.45 (d, J = 6.1 Hz, 1H), 8.31 (s, 1H), 8.23 (s, 1H), 8.10 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 18.5, 7.4 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 3.63 (s, 2H), 2.84 (s, 3H), 2.62 (s, 3H), 2.58 - 2.50 (s, 8H) ).

Example 13 Preparation of N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((thiazolo[4,5-b] Pyridine Pyridin-6-yl)ethynyl)-4-methylbenzamide (Compound 72).

The specific synthesis steps are as follows:

Step 1. Synthesis of 3-amino-5-bromopyridine-2-thiol (Compound 70).

2,5-Dibromopyridin-3-amine (2.2 g, 8.7 mmol) and sodium hydrosulfide (70%, 2.08 g, 26 mmol) were added to 20 mL of 2-pentanol, and the mixture was warmed to 90 ° C overnight. After the reaction was completed, it was cooled to room temperature, and then added with 30 mL of water, and the mixture was evaporated to ethyl acetate (20 mL*3). The yield was 72%. LC-MS (APCI): m / z = 206 (M + 1) +.

Step 2. Synthesis of 6-bromothiazolo[5,4-b]pyridine (Compound 71).

3-Amino-5-bromopyridine-2-thiol (1.27 g, 6.2 mmol) was added to 10 mL of triethyl orthoformate, and the mixture was heated to 120 ° C for 3 hours. After the reaction was completed, it was cooled to room temperature, and then added with 30 mL of water, and ethyl acetate (20 mL*3), and the organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate The yield was 60%. LC-MS (APCI): m / z = 216 (M + 1) +.

The following procedure is identical to Steps 3-5 of Example 5, except that 6-bromothiazolo[5,4-b]pyridine is substituted for 6-bromothiazolo[4,5-b]pyrazine-2 (3H). The ketone finally gave the product compound 72 as a pale yellow solid, a total of 130 mg, yield 76%. LC-MS (APCI): m / z = 550 (M + 1) +; 1 H NMR (400MHz, DMSO-d 6) δ10.56 (s, 1H), 9.65 (s, 1H), 8.90 (d, J = 1.9 Hz, 1H), 8.74 (d, J = 1.9 Hz, 1H), 8.22 (dd, J = 5.9, 2.0 Hz, 2H), 8.07 (dd, J = 8.6, 2.2 Hz, 1H), 7.96 ( Dd, J = 8.1, 1.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 3.57 (s, 2H), 2.60 (s, 3H), 2.40(s,8H), 2.20(s,3H).

Biological activity test

(1) Kinase inhibition

Reagents and consumables: ABL (ThermoFisher, Cat. No PV3585), ABL ^T315I (Thermo Fisher, Cat. No. PR7429B), ATP (Sigma, Cat. No. A7699-1G), DMSO (Sigma, Cat. No. D2650) , 96-well plates (Corning, Cat. No. 3365), 384-well plates (Greiner, Cat. No. 784076), buffer (Thermo Fisher, Cat. No. PR4876B).

Specific experimental methods:

Compound formulation: The test compound was dissolved in DMSO to make a 20 mM mother liquor. Compounds were diluted to 0.1 mM in DMSO prior to use and diluted 3 times in 3 fold increments. When dosing, dilute with buffer to 4 times the final concentration of the dilution.

Kinase detection method: After preparing the buffer, the enzyme is mixed with different concentrations of the compound prepared by pre-diluting, and left at room temperature for 30 minutes, and each concentration is double-replicated. The corresponding substrate and ATP were added and reacted at room temperature for 60 minutes (in which a negative positive control was set). After the reaction was completed, the antibody was added for detection. After incubation at room temperature for 60 minutes, Evnvision was detected and data was collected. Data analysis and mapping according to XLfit5 software. Results Example Inhibition of cell proliferation in vitro embodiment are summarized in the following Table 1, wherein A represents an IC ₅₀ <50nM, B represents 50nM≤IC ₅₀ ≤100nM, C represents 100nM≤IC ₅₀ ≤1000nM, D denotes an IC ₅₀ >1000nM.

