CN117402142A

CN117402142A - (hetero) aryl amides for inhibiting protein kinase activity

Info

Publication number: CN117402142A
Application number: CN202311337298.0A
Authority: CN
Inventors: 王义汉; 赵九洋
Original assignee: Shenzhen Targetrx Inc
Current assignee: Shenzhen Targetrx Inc
Priority date: 2023-10-16
Filing date: 2023-10-16
Publication date: 2024-01-16

Abstract

Provided are (hetero) aryl amide compounds shown in formula (I), tautomers, stereoisomers, prodrugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof, pharmaceutical compositions containing the compounds or derivatives thereof, and preparation methods of the compounds. The compound can be used as an irreversible inhibitor of protein kinase and can be used for preparing various medicaments, including antitumor medicaments.

Description

(hetero) aryl amides for inhibiting protein kinase activity

Technical Field

The invention belongs to the field of medicines. In particular, the present invention relates to (hetero) aryl amides having an inhibitory effect on the tyrosine kinase activity of Abelson protein (Abl 1), abelson related protein (Abl 2) and related chimeric proteins, in particular Bcr-Abl1, pharmaceutical compositions comprising them, and methods for their preparation and use.

Background

Protein Tyrosine Kinases (PTKs) are a class of kinases belonging to the protease family that catalyze the transfer of gamma-phosphate from ATP to protein tyrosine residues, which in turn activate functional proteins by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues. Protein tyrosine kinase plays a very important role in the intracellular signaling pathway and regulates a series of physiological and biochemical processes such as cell growth, differentiation, death and the like. Abnormal expression of protein tyrosine kinases can lead to a disturbance in the regulation of cell proliferation, which in turn leads to the development of tumors. In addition, abnormal expression of protein tyrosine kinase is closely related to invasion and metastasis of tumor, generation of tumor neovascularization and chemotherapy resistance of tumor.

Tyrosine kinases expressed by Bcr-Abl fusion genes can cause changes in cell proliferation, adhesion and survival properties, resulting in the generation of multiple tumors. Inhibition of Bcr-Abl tyrosine kinase is effective in inhibiting tumor growth.

ABL-001 (also known as Asciminib, chemical name (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide, having the following formula) is an allosteric inhibitor of ABL1 kinase developed by the nowa pharmaceutical company, which is targeted to the myristoyl pocket of ABL1 for inactivation thereof, and the combination with an inhibitor of ATP-competitive BCR-ABL tyrosine kinase is effective in preventing the emergence of drug resistance for ATP inhibitor and/or allosteric inhibitor applications. The combination of ABL-001 with the second generation BCR-ABL inhibitor nilotinib has been shown to exert a radical effect on CML in a mouse model (Andrew a. Wyle et al (2017) Nature 543, 733-737). North is developing clinical treatment regimens for ABL-001 in combination with multiple ATP-competitive BCR-ABL inhibitors, including imatinib, nilotinib, and dasatinib.

Therefore, there is a need to further develop new Bcr-Abl inhibitors.

Summary of The Invention

The invention provides a novel (hetero) aryl amide compound, a composition containing the compound and application thereof, which have better Bcr-Abl kinase inhibition activity (especially for T315I mutation), lower side effect and/or better pharmacodynamics/pharmacokinetics performance, and can be used for treating diseases mediated by Bcr-Abl kinase.

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

in a first aspect of the present invention there is provided a (hetero) aryl amide compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein,

Y ₁ selected from CR _a Or N;

y is independently selected from CR _a Or N;

R ₁ selected from hydrogen, halogen, cyano, nitro, C _1-6 Alkyl or C _1-6 Haloalkyl, wherein said C _1-6 Alkyl or C _1-6 Haloalkyl is optionally substituted with R _1a Group substitution;

R ₂ selected from hydrogen, C _1-6 Alkyl or C _1-6 Haloalkyl, wherein said C _1-6 Alkyl or C _1-6 Haloalkyl is optionally substituted with R _2a Group substitution;

z is a bond, O, S (O) _0-2 Or NR (NR) _b ；

or-Z-R ₂ Together represent-SF ₅ ；

Ar is

Wherein X is ₁ 、X ₂ 、X ₃ 、X ₄ 、X ₁₁ 、X ₂₁ 、X ₃₁ And X ₄₁ Independently selected from CR or N, and X ₁ 、X ₂ 、X ₃ And X ₄ At least one of which is N, or X ₁₁ 、X ₂₁ 、X ₃₁ And X ₄₁ At least one of which is N;

wherein each P ₁ And Q ₁ Independently selected from O, S, NR _b Or C (R) ₂ Each P ₂ And Q ₂ Independently selected from CR or N;

or Ar is

Wherein X is ₅ Selected from O, S or NR _b ，X ₆ 、X ₇ 、X ₈ 、X ₅₁ 、X ₆₁ 、X ₇₁ And X ₈₁ Independently selected from CR or N;

and when X ₅ When O or S, X ₆ 、X ₇ And X ₈ One of which is a C atom attached to the parent nucleus; when X is ₅ Is NR (NR) _b When X is ₆ 、X ₇ And X ₈ Is a C atom attached to the parent core and at least one of which is N;

Het is

Wherein X is ₉ Selected from O, S, NR _b Or C (R) ₂ ；

m is 0, 1 or 2;

n is 0, 1, 2, 3, 4, 5 or 6;

R _a independently selected from hydrogen, halogen, cyano, nitro, hydroxy, -NH ₂ 、-NHC _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl or C _1-6 An alkoxy group;

R _b independently selected from hydrogen, C _1-6 Alkyl or C _1-6 A haloalkyl group;

R _1a 、R _2a and R is independently selected from hydrogen, halogen, hydroxy, -NH ₂ 、-NHC _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-to 7-membered heterocycloalkyl, C _6-10 Aryl or 5 to 10 membered heteroaryl;

or two R groups on the same atom or on adjacent atoms may together form C _3-7 Cycloalkyl, 3-to 7-membered heterocycloalkyl, C _6-10 Aryl or 5 to 10 membered heteroaryl.

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

In another aspect, the invention provides kits comprising a compound of the invention, and other therapeutic agents, together with a pharmaceutically acceptable carrier, adjuvant or vehicle.

In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of a Bcr-Abl caused disease.

In another aspect, the invention provides for the treatment and/or prevention of Bcr-Abl-induced diseases in a subject comprising administering to said subject a compound of the invention or a composition of the invention.

In another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of Bcr-Abl caused diseases.

In particular embodiments, the disease may be selected from: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases.

In specific embodiments, the Bcr-Abl-caused disease is chronic granulocytic leukemia, gastrointestinal stromal tumor, acute granulocytic leukemia, thyroid cancer, metastatic invasive cancer, or a combination thereof.

In another aspect, the compounds of the invention are useful for the treatment and/or prevention of diseases or disorders associated with aberrant activated kinase activity of wild-type Abl, including non-malignant diseases or disorders such as CNS diseases, in particular neurodegenerative diseases (e.g. alzheimer's disease, parkinson's disease), motor neuron diseases (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, prion diseases.

In particular embodiments, the compounds are administered orally, subcutaneously, intravenously or intramuscularly. In particular embodiments, the compound is administered chronically.

Other objects and advantages of the present invention will be apparent to those skilled in the art from the detailed description, examples, and claims that follow.

Definition of the definition

Chemical definition

The definition of specific functional groups and chemical terms is described in more detail below.

When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C _1-6 Alkyl "includes C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C _1-6 、C _1-5 、C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-5 、C _2-4 、C _2-3 、C _3-6 、C _3-5 、C _3-4 、C _4-6 、C _4-5 And C _5-6 An alkyl group.

