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WO2018133826A1 - 用于抑制蛋白激酶活性的(杂)芳基酰胺类化合物 - Google Patents

用于抑制蛋白激酶活性的(杂)芳基酰胺类化合物 Download PDF

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Publication number
WO2018133826A1
WO2018133826A1 PCT/CN2018/073338 CN2018073338W WO2018133826A1 WO 2018133826 A1 WO2018133826 A1 WO 2018133826A1 CN 2018073338 W CN2018073338 W CN 2018073338W WO 2018133826 A1 WO2018133826 A1 WO 2018133826A1
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Prior art keywords
compound
group
alkyl
pharmaceutically acceptable
hydrate
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PCT/CN2018/073338
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English (en)
French (fr)
Inventor
王义汉
赵九洋
Original Assignee
深圳市塔吉瑞生物医药有限公司
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Application filed by 深圳市塔吉瑞生物医药有限公司 filed Critical 深圳市塔吉瑞生物医药有限公司
Priority to US16/479,271 priority Critical patent/US10875853B2/en
Priority to EP18741350.5A priority patent/EP3553057B1/en
Priority to CN201880000978.4A priority patent/CN108699039B/zh
Priority to JP2019560439A priority patent/JP6778833B2/ja
Publication of WO2018133826A1 publication Critical patent/WO2018133826A1/zh
Priority to US17/098,675 priority patent/US11319317B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to (hetero) aryl amide compounds which inhibit the tyrosine kinase activity of Abelson protein (Abl1), Abelson-related protein (Abl2) and related chimeric proteins, particularly Bcr-Abl1. , pharmaceutical compositions containing them, and methods for their preparation and use.
  • Protein tyrosine kinases are a class of kinases that are involved in proteinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues by catalyzing phenolic hydroxyl groups on various protein tyrosine residues. Phosphorylation occurs, which in turn activates functional proteins. Protein tyrosine kinase plays an important role in the signal transduction pathway in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis. In addition, the abnormal expression of protein tyrosine kinase is also closely related to tumor invasion and metastasis, tumor angiogenesis, and chemotherapy resistance of tumors.
  • the tyrosine kinase expressed by the Bcr-Abl fusion gene can cause changes in cell proliferation, adhesion and survival properties, leading to the production of various tumors. 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, which has the following structural formula) is an allosteric inhibitor of ABL1 kinase developed by Novartis Pharmaceuticals Co., Ltd., which is inactivated by targeting the myristoyl pocket of ABL1, and competes with ATP for BCR-ABL.
  • the combination of inhibitors of tyrosine kinase is effective in preventing the emergence of drug resistance in the application of ATP inhibitors and/or allosteric inhibitors.
  • ABL-001 has been shown to be combined with the second-generation BCR-ABL inhibitor nilotinib to counteract CML in a mouse model (Andrew A. Wylie et al. (2017) Nature 543, 733-737) .
  • Novartis is developing a clinical treatment regimen of ABL-001 in combination with multiple ATP-competitive BCR-ABL inhibitors, including imatinib, nilotinib, and dasatinib.
  • the present invention provides a novel (hetero)arylamide compound and a composition comprising the same and use thereof, which have better Bcr-Abl kinase inhibitory activity (especially for T315I mutation), lower side effects and / or better pharmacodynamics / pharmacokinetic properties, can be used to treat diseases mediated by Bcr-Abl kinase.
  • Y 1 is selected from CR a or N;
  • Y is independently selected from CR a or N;
  • R 1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl or C 1-6 haloalkyl is optionally R 1a Substitute
  • R 2 is selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with an R 2a group;
  • Z is a chemical bond, O, S(O) 0-2 or NR b ;
  • X 1 is selected from O, S or NR b , and X 2 to X 8 are independently selected from CR or N;
  • X 1 is O or S
  • one of X 2 , X 3 and X 4 is a C atom connected to the mother nucleus
  • X 1 is NR b
  • one of X 2 , X 3 and X 4 is a C atom attached to the mother nucleus and at least one of which is N;
  • X 9 is selected from the group consisting of O, S, NR b or C(R) 2 ;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R a is independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
  • R b is independently selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1a , R 2a and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl;
  • the same atom or two R groups on adjacent atoms may together form a C 3-7 cycloalkyl group, C 3-7 heterocycloalkyl, C 6-10 aryl group or a C 5-10 heteroaryl.
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the invention provides a kit comprising a compound of the invention, and other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prevention of a disease caused by Bcr-Abl.
  • the invention provides a method of treating and/or preventing a Bcr-Abl-causing disease in a subject, comprising administering to the subject a compound of the invention or a composition of the invention.
  • the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of a disease caused by Bcr-Abl.