Table 1 Comparison of Kinase Inhibition of Examples 1-10

实施例编号Example number	ABL IC₅₀ ABL IC ₅₀	ABL^T315IIC₅₀ ABL ^T315I IC ₅₀
实施例1Example 1	AA	AA
实施例2Example 2	AA	AA
实施例3Example 3	AA	AA
实施例4Example 4	AA	AA
实施例5Example 5	AA	AA
实施例6Example 6	AA	AA
实施例7Example 7	AA	AA
实施例8Example 8	AA	BB
实施例9Example 9	AA	AA
实施例10Example 10	AA	AA
实施例11Example 11	AA	AA
实施例12Example 12	AA	AA
实施例13Example 13	AA	AA

(2) Cytotoxicity experiment

The inhibitory effect of the compound of the example on the activity of Ba/F3, Ba/F3Bcr-Abl ^T315I cells was examined.

Consumables and reagents: RPMI-1640 medium (GIBCO, catalog number A10491-01), fetal bovine serum (GIBCO, catalog number 10099141), antibiotic (Penicillin-Streptomycin), IL-3 (PeproTech), puromycin; cell line : Ba/F3, Ba/F3Bcr-Abl T315I (purchased from American Standard Biological Collection Center, ATCC), live cell assay kit CellTiter-Glo4 (Promega, catalog number G7572), 96-well black-wall clear flat-bottom cell culture plate ( Corning, catalog number 3340).

Experimental methods: 1. Preparation of cell plates Ba/F3, Ba/F3Bcr-Abl T315I cells were seeded in 96-well plates, and 8 ng/ml IL-3 was added to Ba/F3 cells, and the cell plates were placed in a carbon dioxide incubator. Train overnight. 2. The test compound was dissolved in DMSO and subjected to a 3.16-fold gradient dilution, 9 compound concentrations, and a three-fold experiment was set. 3. Compound treatment The cells were transferred to a cell plate at a starting concentration of 10 [mu]M. The cell plates were incubated in a carbon dioxide incubator for 3 days. 4. Detection The CellTiter-Glo reagent was added to the cell plate and incubated for 30 minutes at room temperature to stabilize the luminescence signal. Readings were performed using a PerkinElmer Envision multi-label analyzer. Results Example Inhibition of cell proliferation in vitro in the embodiment 2 are summarized in the following table, wherein A represents a IC ₅₀ <100nM, B represents 100nM≤IC ₅₀ ≤500nM, C represents 500nM≤IC ₅₀ ≤1000nM, D denotes an IC ₅₀ >1000nM.

Table 2 Comparison of cytotoxic effects of Examples 1-10

实施例编号Example number	Ba/F3 IC₅₀ Ba/F3 IC ₅₀	Ba/F3Bcr-Abl^T315IIC₅₀ Ba/F3Bcr-Abl ^T315I IC ₅₀
实施例1Example 1	DD	BB
实施例2Example 2	DD	AA
实施例3Example 3	DD	AA
实施例4Example 4	DD	CC
实施例5Example 5	DD	--
实施例6Example 6	DD	AA
实施例7Example 7	DD	BB
实施例8Example 8	DD	BB
实施例9Example 9	DD	BB
实施例10Example 10	DD	BB
实施例11Example 11	DD	CC
实施例12Example 12	DD	BB
实施例13Example 13	DD	BB

The results of the experiments show that the compound of the present invention exhibits a relatively low inhibitory activity against Ba/F3 associated with drug side effects (IC _{50 is} greater than 1000 nM), and exhibits excellent inhibitory activity against cells of the Ba/F3Bcr-Abl T315I mutant (IC). ₅₀ <100 nM or 100 nM ≤ IC ₅₀ ≤ ₅₀₀ nM), therefore, the compound of the present invention can be used as a Bcr-Abl inhibitor for tumor patients suffering from resistance or resistance to tyrosine kinase inhibitor (TKI) treatment, such as chronic granulocytes. Chronic, blast, and accelerated patients with leukemia (CML) and Philadelphia chromosome-positive (Ph ⁺ ) chronic myeloid leukemia and acute lymphoblastic leukemia patients have good prospects.