“C _1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as" lower alkyl ". In some embodiments, C _1-4 Alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C) ₁ ) Ethyl (C) ₂ ) N-propyl (C) ₃ ) Isopropyl (C) ₃ ) N-butyl (C) ₄ ) Tert-butyl (C) ₄ ) Sec-butyl (C) ₄ ) Isobutyl (C) ₄ ) N-pentyl (C) ₅ ) 3-pentyl (C) ₅ ) Amyl (C) ₅ ) Neopentyl (C) ₅ ) 3-methyl-2-butyl (C) ₅ ) Tert-amyl (C) ₅ ) And n-hexyl (C) ₆ ). Regardless of whether the alkyl group is previously modified with "substituted" or not, each of the alkyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined as follows.

“C _1-6 Alkoxy "refers to the group-OR, wherein R is a substituted OR unsubstituted C _1-6 An alkyl group. In some embodiments, C _1-4 Alkoxy groups are particularly preferred. Specific such alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxyHexyloxy and 1, 2-dimethylbutoxy.

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

Thus, "C _1-6 Haloalkyl groups "and" C _1-6 Haloalkoxy "means" C "as described above _1-6 Alkyl "and" C _1-6 Alkoxy ", substituted with one or more halo groups. In some embodiments, C _1-4 Haloalkyl is particularly preferred, more preferably C _1-2 A haloalkyl group. In some embodiments, C _1-4 Haloalkoxy groups are particularly preferred, more preferably C _1-2 Haloalkoxy groups. Exemplary such haloalkyl groups include, but 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-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 so on.

“C _3-7 Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C _3-7 Cycloalkyl is preferred, C _3-6 Cycloalkyl is particularly preferred, more preferably C _5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl 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 ) Cycloheptenyl (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 ) Cyclononyl (C) ₉ ) Cyclononenyl (C) ₉ ) Cyclodecyl (C) ₁₀ ) Cyclodecenyl (C) ₁₀ ) octahydro-1H-indenyl (C) ₉ ) Decalin group (C) ₁₀ ) Spiro [4.5 ]]Decyl (C) ₁₀ ) And so on. Regardless of whether the cycloalkyl group is previously modified with "substituted" or not, each of the cycloalkyl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined as follows.

"3-to 7-membered heterocyclyl" or "3-to 7-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, 3-to 7-membered heterocyclyl groups are preferred, which are 3-to 7-membered non-aromatic ring systems having a ring carbon atom and 1 to 3 ring heteroatoms; in some embodiments, 3-to 6-membered heterocyclyl groups are particularly preferred, which are 3-to 6-membered non-aromatic ring systems having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5-to 6-membered heterocyclic group which is a 5-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl also includes ring systems in which the above heterocyclyl ring is fused to one or more cycloalkyl, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Regardless of whether the heterocyclic group is previously modified with "substituted" or not, each of the heterocyclic groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined as follows.

Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinesGroup, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6 membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl (thianyl). Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexenyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azacyclooctane, oxacyclooctane, and thiacyclooctane. Exemplary AND C ₆ Aryl ring fused 5-membered heterocyclyl groups (also referred to herein as 5, 6-bicyclic heterocyclyl groups) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C ₆ Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“C _6-10 Aryl "refers to a group of a mono-or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C ₆ Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C ₁₀ Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C ₁₄ Aryl "; for example, anthracyl). In some embodiments, C _6-10 Aryl is particularly preferred, more preferably C ₆ Aryl groups. Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Regardless of whether the aryl group is previously modified with "substituted" or not, each of the aryl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined as follows.

"5-to 10-membered heteroaryl" refers to a group of a 5-to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-to 6-membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Regardless of whether the heteroaryl group is previously modified with "substituted" or not, each of the heteroaryl groups is independently optionally substituted, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent, with appropriate substituents being defined as follows.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl, 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 heteroatom include, but are not limited to: a pyridyl group. 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. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.

Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OR ^aa 、-ON(R ^bb ) ₂ 、-N(R ^bb ) ₂ 、-N(R ^bb ) ₃ ⁺ X ^- 、-N(OR ^cc )R ^bb 、-SH、-SR ^aa 、-SSR ^cc 、-C(＝O)R ^aa 、-CO ₂ H、-CHO、-C(OR ^cc ) ₂ 、-CO ₂ R ^aa 、-OC(＝O)R ^aa 、-OCO ₂ R ^aa 、-C(＝O)N(R ^bb ) ₂ 、-OC(＝O)N(R ^bb ) ₂ 、-NR ^bb C(＝O)R ^aa 、-NR ^bb CO ₂ R ^aa 、-NR ^bb C(＝O)N(R ^bb ) ₂ 、-C(＝NR ^bb )R ^aa 、-C(＝NR ^bb )OR ^aa 、-OC(＝NR ^bb )R ^aa 、-OC(＝NR ^bb )OR ^aa 、-C(＝NR ^bb )N(R ^bb ) ₂ 、-OC(＝NR ^bb )N(R ^bb ) ₂ 、-NR ^bb C(＝NR ^bb )N(R ^bb ) ₂ 、-C(＝O)NR ^bb SO ₂ R ^aa 、-NR ^bb SO ₂ R ^aa 、-SO ₂ N(R ^bb ) ₂ 、-SO ₂ R ^aa 、-SO ₂ OR ^aa 、-OSO ₂ R ^aa 、-S(＝O)R ^aa 、-OS(＝O)R ^aa 、-Si(R ^aa ) ₃ 、-OSi(R ^aa ) ₃ 、-C(＝S)N(R ^bb ) ₂ 、-C(＝O)SR ^aa 、-C(＝S)SR ^aa 、-SC(＝S)SR ^aa 、-SC(＝O)SR ^aa 、-OC(＝O)SR ^aa 、-SC(＝O)OR ^aa 、-SC(＝O)R ^aa 、-P(＝O) ₂ R ^aa 、-OP(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-OP(＝O)(R ^aa ) ₂ 、-OP(＝O)(OR ^cc ) ₂ 、-P(＝O) ₂ N(R ^bb ) ₂ 、-OP(＝O) ₂ N(R ^bb ) ₂ 、-P(＝O)(NR ^bb ) ₂ 、-OP(＝O)(NR ^bb ) ₂ 、-NR ^bb P(＝O)(OR ^cc ) ₂ 、-NR ^bb P(＝O)(NR ^bb ) ₂ 、-P(R ^cc ) ₂ 、-P(R ^cc ) ₃ 、-OP(R ^cc ) ₂ 、-OP(R ^cc ) ₃ 、-B(R ^aa ) ₂ 、-B(OR ^cc ) ₂ 、-BR ^aa (OR ^cc ) Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Group substitution;

or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R ^bb ) ₂ 、＝NNR ^bb C(＝O)R ^aa 、＝NNR ^bb C(＝O)OR ^aa 、＝NNR ^bb S(＝O) ₂ R ^aa 、＝NR ^bb Or=nor ^cc Substitution;