  • the disease may be selected from the group consisting of: solid tumor, sarcoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumor, thyroid cancer, gastric cancer, Rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases.
  • the Bcr-Abl-causing disease is chronic myeloid leukemia, gastrointestinal stromal tumor, acute myeloid leukemia, thyroid cancer, metastatic invasive cancer, or a combination thereof.
  • the compounds of the invention are useful for treating and/or preventing a disease or disorder associated with aberrantly activated kinase activity of wild-type Abl, including non-malignant diseases or disorders, such as CNS diseases, particularly nerves Degenerative diseases (eg Alzheimer's disease, Parkinson's disease), motor neuron disease (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, sputum Viral disease.
  • CNS diseases particularly nerves Degenerative diseases (eg Alzheimer's disease, Parkinson's disease), motor neuron disease (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, sputum Viral disease.
  • CNS diseases particularly nerves Degenerative diseases (eg Alzheimer's disease, Parkinson's disease), motor neuron disease (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • 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 alkyl.
  • C 1-6 alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 6 carbon atoms, also referred to herein as “lower alkyl.” In some embodiments, a C 1-4 alkyl group is particularly preferred.
  • alkyl group examples include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), uncle Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5), 3- methyl-2-butyl (C 5), tert-pentyl (C 5) and n-hexyl (C 6).
  • each alkyl group is independently optionally substituted, ie, unsubstituted (“unsubstituted alkyl") or substituted with one or more substituents (“substituted alkyl”) For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the alkyl group is unsubstituted C 1-6 alkyl group (e.g., -CH 3).
  • the alkyl group is a substituted C1-6 alkyl group.
  • C 1-6 alkoxy refers to the group -OR wherein R is a substituted or unsubstituted C 1-6 alkyl group. In some embodiments, a C 1-4 alkoxy group is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, N-Hexyloxy and 1,2-dimethylbutoxy.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the halo group is F, Cl or Br.
  • the halogen group is Cl.
  • the halogen group is F.
  • the halogen group is Br.
  • C1-6 haloalkyl refers to the above “ C1-6 alkyl” which is substituted by one or more halo groups.
  • a C 1-4 haloalkyl group is particularly preferred, more preferably a C 1-2 haloalkyl group.
  • haloalkyl groups include, but the are not limited to: -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 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • C 3-7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having from 3 to 7 ring carbon atoms and zero heteroatoms.
  • a C 3-6 cycloalkyl group is particularly preferred, more preferably a C 5-6 cycloalkyl group.
  • the cycloalkyl group also includes a ring system in which the above cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such a case, the number of carbons continues to be represented The number of carbons in the cycloalkyl system.
  • Exemplary 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 ), cycloheptene (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), and the like.
  • each of the cycloalkyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkane"base").
  • a cycloalkyl group is an unsubstituted C 3-7 cycloalkyl group.
  • the carbocyclyl is a substituted C3-7 cycloalkyl.
  • C 3-7heterocycloalkyl or a group of 3 to 7 membered non-aromatic ring systems having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each hetero atom is independently selected from nitrogen, Oxygen, sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a C 3-6 heterocycloalkyl group is particularly preferred, which is a 3 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably C 5-6 hetero A cycloalkyl group which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring hetero atoms.
  • each of the heterocycloalkyl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents (“substituted Heterocycloalkyl").
  • a heterocycloalkyl group is an unsubstituted C3-7 heterocycloalkyl group. In some embodiments, a heterocycloalkyl group is a substituted C3-7 heterocycloalkyl.
  • Heterocycloalkyl also includes ring systems wherein the above heterocycloalkyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the heterocycloalkyl ring is bonded to one or more An aryl or heteroaryl fused ring system wherein the point of attachment is on a heterocycloalkyl ring; and in such cases, the number of ring members continues to indicate the number of ring members in the heterocycloalkyl ring system.
  • Exemplary 3-membered heterocycloalkyl groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thiorenyl.
  • Exemplary 4-membered heterocycloalkyl groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane.
  • Exemplary 5-membered heterocycloalkyl groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2 , 5-dione.
  • Exemplary 5-membered heterocycloalkyl groups containing two heteroatoms include, but are not limited to, dioxalanyl, oxasulfuranyl, disulfuranyl, and Oxazolidine-2-one.
  • Exemplary 5-membered heterocycloalkyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 6-membered heterocycloalkyl groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocycloalkyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxoalkyl.
  • Exemplary 6-membered heterocycloalkyl groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocycloalkyl groups containing one hetero atom include, but are not limited to, azepanyl, oxaheptyl, and thiaheptanyl.