(3) Metabolic stability evaluation

Microsomal experiments: human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).

Preparation of the stock solution: A powder of the example compound and the positive control was accurately weighed and dissolved to 5 mM with DMSO, respectively.

Preparation of phosphate buffer (100 mM, pH 7.4): Mix 150 mL of pre-formed 0.5 M potassium dihydrogen phosphate and 700 mL of 0.5 M potassium dihydrogen phosphate solution, and adjust the mixture with 0.5 M potassium dihydrogen phosphate solution. The pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.

A solution of NADPH regeneration system (containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride) was prepared and placed on wet ice before use.

Formulation stop solution: acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 μL of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 μL of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 μL of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 μL of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.

Incubation of the sample: The stock solution of the corresponding compound was diluted to 0.25 mM with an aqueous solution containing 70% acetonitrile as a working solution, and was used. 398 μL of human liver microsomes or rat liver microsome dilutions were added to 96-well incubation plates (N=2), and 2 μL of 0.25 mM working solution was added and mixed.

Determination of metabolic stability: 300 μL of pre-cooled stop solution was added to each well of a 96-well deep well plate and placed on ice as a stop plate. The 96-well incubation plate and the NADPH regeneration system were placed in a 37 ° C water bath, shaken at 100 rpm, and pre-incubated for 5 min. 80 μL of the incubation solution was taken from each well of the incubation plate, added to the stopper plate, and mixed, and 20 μL of the NADPH regeneration system solution was added as a sample of 0 min. Then, 80 μL of the NADPH regeneration system solution was added to each well of the incubation plate to start the reaction and start timing. The corresponding compound had a reaction concentration of 1 μM and a protein concentration of 0.5 mg/mL. 100 μL of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min. The plate was centrifuged at 5000 x g for 10 min at 4 °C. 100 in supernatant was taken into a 96-well plate pre-charged with 100 μL of distilled water, mixed, and sample analysis was performed by LC-MS/MS.

Data analysis: The peak area of the corresponding compound and the internal standard was detected by LC-MS/MS system, and the ratio of the peak area of the compound to the internal standard was calculated. The slope is measured by the natural logarithm of the percentage of the remaining amount of the compound versus time, and t _1/2 and CL _{int are} calculated according to the following formula, where V/M is equal to 1/protein concentration.

Experimental results:

The experimental results are shown in Table 3 below, and the compounds of the present invention have superior metabolic stability.

Table 3 Evaluation of liver particle metabolism of the compound of the example

(4) Pharmacokinetic experiments in rats

Eight male Sprague-Dawley rats, 7-8 weeks old, weighing about 210 g, were divided into 2 groups, 4 rats in each group, respectively, given an intravenous dose of 0.5 mg/kg and a single oral dose of 10 mg/kg (a). Control group: reference compound; (b) Test group: Example compounds, comparing their pharmacokinetic differences.

Rats were fed a standard diet and given water. Fasting began 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.

Rats were briefly anesthetized after inhalation of ether, and 300 μL of blood samples were collected from the eyelids in test tubes. There was 30 μL of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.

Immediately after the blood sample is collected, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood samples were centrifuged at 4 5,000 rpm for 5 minutes to separate plasma from red blood cells. Pipette 100 μL of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.

The compounds of the present invention were tested in the pharmacokinetic experiments of the above rats, and the compounds of the present invention were found to have excellent pharmacokinetic properties.

It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention, and the experimental methods in which the specific conditions are not indicated in the examples are generally in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Parts and percentages are parts by weight and percentage by weight unless otherwise stated.

The above is a further detailed description of the present invention in connection with the specific preferred embodiments, and the specific embodiments of the present invention are not limited to the description. It will be apparent to those skilled in the art that the present invention may be made without departing from the spirit and scope of the invention.