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

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

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

R ^dd independently selected from: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OR ^ee 、-ON(R ^ff ) ₂ 、-N(R ^ff ) ₂ ,、-N(R ^ff ) ₃ ⁺ X ^- 、-N(OR ^ee )R ^ff 、-SH、-SR ^ee 、-SSR ^ee 、-C(＝O)R ^ee 、-CO ₂ H、-CO ₂ R ^ee 、-OC(＝O)R ^ee 、-OCO ₂ R ^ee 、-C(＝O)N(R ^ff ) ₂ 、-OC(＝O)N(R ^ff ) ₂ 、-NR ^ff C(＝O)R ^ee 、-NR ^ff CO ₂ R ^ee 、-NR ^ff C(＝O)N(R ^ff ) ₂ 、-C(＝NR ^ff )OR ^ee 、-OC(＝NR ^ff )R ^ee 、-OC(＝NR ^ff )OR ^ee 、-C(＝NR ^ff )N(R ^ff ) ₂ 、-OC(＝NR ^ff )N(R ^ff ) ₂ 、-NR ^ff C(＝NR ^ff )N(R ^ff ) ₂ 、-NR ^ff SO ₂ R ^ee 、-SO ₂ N(R ^ff ) ₂ 、-SO ₂ R ^ee 、-SO ₂ OR ^ee 、-OSO ₂ R ^ee 、-S(＝O)R ^ee 、-Si(R ^ee ) ₃ 、-OSi(R ^ee ) ₃ 、-C(＝S)N(R ^ff ) ₂ 、-C(＝O)SR ^ee 、-C(＝S)SR ^ee 、-SC(＝S)SR ^ee 、-P(＝O) ₂ R ^ee 、-P(＝O)(R ^ee ) ₂ 、-OP(＝O)(R ^ee ) ₂ 、-OP(＝O)(OR ^ee ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^gg Substituted by a group, or by two gem R ^dd Substituents may combine to form =o or =s;

R ^ee is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with one or more of the group consisting of0. 1, 2, 3, 4 or 5R ^gg Group substitution;

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

R ^gg independently is: halogen, -CN, -NO ₂ 、-N ₃ 、-SO ₂ H、-SO ₃ H、-OH、-OC _1-6 Alkyl, -ON (C) _1-6 Alkyl group ₂ 、-N(C _1-6 Alkyl group ₂ 、-N(C _1-6 Alkyl group ₃ ⁺ X ^- 、-NH(C _1-6 Alkyl group ₂ ⁺ X ^- 、-NH ₂ (C _1-6 Alkyl group ⁺ X ^- 、-NH ₃ ⁺ X ^- 、-N(OC _1-6 Alkyl) (C) _1-6 Alkyl), -N (OH) (C _1-6 Alkyl), -NH (OH), -SH, -SC _1-6 Alkyl, -SS (C) _1-6 Alkyl), -C (=o) (C _1-6 Alkyl) -CO ₂ H、-CO ₂ (C _1-6 Alkyl), -OC (=o) (C _1-6 Alkyl), -OCO ₂ (C _1-6 Alkyl), -C (=O) NH ₂ 、-C(＝O)N(C _1-6 Alkyl group ₂ 、-OC(＝O)NH(C _1-6 Alkyl), -NHC (=o) (C _1-6 Alkyl), -N (C) _1-6 Alkyl) C (=O) (C _1-6 Alkyl), -NHCO ₂ (C _1-6 Alkyl), -NHC (=o) N (C) _1-6 Alkyl group ₂ 、-NHC(＝O)NH(C _1-6 Alkyl), -NHC (=o) NH ₂ 、-C(＝NH)O(C _1-6 Alkyl), -OC (=nh) (C _1-6 Alkyl), -OC (=nh) OC _1-6 Alkyl, -C (=nh) N (C _1-6 Alkyl group ₂ 、-C(＝NH)NH(C _1-6 Alkyl), -C (=nh) NH ₂ 、-OC(＝NH)N(C _1-6 Alkyl group ₂ 、-OC(NH)NH(C _1-6 Alkyl), -OC (NH) NH ₂ 、-NHC(NH)N(C _1-6 Alkyl group ₂ 、-NHC(＝NH)NH ₂ 、-NHSO ₂ (C _1-6 Alkyl), -SO ₂ N(C _1-6 Alkyl group ₂ 、-SO ₂ NH(C _1-6 Alkyl), -SO ₂ NH ₂ 、-SO ₂ C _1-6 Alkyl, -SO ₂ OC _1-6 Alkyl, -OSO ₂ C _1-6 Alkyl, -SOC _1-6 Alkyl, -Si (C) _1-6 Alkyl group ₃ 、-OSi(C _1-6 Alkyl group ₃ 、-C(＝S)N(C _1-6 Alkyl group ₂ 、C(＝S)NH(C _1-6 Alkyl), C (=S) NH ₂ 、-C(＝O)S(C _1-6 Alkyl), -C (=S) SC _1-6 Alkyl, -SC (=s) SC _1-6 Alkyl, -P (=o) ₂ (C _1-6 Alkyl), -P (=o) (C _1-6 Alkyl group ₂ 、-OP(＝O)(C _1-6 Alkyl group ₂ 、-OP(＝O)(OC _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₇ Carbocyclyl, C ₆ -C ₁₀ Aryl, C ₃ -C ₇ Heterocyclyl, C ₅ -C ₁₀ Heteroaryl; or two gem R ^gg Substituents may combine to form =o or =s; wherein X is ^- Is a counter ion.

Exemplary substituents on nitrogen atoms include, but are not limited to: hydrogen, -OH, -OR ^aa 、-N(R ^cc ) ₂ 、-CN、-C(＝O)R ^aa 、-C(＝O)N(R ^cc ) ₂ 、-CO ₂ R ^aa 、-SO ₂ R ^aa 、-C(＝NR ^bb )R ^aa 、-C(＝NR ^cc )OR ^aa 、-C(＝NR ^cc )N(R ^cc ) ₂ 、-SO ₂ N(R ^cc ) ₂ 、-SO ₂ R ^cc 、-SO ₂ OR ^cc 、-SOR ^aa 、-C(＝S)N(R ^cc ) ₂ 、-C(＝O)SR ^cc 、-C(＝S)SR ^cc 、-P(＝O) ₂ R ^aa 、-P(＝O)(R ^aa ) ₂ 、-P(＝O) ₂ N(R ^cc ) ₂ 、-P(＝O)(NR ^cc ) ₂ Alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, and heterogenousCyclic, aryl and heteroaryl, or two R's attached to the nitrogen atom ^cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R ^dd Substituted with radicals, and wherein R ^aa 、R ^bb 、R ^cc And R is ^dd As described above.

"cyano" means the group-CN.

"nitro" means a group-NO ₂ 。

Other definitions

The term "pharmaceutically acceptable salts" refers to those salts which, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in Berge et al, J.pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts with 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. Salts formed using methods conventional in the art, such as ion exchange methods, are also included. Other pharmaceutically acceptable salts include: adipic acid salts, alginates, ascorbates, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorsulfonate, citrate, cyclopentapropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodidate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate Salts, oleates, oxalates, palmates, pamates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like. Other pharmaceutically acceptable salts include, if appropriate, nontoxic ammonium, quaternary ammonium and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.

"disease," "disorder," and "condition" are used interchangeably herein.

As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").

"combination" and related terms refer to the simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the compounds of the invention may be administered simultaneously or sequentially in separate unit dosage forms with another therapeutic agent, or simultaneously in a single unit dosage form with another therapeutic agent.

In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. Effective amounts include therapeutically and prophylactically therapeutically effective amounts.

As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of therapeutic agent, 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" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.

As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of therapeutic agent used alone or in combination with other agents, which provides a prophylactic benefit in preventing a disease, disorder or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of other prophylactic agents.

"Bcr-Abl1" refers to a fusion protein formed by the N-terminal exon of the split cluster region (BCR) gene and the main C-terminal part (exons 2-11) of the Abelson (Abl 1) gene. The most common fusion transcript encodes the 210-kDa protein (p 210Bcr-Abl 1), the rarer transcript encoding the 190-kDa protein (p 190 Bcr-Abl 1) and the 230-kDa protein (p 230Bcr-Abl 1). The Abl1 sequences of these proteins comprise Abl1 tyrosine kinase domains that are tightly regulated in wild-type proteins, but are constitutively activated in Bcr-Abl1 fusion proteins. The deregulated tyrosine kinase interacts with a variety of cell signaling pathways that lead to deregulation of cell transformation and proliferation.