  • Exemplary 5-membered heterocycloalkyl groups (also referred to herein as 5,6-bicyclic heterocycloalkyl groups) fused to a C 6 aryl ring include, but are not limited to, indanyl, isoindoline Mercapto, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocycloalkyl fused to a C 6 aryl ring (also referred to herein as 6,6-bicycloheterocycloalkyl) includes, but is not limited to, tetrahydroquinolyl, tetrahydroisoquinoline Base, and so on.
  • C 6-10 aryl refers to a monocyclic or polycyclic (eg, bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (eg, having a cyclic arrangement) Shared 6 or 10 ⁇ electrons) groups.
  • an aryl group having six ring carbon atoms ( “C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (" C10 aryl”; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • the aryl group also includes a ring system in which the above aryl ring is fused to one or more cycloalkyl or heterocycloalkyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues Represents the number of carbon atoms in the aryl ring system.
  • each of the aryl groups is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
  • the aryl group is an unsubstituted C 6-10 aryl group.
  • the aryl group is a substituted C 6-10 aryl group.
  • C 5-10heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (eg, having a shared arrangement in a ring arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more cycloalkyl or heterocycloalkyl groups, and the point of attachment is on the heteroaryl ring, in this case a carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • a C5-6 heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms.
  • each of the heteroaryl groups is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"base").
  • the heteroaryl is an unsubstituted 5-10 membered heteroaryl.
  • the heteroaryl is a substituted 5-10 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • Cyano means a group -CN.
  • Niro means the group -NO 2 .
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "person,” “patient,” and “subject” are used interchangeably herein.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), but also the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. Delay or minimize.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent disease, unless otherwise stated. The number of relapses of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other agents that provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall amount of prevention, or enhances the prophylactic efficacy of other prophylactic agents.
  • Bcr-Abl1 refers to a fusion protein formed by the N-terminal exon of the split-cluster region (BCR) gene and the major C-terminal portion of the Abelson (Abl1) gene (exons 2-11).
  • the most common fusion transcript encodes the 210-kDa protein (p210Bcr-Abl1), the less common transcript encodes the 190-kDa protein (p190Bcr-Abl1) and the 230-kDa protein (p230Bcr-Abl1).
  • the Abl1 sequences of these proteins contain the Abl1 tyrosine kinase domain that is tightly regulated in the wild-type protein but constitutively activated in the Bcr-Abl1 fusion protein. This dysregulated tyrosine kinase interacts with a variety of cellular signaling pathways that lead to cell transformation and proliferation dysregulation.
  • 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, His396 ⁇ Pro, Phe311 ⁇ Ile, His396 ⁇ Arg, Phe311 ⁇ Leu, Ser417 ⁇ Tyr, Thr315 ⁇ Ile, Glu459 ⁇ Lys and Phe486 ⁇ Ser.
  • c-Abl refers to the full length gene product of a non-mutated wild-type Abl1.
  • the "compound of the present invention” means a compound of the following formula (I), formula (Ia) and formula (Ib), a pharmaceutically acceptable salt, a stereoisomer, a solvate or a hydrate thereof.
  • the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Y 1 is selected from CR a or N;
  • Y is independently selected from CR a or N;
  • R 1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 alkyl or C 1-6 haloalkyl, wherein said C 1-6 alkyl or C 1-6 haloalkyl is optionally R 1a Substitute
  • R 2 is selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl, wherein the C 1-6 alkyl or C 1-6 haloalkyl is optionally substituted with an R 2a group;
  • Z is a chemical bond, O, S(O) 0-2 or NR b ;
  • X 1 is selected from O, S or NR b , and X 2 to X 8 are independently selected from CR or N;
  • X 1 is O or S
  • one of X 2 , X 3 and X 4 is a C atom connected to the mother nucleus
  • X 1 is NR b
  • one of X 2 , X 3 and X 4 is a C atom attached to the mother nucleus and at least one of which is N;
  • X 9 is selected from the group consisting of O, S, NR b or C(R) 2 ;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • R a is independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy;
  • R b is independently selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1a , R 2a and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl;
  • the same atom or two R groups on adjacent atoms may together form a C 3-7 cycloalkyl group, C 3-7 heterocycloalkyl, C 6-10 aryl group or a C 5-10 heteroaryl.
  • the present invention relates to the above compounds, wherein
  • X 1 is S, X 2 to X 4 are independently selected from CR or N; and one of X 2 , X 3 and X 4 is a C atom attached to the mother nucleus;
  • Ar is selected from the group consisting of the following groups optionally substituted by one or two R:
  • the present invention relates to the aforementioned compound, which is of Formula (Ia), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • the present invention relates to the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Ar is Wherein X 1 to X 4 are as defined herein;
  • Ar is selected from the group consisting of the following groups optionally substituted by one or two R:
  • R and R b are as defined herein.