Claims

a compound of formula (I),

Wherein ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring; wherein the heteroaryl ring or heterocyclic ring contains 1-3 heteroatoms selected from N, O and S, and the ring It may be selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3- C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl Substituted with a substituent in a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylamino group or a C 1 -C 6 alkanoyl group;

K is selected from CH, NH or S;

M is selected from CH, C or N;

X 1 , X 2 , X 3 , X 4 and X 5 are independently N or CR 1 , and R 1 is independently H, hydroxy, halogen, silane, nitrile, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl , C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl;

L is selected from O, S, NR 2 , CR 2 R 2 , C(=O), C(=O)NR 2 , NR 2 C(=O), NR 2 C(=O)NR 2 , OC(= O) NR 2 , NR 2 C(=O)O, S(=O), S(=O) 2 , S(=O)NR 2 , S(=O) 2 NR 2 , NR 2 S(=O ), NR 2 S(=O) 2 , NR 2 S(=O)NR 2 , NR 2 S(=O) 2 NR 2 , OP(=O)R 2 , P(=O)OR 2 , where R 2 independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 olefin a group, a C 2-6 alkynyl group, a C 6-10 aryl group, a C 3-7 heterocycloalkyl group or a C 3-7 heterocycloalkenyl group;

Ring C is a 5-6 membered aromatic ring having 1 to 5 substituents or a 5-6 membered heteroaryl ring having 1 to 5 substituents, which may be selected from halogen, -R, -CN, - COOH, -OH, -SH, -OR, -C(=O)R, -C(=O)OR, -OC(=O)R, -S(=O)R, -S(=O) 2 R, -NR 2 , -NHC(=O)R, -NHC(=O)OR, -C(=O)NHR, -C(=O)ONHR, where R is independently H, C 1-6 alkane , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6- 10 aryl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl; two adjacent R and the carbon atom on ring C to which they are attached may together form an optionally substituted C 5-8 carbon a cyclo group, an optionally substituted 5 to 8 membered heterocyclic group, an optionally substituted C 6-14 aryl group or an optionally substituted 5 to 10 membered heteroaryl group;

Or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof.
The compound according to claim 1, wherein the ring of the ring A and the ring B has the following structure:

Wherein M is C or N, ring A is a 5-6 membered heteroaryl ring or a 5-6 membered heterocyclic ring; and R a is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino or C 1 -C 6 An alkanoyl group, and m is 0, 1, 2, 3 or 4; X 5 is as defined in claim 1.
The compound according to claim 1, wherein the ring of the ring A and the ring B has the following structure:

Wherein X 5 is N or CR 1 , and R 1 is independently H, hydroxy, halogen, silane, nitrile, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C 3 -7 heterocyclenyl; X 6 , X 7 and X 8 are independently C(R a ) 2 , CR a , NR a , N, O or S, and R a is selected from hydrogen, halogen, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, carboxy, oxo, C 3 -C 7 cycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 3 -C 7 heterocycloalkyl, C 3 -C 7 heterocycloalkenyl, C 1 -C 6 alkylthio, C 1 a -C 6 alkylamino group or a C 1 -C 6 alkanoyl group; where chemistry permits, the bond between X 6 , X 7 and X 8 may be selected from a single bond or a double bond;

Preferably, the ring comprising ring A and ring B is selected from the group consisting of:

Wherein X 5 , X 6 , X 7 and X 8 are as defined in claims 1-3;

Preferably, the ring comprising ring A and ring B is selected from the group consisting of:

Wherein X 5 and R a are as defined in claims 1-3.
The compound according to claims 2-3, wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently N or CR 1 , and R 1 is independently H, hydroxy, halogen, silane, nitrile, Nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl.
The compound according to claim 4, wherein X 1 , X 2 , X 3 and X 4 are CR 1 and X 5 is N or CR 1 , and R 1 is independently H, a hydroxyl group, a halogen, a silyl group, a nitrile group, Nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl.
A compound according to claims 2-3, wherein L is selected from the group consisting of O, S, NR 2 , CR 2 R 2 , C(=O), C(=O)NR 2 , NR 2 C(=O), NR 2 C(=O)NR 2 , OC(=O)NR 2 , NR 2 C(=O)O, S(=O), S(=O) 2 , S(=O)NR 2 , S(=O 2 NR 2 , NR 2 S(=O), NR 2 S(=O) 2 , NR 2 S(=O)NR 2 , NR 2 S(=O) 2 NR 2 , OP(=O)R 2 , P(=O)OR 2 , wherein R 2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3 -7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C 3-7 heterocycloalkenyl.
The compound according to claim 6, wherein L is selected from the group consisting of C(=O)NR 2 , NR 2 C(=O), NR 2 C(=O)NR 2 , OC(=O)NR 2 , NR 2 C ( =O)O, S(=O), S(=O) 2 , S(=O)NR 2 , S(=O) 2 NR 2 , NR 2 S(=O), NR 2 S(=O) 2 , NR 2 S(=O)NR 2 , NR 2 S(=O) 2 NR 2 , OP(=O)R 2 , P(=O)OR 2 , wherein R 2 is independently selected from H or C 1- 6 alkyl.
The compound according to Claims 2-3, wherein Ring C is a 5-6 membered aromatic ring having 1 to 5 substituents or a 5-6 membered heteroaryl ring having 1 to 5 substituents, and the substituent may be Selected from halogen, -R, -CN, -COOH, -OH, -SH, -OR, -C(=O)R, -C(=O)OR, -OC(=O)R, -S(= O) R, -S(=O) 2 R, -NR 2 , -NHC(=O)R, -C(=O)NHR, -NHC(=O)OR, -C(=O)ONHR, where R is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl a C 2-6 alkynyl group, a C 6-10 aryl group, a C 3-7 heterocycloalkyl group or a C 3-7 heterocycloalkenyl group, the carbon atoms of the two adjacent R and the ring C to which they are attached may be Together, an optionally substituted C 5-8 carbocyclic group, an optionally substituted 5 to 8 membered heterocyclic group, an optionally substituted C 6-14 aryl group or an optionally substituted 5 to 10 membered heteroaryl group are formed.
The compound according to claim 8, wherein Ring C is a benzene ring of 1 to 5 substituents, and the substituent may be selected from the group consisting of halogen, -R, -CN, -COOH, -OH, -SH, -OR, - C(=O)R, -C(=O)OR, -OC(=O)R, -S(=O)R, -S(=O)2R, -NR2, -NHC(=O)R, -NHC(=O)OR, -C(=O)NHR, -C(=O)ONHR, wherein R is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Oxyl, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 heterocycloalkyl or C a 3-7 heterocycloalkenyl group, two adjacent R and a carbon atom on the ring C to which they are attached may together form an optionally substituted C 5-8 carbocyclic group, an optionally substituted 5 to 8 membered heterocyclic group. An optionally substituted C 6-14 aryl group or an optionally substituted 5 to 10 membered heteroaryl group;

Preferably, ring C is:

Wherein R is as defined in claim 8 or 9, and L 1 is substituted or unsubstituted (CH 2 ) x , O(CH 2 ) x , NR(CH 2 ) x , S(CH 2 ) x , or (CH 2 ) x NRC(O)(CH 2 ) x , x is 1, 2 , 3 or 4;

Preferably, ring C is selected from:
A compound according to claim 1 which may be selected from the group consisting of:
A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof, and pharmaceutically acceptable Acceptable excipients.
The pharmaceutical composition of claim 11 further comprising an additional therapeutic agent.
A kit comprising:

a first container comprising a compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof;

Optionally, a second container containing other therapeutic agents; and

Optionally, a third container containing a pharmaceutically acceptable excipient for diluting or suspending the compound and/or other therapeutic agent.
A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form, prodrug or isotopic variation thereof, for use in the treatment of an anti-tumor or other The use of drugs for the disease.
The use of claim 14, wherein the disease is a proliferative disease caused by Bcr-Abl.
The use according to claim 15, wherein said proliferative disorder is selected from the group consisting of solid tumors, sarcomas, chronic myelogenous leukemias, chronic myeloid leukemia, gastrointestinal stromal tumors, acute myeloid leukemia, thyroid cancer, gastric cancer, rectal cancer. Multiple myeloma, neoplasia, and other proliferative or proliferative diseases.