"Bcr-Abl1 mutant" refers to a plurality of single site mutations in Bcr-Abl1, including: glu255→Lys, glu255→Val, thr315→Ile, met244→Val, phe317→Leu, leu248→Val, met343→Thr, gly250→Ala, met351→Thr, gly250→Glu, glu355→Gly, gln252→His, phe358→Ala, gln252→Arg, phe359→Val, tyr253→His, val379→Ile, tyr253→Phe, phe382→Leu, glu255→Lys Leu387→Met Glu255→Val Val His396→Pro, phe311→Ile, his396→Arg Phe311→Leu, ser417→Tyr, thr315→Ile, glu459→Lys Phe Ile and Phe486→Ser.

"c-Abl" refers to the full length gene product of a non-mutated wild-type Abl 1.

Detailed Description

Compounds of formula (I)

Herein, "the compounds of the present invention" refers to the compounds of formula (I) below (including subsets of the formulae), or pharmaceutically acceptable salts, hydrates or solvates thereof.

In one embodiment, the present invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein,

Y ₁ selected from CR _a Or N;

y is independently selected from CR _a Or N;

R ₁ selected from hydrogen, halogen, cyano, nitro, C _1-6 Alkyl or C _1-6 Haloalkyl, wherein said C _1-6 Alkyl or C _1-6 Haloalkyl is optionally substitutedR _1a Group substitution;

z is a bond, O, S (O) _0-2 Or NR (NR) _b ；

or-Z-R ₂ Together represent-SF ₅ ；

Ar is

or Ar is

het is

Wherein X is ₉ Selected from O, S, NR _b Or C (R) ₂ ；

m is 0, 1 or 2;

n is 0, 1, 2, 3, 4, 5 or 6;

In one embodiment, the present invention relates to the above compound, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein,

ar is

Wherein X is ₁ Is CR, X ₂ To X ₄ Independently selected from CR or N, and X ₂ 、X ₃ And X ₄ At least one of which is N.

In another embodiment, the invention relates to the above compound, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein Ar is

Wherein X is ₅ Is S, X ₆ To X ₈ Independently selected from CR or N; and X is ₆ 、X ₇ And X ₈ Is a C atom attached to the parent nucleus.

In one embodiment, the present invention relates to the above compound, which is of formula (Ia), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein Ar and Het are as defined herein.

wherein,

ar is

Wherein X is ₁ To X ₄ As defined herein;

alternatively, ar is selected from the following groups optionally substituted with one, two or three R:

wherein R is as defined herein.

Wherein Ar is selected from the following groups optionally substituted with one, two or three R:

wherein R is as defined herein.

wherein,

ar is

Wherein X is ₁₁ 、X ₂₁ 、X ₃₁ And X ₄₁ As defined herein;

wherein R is as defined herein.

wherein,

ar is

Wherein P is ₁ 、P ₂ 、Q ₁ And Q ₂ As defined herein.

wherein,

ar is

Wherein X is ₅ To X ₈ As defined herein;

alternatively, ar is selected from the following groups optionally substituted with one or two R:

wherein R and R _b As defined herein.

Wherein Ar is selected from the following groups optionally substituted with one or two R:

wherein R is as defined herein.

wherein,

ar is

Wherein X is ₅₁ 、X ₆₁ 、X ₇₁ And X ₈₁ As defined herein;

alternatively, ar is selected from the following groups optionally substituted with R:

wherein R is as defined herein.

wherein,

het is

Wherein X is ₉ Is C (R) ₂ And m, n and R are as defined herein;

alternatively, het is selected from the following groups optionally substituted with one, two, three or more R:

wherein R is as defined herein;

alternatively, het is selected from the following groups:

wherein,

het is

Wherein one X ₉ Selected from O, S or NR _b Optionally other X ₉ Is C (R) ₂ And m, n, R and R _b As defined herein;

alternatively, het is selected from the following groups:

in one embodiment, the present invention relates to the above compound, which is of formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein:

ar is

Wherein X is ₁ To X ₄ As defined herein;

r is selected from hydrogen, halogen, hydroxy, -NH ₂ 、-NHC _1-6 Alkyl or-N (C) _1-6 Alkyl group ₂ 。

wherein:

ar is selected from the following groups optionally substituted with one, two or three R:

wherein:

Ar is selected from the following groups:

wherein:

ar is

R is selected from hydrogen, halogen or hydroxy.

wherein:

ar is

Wherein X is ₁₁ 、X ₂₁ 、X ₃₁ And X ₄₁ As defined herein;

In another embodiment, the invention relates to the above compound, which is of formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein:

ar is

Wherein X is ₆ To X ₈ Independently selected from CR or N, and X ₆ 、X ₇ And X ₈ One of which is a C atom attached to the parent nucleus;

wherein:

ar is selected from the following groups optionally substituted with one or two R:

wherein:

r is selected from hydrogen or hydroxy.

wherein:

r is selected from hydrogen, halogen or hydroxy.

Wherein:

r is selected from hydrogen or hydroxy.

wherein:

r is selected from hydrogen, halogen or hydroxy.

wherein:

ar is

Wherein X is ₆ To X ₈ Independently selected from CR or N, and X ₆ 、X ₇ And X ₈ Is a C atom attached to the parent core, and at least one of which is N;

alternatively, ar is selected from the following groups optionally substituted with one R:

R _b selected from hydrogen, C _1-6 Alkyl or C _1-6 A haloalkyl group;

In one embodiment, the present invention relates to the above compound, which is of formula (Ic), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

Wherein,

ar is selected from the following groups:

wherein,

ar is selected from the following groups:

wherein,

ar is selected from the following groups:

wherein,

ar is selected from the following groups:

in another embodiment, the invention relates to the above compound, which is of formula (Ic), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein,

ar is selected from the following groups:

wherein,

ar is selected from the following groups:

Y ₁ and Y

In a specific embodiment, Y ₁ Is N; in another embodiment, Y ₁ Is CR (CR) _a The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y ₁ CH.

In one embodiment, Y is CR _a The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y is N; in another embodiment, Y is CH.

R ₁

In a specific embodiment, R ₁ Selected from hydrogen, halogen, cyano, nitro, C _1-6 Alkyl or C _1-6 A haloalkyl group; in another embodiment, R ₁ Selected from hydrogen, halogen, cyano, nitro or C _1-6 An alkyl group; in another embodiment, R ₁ Selected from hydrogen or halogen; in another embodiment, R ₁ Is hydrogen; in another embodiment, R ₁ Halogen (F, cl, br or I); in another embodiment, R ₁ Is cyano; in another embodiment, R ₁ Is nitro; in another embodiment, R ₁ Is C _1-6 Alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, etc.); in another aspectIn one embodiment, R ₁ Is C _1-6 Haloalkyl (-CF) ₃ 、-CH ₂ F、-CHF ₂ 、-CClF ₂ 、-CHFCH ₂ F、-CH ₂ CHF ₂ 、-CF ₂ CF ₃ 、-CF ₂ CClF ₂ 、-CF ₂ CH ₃ 、-CCl ₃ 、-CH ₂ Cl、-CHCl ₂ 2, 2-trifluoro-1, 1-dimethyl-ethyl, etc.).

R ₂ And Z

In a specific embodiment, R ₂ Selected from hydrogen, C _1-6 Alkyl or C _1-6 A haloalkyl group; in another embodiment, R ₂ Selected from C _1-6 Alkyl or C _1-6 A haloalkyl group; in another embodiment, R ₂ Is hydrogen; in another embodiment, R ₂ Is C _1-6 Alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, etc.); in another embodiment, R ₂ Is C _1-6 Haloalkyl (-CF) ₃ 、-CH ₂ F、-CHF ₂ 、-CClF ₂ 、-CHFCH ₂ F、-CH ₂ CHF ₂ 、-CF ₂ CF ₃ 、-CF ₂ CClF ₂ 、-CF ₂ CH ₃ 、-CCl ₃ 、-CH ₂ Cl、-CHCl ₂ 2, 2-trifluoro-1, 1-dimethyl-ethyl, etc.).