  • the present invention relates to the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Ar is Wherein X 5 to X 8 are as defined herein;
  • Ar is selected from the group consisting of the following: optionally substituted by R:
  • the present invention relates to the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Het is selected from the group consisting of the following groups optionally substituted by one, two, three or more R:
  • Het is selected from the group consisting of:
  • the present invention relates to the aforementioned compound, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Het is Wherein one of X 9 is selected from O, S or NR b , the other X 9 optionally present is C(R) 2 , and m, n, R and R b are as defined herein;
  • Het is selected from the group consisting of:
  • the present invention relates to the aforementioned compound, which is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Ar is Wherein X 2 to X 4 are independently selected from CR or N, and one of X 2 , X 3 and X 4 is a C atom attached to the mother nucleus;
  • Ar is selected from the group consisting of the following groups optionally substituted by one or two R:
  • R is selected from the group consisting of hydrogen, halogen, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 .
  • the present invention relates to the aforementioned compound, which is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Ar is selected from the following groups optionally substituted by one or two R:
  • R is selected from the group consisting of hydrogen, halogen, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 .
  • the present invention relates to the aforementioned compound, which is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Ar is selected from the following groups optionally substituted by one or two R:
  • R is selected from hydrogen and a hydroxyl group.
  • the present invention relates to the aforementioned compound, which is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Ar is selected from the following groups optionally substituted by one or two R:
  • R is selected from the group consisting of hydrogen, halogen, and hydroxyl.
  • the present invention relates to the aforementioned compound, which is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Ar is selected from the following groups optionally substituted by one or two R:
  • R is selected from hydrogen and a hydroxyl group.
  • the present invention relates to the aforementioned compound, which is of Formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof:
  • Ar is selected from the following groups optionally substituted by one or two R:
  • R is selected from the group consisting of hydrogen, halogen, and hydroxyl.
  • the present invention relates to the aforementioned compound, which is a compound of the formula (Ib), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Ar is Wherein X 2 to X 4 are independently selected from CR or N, and one of X 2 , X 3 and X 4 is a C atom attached to the mother nucleus and at least one of them is N;
  • Ar is selected from the following groups optionally substituted with one R:
  • R b is selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R is selected from the group consisting of hydrogen, halogen, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 .
  • the present invention relates to the aforementioned compound, which is a compound of the formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Ar is selected from the following groups optionally substituted by one or two R:
  • R is selected from the group consisting of hydrogen, halogen, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 .
  • the present invention relates to the aforementioned compound, which is a compound of the formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Ar is selected from the following groups:
  • the present invention relates to the aforementioned compound, which is a compound of the formula (Ic), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, wherein:
  • Ar is selected from the following groups:
  • Y 1 is N; in another specific embodiment, Y 1 is CR a ; in another specific embodiment, Y 1 is CH.
  • Y is CR a ; in another specific embodiment, Y is N; in another specific embodiment, Y is CH.
  • R 1 is selected from hydrogen, halogen, nitrile, nitro, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R 1 is selected from hydrogen, halo , nitrile, nitro or C 1-6 alkyl; in another embodiment, R 1 is selected from hydrogen or halogen; in another particular embodiment, R 1 is hydrogen; in another specific embodiment R 1 is halogen (F, Cl, Br or I); in another specific embodiment, R 1 is a nitrile group; in another specific embodiment, R 1 is a nitro group; in another embodiment , R 1 is C 1-6 alkyl (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, etc.); in particular embodiments, R 1 is C 1-6 haloalkyl group (-CF 3, -CH 2 F, -CHF 2, -CC
  • R 2 is selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R 2 is selected from C 1-6 alkyl or C 1-6 Haloalkyl; in another specific embodiment, R 2 is hydrogen; in another specific embodiment, R 2 is C 1-6 alkyl (methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, tert-butyl, pentyl, isopentyl, hexyl, etc.); in another specific 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 , 2-trifluoride
  • Z is a chemical bond; in another specific embodiment, Z is O; in another specific embodiment, Z is S(O) 0-2 ; in another specific embodiment, Z Is NR b ; in another specific embodiment, Z is NH.
  • -ZR 2 together represents -SF 5 .
  • Ar is Wherein X 1 is O or S; in a more specific embodiment, Ar is In a more specific embodiment, Ar is In a more specific embodiment, Ar is
  • X 2 is CR; in another specific embodiment, X 2 is CH; in another specific embodiment, X 2 is N.
  • X 3 is CR; in another specific embodiment, X 3 is CH; in another specific embodiment, X 3 is N.
  • X 4 is CR; In another embodiment, X 4 is CH; In another embodiment, X 4 is N.
  • one of X 2 , X 3 and X 4 is a C atom attached to the parent core; in a specific embodiment, X 2 is a C atom attached to the parent core; in another embodiment Wherein X 3 is a C atom attached to the mother nucleus; in another specific embodiment, X 4 is a C atom attached to the parent nucleus.
  • Ar is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethy
  • X 2 is CR; in another specific embodiment, X 2 is CH; in another specific embodiment, X 2 is N.
  • X 3 is CR; in another specific embodiment, X 3 is CH; in another specific embodiment, X 3 is N.
  • X 4 is CR; In another embodiment, X 4 is CH; In another embodiment, X 4 is N.
  • one of X 2 , X 3 and X 4 is a C atom bonded to the mother nucleus and at least one of them is N; in a specific embodiment, X 2 is a C atom bonded to the mother nucleus, X 3 is N; in another specific embodiment, X 2 is a C atom attached to the parent core, and X 4 is N; in another specific embodiment, X 3 is a C atom attached to the parent core, X 2 Is N; in another specific embodiment, X 3 is a C atom attached to the mother nucleus, and X 4 is N; in another specific embodiment, X 4 is a C atom attached to the mother nucleus, and X 2 is N In another specific embodiment, X 4 is a C atom attached to the parent core and X 3 is N.
  • X 5 is CR; In another embodiment, X 5 is CH; In another embodiment, X 5 is N.
  • X 6 is CR; In another embodiment, X 6 are CH; In another embodiment, X 6 is N.
  • X 7 is CR; In another particular embodiment, X 7 is CH; In another particular embodiment, X 7 is N.
  • X 8 is CR; In another embodiment, X 8 is CH; In another embodiment, X 8 is N.
  • Ar is the following group optionally substituted with one or two R:
  • Ar is the following group optionally substituted with one R:
  • Ar is the following group optionally substituted by R:
  • Het is
  • X 9 is O; in another specific embodiment, X 9 is S; in another specific embodiment, X 9 is NR b ; in another specific embodiment, X 9 is C(R) 2 .
  • m is 0; in another specific embodiment, m is 1; in another specific embodiment, m is 2.
  • n is 0; in another specific 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.
  • Het is Wherein X 9 is C(R) 2 . In a more specific embodiment, Het is selected from the group consisting of: one, two, three or more, R, substituted:
  • Het is selected from the group consisting of:
  • Het is Wherein one of X 9 is selected from O, S or NR b , and the other X 9 optionally present is C(R) 2 ; in a more specific embodiment, Het is selected from the group consisting of:
  • R a is independently selected from the group consisting of hydrogen, halogen, nitrile, nitro, hydroxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; in another specific embodiment, R a is hydrogen; in another specific embodiment, R a is halogen; In a particular embodiment, R a is a nitrile group; in another specific embodiment, R a is a nitro group; in another specific embodiment, R a is a hydroxyl group; in another specific embodiment, R a is - NH 2 ; In another specific embodiment, R a is -NHC 1-6 alkyl; in another specific embodiment, R a is -N(C 1-6 alkyl) 2 ; In one embodiment, R a is C 1-6 alkyl; in another specific embodiment, R a is C 1-6 haloalkyl; in one embodiment, R
  • R b is independently selected from hydrogen, C 1-6 alkyl or C 1-6 haloalkyl; in another specific embodiment, R b is hydrogen; in another specific embodiment, R b is C 1-6 alkyl; in another specific embodiment, R b is C 1-6 haloalkyl.
  • R 1a , R 2a and R are independently selected from the group consisting of hydrogen, halogen, hydroxy, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, C 6-10 aryl or C 5-10 heteroaryl
  • R 1a , R 2a and R are hydrogen; in another specific embodiment, R 1a , R 2a and R are halogen; in another specific embodiment, R 1a , R 2a and R are hydroxy; in another specific embodiment, R 1a , R 2a and R are -NH 2 ; in another specific embodiment, R 1a , R 2a and R are -NHC 1-6 alkyl; In another specific embodiment, R 1a , R 2a and R are -N(C 1-6 alkyl) 2
  • two R groups on the same atom or on adjacent atoms may together form a C3-7 cycloalkyl, C3-7 heterocycloalkyl, C6-10 aryl or C5- 10 heteroaryl; in another embodiment, the same atom or two adjacent atoms on the R groups can together form a C 3-7 cycloalkyl group; in another embodiment, the same atom or adjacent The two R groups on the atom may together form a C3-7 heterocycloalkyl group. In another specific embodiment, two R groups on the same atom or adjacent atoms may together form a C 6-10 aryl group; in another specific embodiment, two R on the same atom or adjacent atoms The groups may together form a C 5-10 heteroaryl group.