In a specific embodiment, Z is a bond; in another embodiment, Z is O; in another embodiment, Z is S (O) _0-2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Z is NR _b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Z is NH.

In one embodiment, -Z-R ₂ Together represent-SF ₅ 。

Ar、X ₁ To X ₈ 、X ₁₁ 、X ₂₁ 、X ₃₁ 、X ₄₁ 、X ₅₁ 、X ₆₁ 、X ₇₁ 、X ₈₁ 、P ₁ 、P ₂ 、Q ₁ And Q ₂

In one embodiment, ar is

Wherein X is ₁ To X ₄ Independently selected from CR or N, and X ₁ 、X ₂ 、X ₃ And X ₄ At least one of which is N;

in one embodiment, ar is

Wherein X is ₁₁ 、X ₂₁ 、X ₃₁ And X ₄₁ Independently selected from CR or N, and X ₁₁ 、X ₂₁ 、X ₃₁ And X ₄₁ At least one of which is N.

In the above specific embodiment with respect to Ar, X ₁ Is CR; in a specific embodiment, X ₁ CH; in a specific embodiment, X ₁ Is N. In the above specific embodiment with respect to Ar, X ₂ Is CR; in a specific embodiment, X ₂ CH; in a specific embodiment, X ₂ Is N. In the above specific embodiment with respect to Ar, X ₃ Is CR; in a specific embodiment, X ₃ CH; in a specific embodiment, X ₃ Is N. In the above specific embodiment with respect to Ar, X ₄ Is CR; in a specific embodiment, X ₄ CH; in a specific embodiment, X ₄ Is N. In the above specific embodiment with respect to Ar, X ₁₁ Is CR; in a specific embodiment, X ₁₁ CH; in a specific embodiment, X ₁₁ Is N. In the above specific embodiment with respect to Ar, X ₂₁ Is CR; in a specific embodiment, X ₂₁ CH; in a specific embodiment, X ₂₁ Is N. In the above specific embodiment with respect to Ar, X ₃₁ Is CR; in one ofIn a specific embodiment, X ₃₁ CH; in a specific embodiment, X ₃₁ Is N. In the above specific embodiment with respect to Ar, X ₄₁ Is CR; in a specific embodiment, X ₄₁ CH; in another embodiment, X ₄₁ Is N.

In more specific embodiments, ar is selected from the following groups optionally substituted with one, two or three R:

wherein R is as defined herein.

In one embodiment, ar is

In the above specific embodiment with respect to Ar, P ₁ Is O; in another embodiment, P ₁ S is the same as the original formula; in another embodiment, P ₁ Is NR (NR) _b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, P ₁ Is NH; in another embodiment, P ₁ Is C (R) ₂ The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, P ₁ Is CH ₂ . In the above specific embodiments for Ar, Q ₁ Is O; in another embodiment, Q ₁ S is the same as the original formula; in another embodiment, Q ₁ Is NR (NR) _b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Q ₁ Is NH; in another embodiment, Q ₁ Is C (R) ₂ The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Q ₁ Is CH ₂ . In the above specific embodiment with respect to Ar, P ₂ Is CR; in another embodiment, P ₂ CH; in another embodiment, P ₂ Is N. In the above specific embodiments for Ar, Q ₂ Is CR; in another embodiment, Q ₂ CH; in another embodiment, Q ₂ Is N.

In a more specific embodiment, the

The moiety is selected from the following groups:

in a more specific embodiment, the

The moiety is selected from the following groups:

in a more specific embodiment, the

The moiety is selected from the following groups:

in a more specific embodiment, the

The moiety is selected from the following groups:

in a more specific embodiment, the

The moiety is selected from the following groups:

in a more specific embodiment, ar is selected from the group consisting of optionally R _b Or R is substituted with the following groups:

in another embodiment, ar is

Wherein X is ₅ Is O or S;

in another more specific embodiment, ar is

In another more specific embodiment, ar is

In the above specific embodiment with respect to Ar, X ₆ Is CR; in another embodiment, X ₆ CH; in another embodiment, X ₆ Is N. In the above specific embodiment with respect to Ar, X ₇ Is CR; in another embodiment, X ₇ CH; in another embodiment, X ₇ Is N. In the above specific embodiment with respect to Ar, X ₈ Is CR; in another embodiment, X ₈ CH; in another embodiment, X ₈ Is N.

In the above embodiment, X ₆ 、X ₇ And X ₈ One of which is a C atom attached to the parent nucleus; in a specific embodiment, X ₆ Is a C atom attached to the parent nucleus; in another embodiment, X ₇ Is a C atom attached to the parent nucleus; in a further embodiment of the present invention,X ₈ is a C atom attached to the parent nucleus.

In another more specific embodiment, ar is

In the above specific embodiment with respect to Ar, X ₆ Is CR; in another embodiment, X ₆ CH; in another embodiment, X ₆ Is N. In the above specific embodiment with respect to Ar, X ₇ Is CR; in another embodiment, X ₇ CH; in another embodiment, X ₇ Is N. In the above specific embodiment with respect to Ar, X ₇ Is CR; in another embodiment, X ₇ CH; in another embodiment, X ₇ Is N.

In the above embodiment, X ₆ 、X ₇ And X ₈ Is a C atom attached to the parent core and at least one of which is N; in a specific embodiment, X ₆ To the C atom, X, bound to the parent nucleus ₇ Is N; in another embodiment, X ₆ To the C atom, X, bound to the parent nucleus ₈ Is N; in another embodiment, X ₇ To the C atom, X, bound to the parent nucleus ₆ Is N; in another embodiment, X ₇ To the C atom, X, bound to the parent nucleus ₈ Is N; in another embodiment, X ₈ To the C atom, X, bound to the parent nucleus ₆ Is N; in another embodiment, X ₈ To the C atom, X, bound to the parent nucleus ₇ Is N.

In another more specific embodiment, ar is

In the above specific embodiment with respect to Ar, X ₅₁ Is CR; in another embodiment, X ₅₁ CH; in another embodiment, X ₅₁ Is N. In the above specific embodiment with respect to Ar, X ₆₁ Is CR; in another embodiment, X ₆₁ CH; in another embodiment, X ₆₁ Is N. In the above specific embodiment with respect to Ar, X ₇₁ Is CR; in another embodiment, X ₇₁ CH; in another embodiment, X ₇₁ Is N. In the above specific embodiment with respect to Ar, X ₈₁ Is CR; in another embodiment, X ₈₁ CH; in another embodiment, X ₈₁ Is N.

In another more specific embodiment, ar is the following group optionally substituted with one or two R:

in another more specific embodiment, ar is the following group optionally substituted with one R:

in another more specific embodiment, ar is the following group optionally substituted with R:

Het、X ₉ m and n

In one embodiment, het is

In the above specific embodiments with respect to Het, X ₉ Is O; in another embodiment, X ₉ S is the same as the original formula; in another embodiment, X ₉ Is NR (NR) _b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, X ₉ Is C (R) ₂ . In the above specific embodiments for Het, m is 0; in another specific embodiment, m is 1; in another embodiment, m is 2. In the above specific embodiments for Het, n is 0; in another embodiment, n is 1; in another specific embodiment, n is 2; in another specific embodiment, n is 3; in another specific embodiment, n is 4; in another specific embodiment, n is 5; in another specific embodiment, n is 6.