  • any one of the above specific embodiments, or any combination thereof, may be combined with any one of the other specific embodiments or any combination thereof.
  • any one of Y 1 or any combination thereof may be combined with Y, R 1 , R 2 , Z, Ar, X 1 to X 9 , Het, m, n, R a , R b , R 1a , R Any of the technical solutions of 2a and R or any combination thereof.
  • the present invention is intended to include a combination of all such technical solutions, which are limited in scope and are not listed one by one.
  • the compounds of the invention may be selected from the group consisting of:
  • 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.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the compounds of the invention show therapeutic efficacy especially for diseases or disorders that are dependent on the activity of Bcr-Abll.
  • the compounds of the invention inhibit the ATP binding site of Bcr-Abl1 (including wild-type Bcr-Abl1 and/or its mutations (including T315I mutations)).
  • Invasive pseudopods are used to degrade extracellular matrices during tumor cell invasion and metastasis.
  • Abl kinase activity is required for Src-induced invasion of pseudopod formation, which regulates the different stages and functions of invasive pseudopod assembly.
  • the compounds of the invention as Abl inhibitors have potential as therapeutics for the treatment of metastatic invasive cancers.
  • Inhibitors of c-Abl kinase can be used to treat brain cancer: including glioblastoma, the most common and most aggressive malignant primary brain tumor, in which immunohistochemistry can be achieved in a subset of patients The technique detects the expression of c-Abl.
  • new c-Abl inhibitors with high brain exposure represent a solid therapeutic approach to glioblastoma and other brain cancers.
  • the compounds of the invention may be used to treat viruses.
  • viral infection can 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. It is therefore expected that a compound of the invention that inhibits c-Abl kinase can be used to reduce the ability of a pathogen to replicate.
  • 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 patients with sporadic Parkinson's disease. At the same time, Parkin is tyrosine-phosphorylated, causing loss of its ubiquitin protein ligase and cytoprotective activity, as shown by the accumulation of Parkin substrate.
  • the compounds or compositions of the invention are also useful in the treatment of diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis , ulcerative colitis, Crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor , thyroid cancer, systemic mastocytosis, eosinophilia syndrome, fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease , seminoma, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial neoplasia, melanom
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the drug composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose; a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrant For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • 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, part 8 of which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the invention are also useful in the treatment of diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative Colitis, Crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after transplantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumor, thyroid cancer , systemic mastocytosis, eosinophilia syndrome, fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft versus host disease, neurofibromatosis, pulmonary hypertension, Alzheimer's disease, spermatogenesis Cell tumor, dysgerminoma, mast cell tumor, lung cancer, bronchial carcinoma, dysgerminoma, testicular intraepithelial neoplasia, melanoma
  • the 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 be, for example, in the form of an abnormal increase in activity, or a timing and/or controlled aberration of Bcr-Abl activity.
  • Such inappropriate activity can result, for example, from overexpression or mutation of an activated protein kinase that results in inappropriate or uncontrolled.
  • the invention relates to a method of modulating, modulating or inhibiting Bcr-Abl for the prevention and/or treatment of a disorder associated with dysregulated or inappropriate Bcr-Abl activity.
  • condition mediated by Bcr-Abl activity is a respiratory disease.
  • condition is a proliferative disorder.
  • condition is cancer.
  • condition is leukemia.
  • the compounds of the invention may also be used to treat neurodegeneration.
  • natural c-ABL tyrosine kinase remains relatively static in healthy adult brains, it can be activated in the brains of patients with CNS disease, including neurodegenerative diseases such as Alzheimer's disease (AD). , Parkinson's disease (AD), frontotemporal dementia (FTD), Pick's disease, Type N Niemann-Pick disease (NPC) and other degenerative diseases, inflammatory diseases and autoimmune diseases and Ageing.
  • AD Alzheimer's disease
  • FTD frontotemporal dementia
  • NPC Type N Niemann-Pick disease
  • an effective amount of a compound of the invention will generally be administered in a single or multiple doses at an average daily dose of from 0.01 mg to 50 mg of compound per kilogram of patient body weight, preferably from 0.1 mg to 25 mg of compound per kilogram of patient body weight.
  • the compounds of the invention may be administered to a patient in need of such treatment in a daily dosage range of from about 1 mg to about 3500 mg per patient, preferably from 10 mg to 1000 mg.
  • the daily dose per patient can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000 mg. It can be administered one or more times daily, weekly (or several days apart) or on an intermittent schedule.
  • the compound can be administered one or more times per day on a weekly basis (e.g., every Monday), continually or for several weeks, such as 4-10 weeks.
  • the administration may be continued for several days (e.g., 2-10 days), followed by a few days (e.g., 1-30 days) without administration of the compound, and the cycle may be repeated indefinitely or repeated for a given number of times, such as 4-10 Cycles.
  • the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then administered daily for 5 days, then intermittent for 9 days, and so on, optionally repeating the cycle or repeating 4-10 times.
  • the compounds of the present invention can be prepared according to conventional methods in the art and using suitable reagents, starting materials, and purification methods known to those skilled in the art.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Step 1 Synthesis of 6-chloro-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 2).
  • Step 2 Synthesis of (R)-6-(3-hydroxypyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 4).
  • Step 3 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of 2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 5).
  • Step 4 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(isothiazol-3-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide Synthesis of (Compound 6).
  • Step 1 Synthesis of 6-chloro-5-(2-trimethylsilylethyn-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 9).
  • Step 2 Synthesis of 6-chloro-5-ethynyl-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 10).
  • Step 3 Synthesis of 6-chloro-5-(1H-1,2,3-triazol-5-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 11) .
  • Step 4 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-1,2,3-triazol-5-yl)-N-(4-(chlorodifluoromethyl) Synthesis of oxy)phenyl)nicotinamide (Compound 12).
  • Step 1 (R)-6-(3-tert-Butyldimethylsilyloxypyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl) Synthesis of amide (Compound 13).
  • Step 2 (R)-6-(3-tert-Butyldimethylsilylpyrrolidin-1-yl)-5-cyano-N-(4-(chlorodifluoromethoxy)phenyl) Synthesis of nicotinamide (Compound 14).
  • Step 3 (R)-6-(3-tert-Butyldimethylsilyloxypyrrolidin-1-yl)-5-(1H-1,2,3,4-tetrazol-5-yl)- Synthesis of N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 15).
  • Step 4 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-1,2,3,4-tetrazol-5-yl)-N-(4-(chlorodi) Synthesis of fluoromethoxy)phenyl)nicotinamide (Compound 16).
  • Step 1 Synthesis of (R)-6-(3-hydroxypyrrolidin-1-yl)-5-cyano-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 17) .
  • Step 2 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-aminothioformyl-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 18 )Synthesis.
  • Step 3 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-((dimethylamino)methyleneaminothioformyl)-N-(4-(chlorodifluoromethoxy) Synthesis of phenyl)nicotinamide (Compound 19).
  • Step 4 (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1,2,4-thiadiazol-5-yl)-N-(4-(chlorodifluoromethoxy) Synthesis of phenyl)nicotinamide (Compound 20).
  • Step 1 Synthesis of (R)-6-(3-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 21).
  • Step 2 (R)-6-(3-Fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of 2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 22).
  • Step 3 (R)-6-(3-Fluoropyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide Synthesis of (Compound 23).
  • Step 1 (R)-6-(3-Dimethylaminopyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 29) synthesis.
  • Step 2 (R)-6-(3-Dimethylaminopyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane Synthesis of pentan-2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 30).
  • Step 3 (R)-6-(3-Dimethylaminopyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl) Synthesis of nicotinamide (Compound 31).
  • Step 1 Synthesis of 3-hydroxy-4-fluoro-N-tert-butoxycarbonylpyrrolidine (Compound 38).
  • Step 3 Synthesis of 6-(3-hydroxy-4-fluoropyrrolidin-1-yl)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 40).
  • Step 4 6-(3-Hydroxy-4-fluoropyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Synthesis of 2-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Compound 41).
  • Step 5 6-(3-Hydroxy-4-fluoropyrrolidin-1-yl)-5-(isothiazol-4-yl)-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide Synthesis of (Compound 42).
  • 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 parental cell, Ba/F 3 Bcr-Abl T315I (purchased from American Standard Collection of Biological Products, ATCC), live cell assay kit CellTiter-Glo4 (Promega, catalog number G7572), 96-well black Wall clear flat bottom cell culture plates (Corning, Cat. No. 3340).
  • test compound was dissolved in DMSO and subjected to a 3.16-fold gradient dilution, 9 compound concentrations, and a three-fold experiment was performed with a starting concentration of 10 ⁇ M.
  • Compound Treatment of Cells Compounds of various concentrations were transferred to cell plates. The cell plates were incubated in a carbon dioxide incubator for 3 days.
  • Example proliferation embodiment are summarized in the following Table 1, wherein A represents an IC 50 ⁇ 100nM, B represents 100nM ⁇ IC 50 ⁇ 500nM, C represents 500nM ⁇ IC 50 ⁇ 1000nM, D represents the IC 50> 1000nM.