In a more specific embodiment, het is

Wherein X is ₉ Is C (R) ₂ 。

In more specific embodiments, het is selected from the following groups optionally substituted with one, two, three or more R:

in a more specific embodiment, het is selected from the following groups:

in a more specific embodiment, het is

Wherein one X ₉ Selected from O, S or NR _b Optionally other X ₉ Is C (R) ₂ ；

In a more specific embodiment, het is selected from the following groups:

R _a 、R _b 、R _1a 、R _2a and R is

In a specific embodiment, R _a Independently selected from hydrogen, halogen, cyano, nitro, hydroxy, -NH ₂ 、-NHC _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl or C _1-6 An alkoxy group; in another embodiment, R _a Is hydrogen; in another embodiment, R _a Is halogen; in another embodiment, R _a Is cyano; in another embodiment, R _a Is nitro; in another embodiment, R _a Is hydroxyl; in another embodiment, R _a is-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R _a is-NHC _1-6 An alkyl group; in another embodiment, R _a is-N (C) _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R _a Is C _1-6 An alkyl group; in another embodiment, R _a Is C _1-6 A haloalkyl group; in another embodiment, R _a Is C _1-6 An alkoxy group.

In a specific embodiment, R _b Independently selected from hydrogen, C _1-6 Alkyl or C _1-6 A haloalkyl group; in another embodiment, R _b Is hydrogen; in another embodiment, R _b Is C _1-6 An alkyl group; in another embodiment, R _b Is C _1-6 A haloalkyl group.

In a specific embodiment, R _1a 、R _2a And R is independently selected from hydrogen, halogen, hydroxy, -NH ₂ 、-NHC _1-6 Alkyl, -N (C) _1-6 Alkyl group ₂ 、C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _3-7 Cycloalkyl, 3-to 7-membered heterocycloalkyl, C _6-10 Aryl or 5-to 10-membered heteroarylA base; in another embodiment, R _1a 、R _2a And R is hydrogen; in another embodiment, R _1a 、R _2a And R is halogen; in another embodiment, R _1a 、R _2a And R is hydroxy; in another embodiment, R _1a 、R _2a And R is-NH ₂ The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R _1a 、R _2a And R is-NHC _1-6 An alkyl group; in another embodiment, R _1a 、R _2a And R is-N (C) _1-6 Alkyl group ₂ The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R _1a 、R _2a And R is C _1-6 An alkyl group; in another embodiment, R _1a 、R _2a And R is C _1-6 A haloalkyl group; in another embodiment, R _1a 、R _2a And R is C _1-6 An alkoxy group; in another embodiment, R _1a 、R _2a And R is C _3-7 Cycloalkyl; in another embodiment, R _1a 、R _2a And R is a 3 to 7 membered heterocycloalkyl; in another embodiment, R _1a 、R _2a And R is C _6-10 An aryl group; in another embodiment, R _1a 、R _2a And R is a 5 to 10 membered heteroaryl.

In one embodiment, two R groups on the same atom or on adjacent atoms may together form C _3-7 Cycloalkyl, 3-to 7-membered heterocycloalkyl, C _6-10 Aryl or 5 to 10 membered heteroaryl; in another embodiment, two R groups on the same atom or on adjacent atoms may together form C _3-7 Cycloalkyl; in another embodiment, two R groups on the same atom or on adjacent atoms may together form C _3-7 A heterocycloalkyl group. In another embodiment, two R groups on the same atom or on adjacent atoms may together form C _6-10 An aryl group; in another embodiment, two R groups on the same atom or on adjacent atoms may together form a 5-to 10-membered heteroaryl.

Any one of the above embodimentsAny one of the technical schemes or any combination thereof in the scheme can be combined with any one of the technical schemes or any combination thereof in other specific embodiments. For example, Y ₁ Any one of the technical schemes or any combination thereof can be combined with Y, R ₁ 、R ₂ 、Z、Ar、X ₁ To X ₉ 、X ₁₁ 、X ₂₁ 、X ₃₁ 、X ₄₁ 、X ₅₁ 、X ₆₁ 、X ₇₁ 、X ₈₁ 、P ₁ 、P ₂ 、Q ₁ 、Q ₂ 、Het、m、n、R _a 、R _b 、R _1a 、R _2a And R, or any combination thereof. The invention is intended to include all such combinations, limited to the extent that they are not listed.

In particular embodiments, the compounds of the present invention may be selected from the following compounds:

the compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC), formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.

"tautomer" refers to a compound in which one functional group changes its structure to another functional group isomer and can rapidly interconvert to two isomers in dynamic equilibrium, and the two isomers are called tautomers.

Those skilled in the art will appreciate that the organic compound may form a complex with a solvent in or from which it reacts or from which it precipitates or crystallizes. 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 present invention.

The term "solvate" refers to a form of a compound or salt thereof that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes both solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrates of the compounds can be used, for example, of the formula R x H ₂ O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (r.0.5H) ₂ O)) and polyhydrates (x is a number greater than 1, e.g., dihydrate (r.2h) ₂ O) and hexahydrate (R.6H) ₂ O))。

The compounds of the present invention may be in amorphous or crystalline form (crystalline or polymorphic). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example ² H、 ³ H、 ¹³ C、 ¹¹ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ O、 ¹⁷ O、 ³¹ P、 ³² P、 ³⁵ S、 ¹⁸ F and F ³⁶ Cl. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, e.g., for incorporation of a radioisotope (e.g. ³ H and ¹⁴ c) Those useful in drug and/or substrate tissue distribution assays. Tritium, i.e. tritium ³ H and carbon-14 ¹⁴ The C isotopes are particularly preferred because they are easy to prepare and detect. Further, substitution by heavier isotopes, e.g. deuterium, i.e ² H, because of its higher metabolic stability, may provide therapeutic benefits, such as increased in vivo half-life or reduced dosage requirements, and thus may in some casesCan be preferred. Isotopically-labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.

In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, e.g. in blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in t.higuchi and v.stilla, prodrugs as Novel Delivery Systems, a.c. s.symposium Series vol.14, edward b.roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ", advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.

Prodrugs are any covalently bonded compounds of the invention which, when administered to a patient, release the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification may be performed by conventional procedures or cleavage in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, may cleave to form the hydroxy, amino, or sulfhydryl group. Representative examples of prodrugs therefore include, but are not limited to, acetate, formate and benzoate/amide derivatives of hydroxy, mercapto and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The esters themselves may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or salt thereof.

Pharmacology and efficacy

The compounds of the invention show therapeutic efficacy especially for diseases or disorders that depend on the activity of Bcr-Abl 1. In particular, the compounds of the invention inhibit the ATP binding site of Bcr-Abl1 (including wild-type Bcr-Abl1 and/or mutations thereof (including T315I mutations)).

Extracellular matrix is degraded during cancer cell tumor invasion and metastasis by invasion pseudopodia (invapodia). Abl kinase activity is required for Src-induced invasive pseudopodogenesis, which regulates the different stages and functions of invasive pseudopodium assembly. Thus, the compounds of the present invention as Abl inhibitors have potential as therapeutics for the treatment of metastatic invasive cancer.

Inhibitors of c-Abl kinase may be useful in the treatment of brain cancers: including glioblastomas, which are the most common and aggressive malignant primary brain tumors, wherein c-Abl expression is detectable by immunohistochemical techniques in a subset of patients. Thus, new c-Abl inhibitors with high brain exposure represent solid treatment approaches to glioblastomas and other brain cancers.

The compounds of the invention may be used for the treatment of viruses. For example, viral infection may be mediated by Abl1 kinase activity, as in the case of poxviruses and ebola viruses. Imatinib and nilotinib have been shown to stop the release of ebola virus particles from infected cells in vitro. Compounds of the invention that inhibit c-Abl kinase are therefore expected to be useful in reducing the replication capacity of pathogens.

Parkinson's disease is the second most common chronic neurodegenerative disease, with the most common familial autosomal recessive form caused by mutations in the E3 ubiquitin protein ligase (parkin). Recent studies have shown that activated c-ABL is found in the striatum of sporadic parkinson's disease patients. Meanwhile, parkin is tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activity as indicated by accumulation of parkin substrate.

The compounds or compositions of the invention are also useful for treating the following diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after implantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumors, thyroid cancer, systemic mastocytosis, eosinophilic syndrome, fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease, neurofibromatosis, pulmonary hypertension, alzheimer's disease, seminomas, atheroma, mast cell tumors, lung cancer, bronchogenic carcinoma, asexual cell tumor, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular parathyroid hyperplasia/adenoma, colon cancer, colorectal 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, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, neoplasias, and other proliferative or proliferative disorders, or a combination 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 an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

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

The following formulation examples illustrate representative pharmaceutical compositions that may be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

Exemplary formulation 1-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into tablets of 0.3-30mg (each tablet containing 0.1-10mg of active compound) in a tablet press.

Exemplary formulation 2-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into tablets of 30-90mg (each tablet containing 10-30mg of active compound) in a tablet press.

Exemplary formulation 3-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into tablets of 90-150mg (each tablet containing 30-50mg of active compound) in a tablet press.

Exemplary formulation 4-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 150-240mg tablets (each tablet containing 50-80mg of active compound) in a tablet press.

Exemplary formulation 5-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 240-270mg tablets (each tablet containing 80-90mg of active compound) in a tablet press.

Exemplary formulation 6-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 270-450mg tablets (each tablet containing 90-150mg of active compound) in a tablet press.

Exemplary formulation 7-tablet: the compounds of the present invention in dry powder form may be mixed with a dry gel binder in a weight ratio of about 1:2. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 450-900mg tablets (each tablet containing 150-300mg of active compound) in a tablet press.

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

Exemplary formulation 9-liquid: the compound of the present invention (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture may be blended, passed through a No.10 mesh U.S. sieve, and then mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavouring and colouring agents were diluted with water and added with stirring. Sufficient water may then be added to give a total volume of 5 mL.

Exemplary formulation 10-injection: the compounds of the present invention may be dissolved or suspended in buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.

Administration of drugs

The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intramuscularly, and intracranial injection or infusion techniques.

Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, 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, and the like.

When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.

The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.

Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to rapidly increase the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of the active ingredient, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.

Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate 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 material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.

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

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

From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.

Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose, disintegrants, for example alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.

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

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

The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.

The above components of the compositions 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, section 8, incorporated herein by reference.

The compounds of the present 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 also 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 α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).

Treatment of

The compounds of the invention are also useful for treating the following diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after implantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumors, thyroid cancer, systemic mastocytosis, eosinophilic syndrome, fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease, neurofibromatosis, pulmonary hypertension, alzheimer's disease, seminomas, atheroma, mast cell tumors, lung cancer, bronchogenic carcinoma, asexual cell tumor, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular parathyroid hyperplasia/adenoma, colon cancer, colorectal 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, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, neoplasias, and other proliferative or proliferative disorders, or a combination thereof.

The present invention thus provides compounds of the invention 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 take the form of, for example: abnormal increase in activity, or aberrations in timing and or control of Bcr-Abl activity. Such inappropriate activity could then be caused, for example, by overexpression or mutation of the protein kinase resulting in inappropriate or uncontrolled activation.

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

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

In another embodiment, the compounds of the invention may also be used to treat neurodegeneration. While the native C-ABL tyrosine kinase remains relatively stationary in healthy adult brains, it can be activated in brains of CNS disease patients including neurodegenerative diseases such as Alzheimer's Disease (AD), parkinson's disease (AD), frontotemporal dementia (frontotemporal dementia) (FTD), pick's disease, niemann-pick's disease type C (NPC) and other degenerative, inflammatory and autoimmune diseases and aging.

The effective amount of the compound of the present invention is generally in the range of 0.01mg to 50mg compound per kilogram of patient body weight, preferably 0.1mg to 25mg compound per kilogram of patient body weight, in single or multiple administrations. In general, the compounds of the invention may be administered to the patient in need of such treatment in a daily dosage range of from about 1mg to about 3500mg, preferably from 10mg to 1000mg, per patient. For example, the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000mg. The administration may be one or more times daily, weekly (or at intervals of days), or on an intermittent schedule. For example, the compounds may be administered on a weekly basis (e.g., once a week), once or more times a day, indefinitely or for a few weeks, e.g., 4-10 weeks. Alternatively, the administration may be continued for several days (e.g., 2-10 days) and then several days (e.g., 1-30 days) without administration of the compound, with the cycle being repeated indefinitely or for a given number of cycles, e.g., 4-10 cycles. For example, the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then daily for another 5 days, then intermittently for 9 days, and so on, with the cycle being repeated indefinitely or for a total of 4-10 times.

Examples

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentages by weight unless otherwise indicated.

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

Abbreviations used herein have the following meanings:

NBS: n-bromosuccinimide;

HATU: o- (7-azabenzotriazol-1-yl) -N, N' -tetramethylurea hexafluorophosphate;

DIEA: n, N-diisopropylethylamine;

DCM: dichloromethane;

DMF: n, N-dimethylformamide;

DMSO: dimethyl sulfoxide;

Pd(PPh ₃ ) ₄ : tetrakis (triphenylphosphine) palladium;

and (3) Tol: toluene.

Example 1 (R) -2-amino-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-fluoropyrrolidin-1-yl) -5- (pyri-dine) Preparation of oxazin-2-yl) nicotinamide

The following synthetic route was adopted:

step 1 Synthesis of 2-amino-5-bromo-6-chloronicotinic acid as Compound

To the flask were added 2-amino-6-chloronicotinic acid (5.0 g,29.1 mmol) and dichloromethane (50 mL), NBS (6.21 g,34.9 mmol) was added under nitrogen protection, and the reaction was stirred at room temperature for 4-6 hours, and TLC was monitored to complete the reaction. The solvent was removed by concentration, slurried in 80mL of water for 1 hour, filtered, and the cake dried in vacuo to give 5.9g of product in 81% yield. LC-MS (APCI) M/z= 251.2 (M+1) ⁺ 。

Step 2 Synthesis of Compound 2-amino-5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide

To the reaction flask were added 2-amino-5-bromo-6-chloronicotinic acid (5.9 g,23.6 mmol), 4- (chlorodifluoromethoxy) aniline (5.5 g,28.3 mmol) andHATU (13.4 g,35.4 mmol) and DIEA (6.1 g,47.2 mmol) were added to anhydrous DMF (40 mL) in ice bath, the reaction stirred at room temperature for 12 h and TLC monitored the completion of the reaction. Diluting with water, extracting with ethyl acetate for 3-4 times, mixing the organic phases, washing with saturated saline, concentrating, and purifying by silica gel column chromatography to obtain 6.5g yellow solid with a yield of 65%. LC-MS (APCI) M/z= 425.8 (M+1) ⁺ 。

Step 3 Synthesis of Compound (R) -2-amino-5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-fluoropyrrolidin-1-yl) nicotinamide

To the reaction flask was added 2-amino-5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide (3.0 g,7.06 mmol), (R) -3-fluoropyrrolidine hydrochloride (0.9 g,7.06 mmol) and anhydrous sodium carbonate (1.5 g,14.1 mmol), DMSO (20 mL) under nitrogen protection, heated to 70℃and stirred for 6-8 hours, and TLC monitored the reaction. The reaction mixture was quenched with water, extracted 3-4 times with ethyl acetate, the organic phases were combined, concentrated and purified by silica gel column chromatography to give 3.1g of a pale yellow solid in 91% yield. LC-MS (APCI) M/z= 479.3 (M+1) ⁺ 。

Step 4 Synthesis of Compound example 1

To the reaction flask was added (R) -2-amino-5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-fluoropyrrolidin-1-yl) nicotinamide (110 mg,0.23 mmol), pyrazine-2-boronic acid (57 mg,0.46 mmol), potassium phosphate (123 mg,0.58 mmol), tetrakis (triphenylphosphine) palladium (13 mg,0.01 mmol) and toluene (3 mL), nitrogen was bubbled for 5 minutes, and the reaction was stirred under nitrogen protection at a temperature of 100℃for 4-6 hours with stirring, and TLC monitoring was completed. After concentration, purification by silica gel column chromatography gave 23mg of a white solid in 21% yield. LC-MS (APCI) M/z= 479.4 (M+1) ⁺ 。 ¹ H NMR(400MHz,DMSO-d ₆ )δ9.89(s,1H),8.65(s,1H),8.53(s,1H),8.17(s,1H),8.15(s,1H),7.76(d,J＝9.1Hz,2H),7.36-7.23(m,5H),5.25(d,J＝54Hz,1H),3.62-3.43(m,2H),3.30-3.16(m,2H),2.04(d,J＝11.6Hz,2H)。

Biological Activity test

Example 2 cytotoxicity assay

Detection example Compound pair Ba/F ₃ Parent cell, ba/F ₃ Bcr-Abl ^T315I Cell, K562 fineInhibition of cell, KCL22-s activity.

Consumable and reagent: RPMI-1640 medium (GIBCO, catalog number A10491-01), fetal bovine serum (GIBCO, catalog number 10099141), antibiotics (penicillin-streptomycin), IL-3 (PeproTech), puromycin; cell line: ba/F ₃ Parent cell, ba/F ₃ Bcr-Abl ^T315I K562 cells, KCL22-s (available from American standard biological Collection, ATCC), living cell detection kit CellTiter-Glo4 (Promega, catalog number G7572), 96 Kong Heibi transparent flat bottom cell culture plates (Corning, catalog number 3340).

The experimental method comprises the following steps:

1. preparation of cell plates: ba/F ₃ Parent cell, ba/F ₃ Bcr-Abl ^T315I K562 cells, KCL22-s cells were seeded in 96-well plates, respectively, and in Ba/F ₃ IL-3 (8 ng/mL) was added to the parental cells and the cell plates were placed in a carbon dioxide incubator overnight for culture.

2. Preparation of test compounds: the test compounds were dissolved in DMSO and subjected to 3.16-fold gradient dilution, 9 compound concentrations, and a three-well assay was set up with an initial compound concentration of 10 μm.

3. Compound-treated cells: the compounds at each concentration were transferred to cell plates. The cell plates were placed in a carbon dioxide incubator for 3 days.

4. And (3) detection: cellTiter-Glo4 reagent was added to the cell plate and incubated at room temperature for 30 min to stabilize the luminescence signal. A PerkinElmer Envision multi-label analyzer reading was used.

The results of the inhibition of proliferation of cells in vitro in the examples are summarized in Table 1 below, wherein A represents IC ₅₀ 50nM or less, B represents 50nM<IC ₅₀ Less than or equal to 500nM, C represents 500nM<IC ₅₀ Less than or equal to 1000nM, D represents IC ₅₀ >1000nM。

Table 1 cytotoxicity of the example compounds

Examples numbering	Example 1
		Ba/F ₃ Parental cell IC ₅₀	D
Ba/F ₃ Bcr-Abl1 ^T315I IC ₅₀	A
		K562 cell IC ₅₀	A
KCL22-s cell IC ₅₀	A

Experimental results show that the compound of the invention has the effect on Ba/F related to side effects of medicaments ₃ Cells exhibit relatively low inhibitory activity (IC ₅₀ >1000 nM), and for Ba/F ₃ Bcr-Abl ^T315I Cells of the mutants showed excellent inhibitory activity (IC ₅₀ Less than or equal to 50 nM). Meanwhile, the compound of the invention has excellent inhibitory activity (IC) on human chronic granulocytic leukemia cells (K562) and human acute phase chronic granulocytic leukemia (KCL 22-s) ₅₀ ≤50nM)。

The compounds of the invention are therefore useful as Bcr-Abl inhibitors for the treatment of drug-resistant or resistant oncological patients with existing Tyrosine Kinase Inhibitors (TKIs), e.g. chronic, acute, acceleration stage patients with Chronic Myelogenous Leukemia (CML), and Philadelphia chromosome-positive (Ph) ⁺ ) Has good prospect for patients with chronic granulocytic leukemia and acute lymphoblastic leukemia.

The invention also comprises the following technical scheme:

a compound according to claim one, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, selected from the group consisting of:

a second aspect, a pharmaceutical composition comprising a compound of any one of the embodiments or aspects of the invention, or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

The third technical proposal is that the kit comprises

A first container containing a compound of any one of the embodiments or aspects of the invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and optionally, a second container containing other therapeutic agents; and optionally, a third container containing pharmaceutically acceptable excipients for diluting or suspending the compound and/or other therapeutic agent.

The use of a compound according to claim four, any one of the embodiments of the invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof in the manufacture of a medicament for the treatment and/or prophylaxis of a Bcr-Abl caused disease.

Technical solution a method of treating and/or preventing a Bcr-Abl-induced disease in a subject, the method comprising administering to the subject a compound of any one of the embodiments or technical solutions of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of technical solution two.

A compound of claim six, any one of the embodiments or embodiments of the invention or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition of claim two for use in the treatment and/or prevention of a Bcr-Abl-induced disease.

The seventh aspect, the use according to the fourth aspect, the method of the fifth aspect or the use of the compound of the sixth aspect, wherein the Bcr-Abl-induced disease is a proliferative disease selected from the group consisting of: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases; or the Bcr-Abl-caused disease is metastatic invasive cancer, a viral infection or a CNS disorder.

The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims

1. A compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein,

Y ₁ selected from CR _a Or N;

y is independently selected from CR _a Or N;

R ₁ selected from hydrogen, halogen, cyano, nitro, C _1-6 Alkyl or C _1-6 HaloalkylWherein said C _1-6 Alkyl or C _1-6 Haloalkyl is optionally substituted with R _1a Group substitution;

z is a bond, O, S (O) _0-2 Or NR (NR) _b ；

or-Z-R ₂ Together represent-SF ₅ ；

Ar is

Wherein X is ₁ Is CR, X ₂ To X ₄ Independently selected from CR or N, and X ₂ 、X ₃ And X ₄ At least one of which is N;

or Ar is

Wherein X is ₅ Is S, X ₆ To X ₈ Independently selected from CR or N; and X is ₆ 、X ₇ And X ₈ One of which is a C atom attached to the parent nucleus;

het is

Wherein X is ₉ Selected from O, S, NR _b Or C (R) ₂ ；

m is 0, 1 or 2;

n is 0, 1, 2, 3, 4, 5 or 6;

2. The compound of claim 1, which is formula (Ia), or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein Ar and Het are as defined in claim 1.

3. The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

wherein R is as defined in claim 1.

4. The compound of claim 1 or 2, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

wherein R is as defined in claim 1.

5. The compound of any one of claims 1-4, or a tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:

Het is

Wherein X is ₉ Is C (R) ₂ And m, n and R are as defined in claim 1;

wherein R is as defined in claim 1;

alternatively, het is selected from the following groups:

6. a compound according to any one of claims 1-3, which is of formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein:

7. A compound according to any one of claims 1-3, which is of formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof:

wherein:

r is selected from hydrogen, halogen or hydroxy.

8. The compound according to any one of claims 1-2 or 4, which is formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

Wherein:

9. The compound according to any one of claims 1-2 or 4, which is formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein:

r is selected from hydrogen or hydroxy.

10. The compound according to any one of claims 1-2 or 4, which is formula (Ib), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvate thereof:

wherein:

r is selected from hydrogen or hydroxy.