  • the compounds of the present invention exhibited relatively low inhibitory activity against Ba/F 3 cells associated with drug side effects (IC 50 greater than 1000 nM), while cells expressing Ba/F 3 Bcr-Abl T315I mutants showed excellent results. Inhibitory activity (optimal IC 50 ⁇ 100 nM), therefore the compounds of the invention can be used as Bcr-Abl inhibitors for tumor patients who are resistant or resistant to treatment with existing tyrosine kinase inhibitors (TKI), for example, chronic Patients with chronic, blast, and accelerated phase of granulocytic leukemia (CML) and Philadelphia chromosome-positive (Ph + ) chronic myeloid leukemia and acute lymphoblastic leukemia have good prospects.
  • TKI tyrosine kinase inhibitors
  • the compounds of the present invention has excellent therapeutic index (obtained from the Ba / F 3 IC 50 divided by the parent cell Ba / F 3 Bcr-Abl T315I of the IC 50), for example the compound of Example 2 has a higher 180 The therapeutic index, the compound of Example 3 has a therapeutic index above 90.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • Example 18 Pharmacodynamic evaluation of BA/F3 (BCR-ABL T315I ) subcutaneous tumor model
  • mice NOD/SCID mice, female, 7-8 weeks (week age at tumor cell inoculation), average body weight 21.8 g, 32, purchased from Beijing Huakang Biotechnology Co., Ltd., animal certificate number :11401300068166.
  • Feeding environment SPF level.
  • the experimental animals were kept in a separate ventilated box with constant temperature and humidity.
  • the temperature of the breeding room was 22.3-24.5 °C, the humidity was 51-58%, the ventilation was 10-20 times/hour, and the alternating time between day and night was 12h. /12h;
  • the rat rat box is a polysulfone mouse box, which is used after autoclaving.
  • the specification is 325mm ⁇ 210mm ⁇ 180mm.
  • the litter is autoclaved corn cob, 4 animals per box.
  • the IACUC approval number, experiment number and experiment are indicated on the cage card. Start time, project leader, experimenter, animal source, group, animal number, etc.; experimental animals were tagged with ear tags.
  • Each NOD/SCID mouse was subcutaneously inoculated with 5 ⁇ 10 6 BA/F3 (BCR-ABL T315I ) cells in the right dorsal area. The cells were resuspended in PBS (0.1 ml/d) to establish a subcutaneous tumor model.
  • the test was divided into vehicle control group, positive control ABL001 15 mg/kg group, compound example 2 15 mg/kg group; 6 mice in each group were administered twice a day, vehicle control group was administered for 15 days, positive control ABL00115 mg/kg. The group was administered for 19 days, and the compound example 2 was administered for 15 days in the 15 mg/kg group.
  • TGI tumor inhibition rate
  • TGI% (1-T/C) ⁇ 100%.
  • T/C% is the relative tumor growth rate, that is, the percentage of tumor volume or tumor weight relative to the treatment group and the control group at a certain time point.
  • T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively.
  • the compounds of the invention have better anti-tumor effects and better safety.
  • TGI tumor inhibition rate

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Abstract

提供了一种式(I)所示的对蛋白激酶活性具有抑制作用的（杂）芳基酰胺类化合物、其药学上可接受的盐、立体异构体、溶剂合物或水合物，含有该化合物或其衍生物的药物组合物，以及化合物的制备方法。该化合物可作为蛋白激酶的不可逆抑制剂，用于制备多种药物，包括抗肿瘤药物。

Description

用于抑制蛋白激酶活性的(杂)芳基酰胺类化合物 技术领域
本发明属于医药领域。具体地，本发明涉及对Abelson蛋白(Abl1)、Abelson相关蛋白(Abl2)和相关的嵌合蛋白质、特别是Bcr-Abl1的酪氨酸激酶酶活性具有抑制作用的(杂)芳基酰胺类化合物，包含它们的药物组合物，以及它们的制备方法和用途。
背景技术
蛋白酪氨酸激酶(PTKs)是一类属于蛋白质酶系的激酶，其能够催化ATP上γ-磷酸转移到蛋白酪氨酸残基上，通过催化多种蛋白酪氨酸残基上的酚羟基发生磷酸化，进而激活功能蛋白。蛋白酪氨酸激酶在细胞内的信号传导通路中占据着十分重要的地位，调节细胞生长、分化、死亡等一系列生理生化过程。蛋白酪氨酸激酶的异常表达可以导致细胞增殖调节发生紊乱，进而导致肿瘤的发生。此外，蛋白酪氨酸激酶的异常表达还与肿瘤的侵袭和转移，肿瘤新生血管的生成，肿瘤的化疗抗药性密切相关。
Bcr-Abl融合基因表达出的酪氨酸激酶能引起细胞增殖、黏附和生存性质的改变，导致多种肿瘤的产生。抑制Bcr-Abl酪氨酸激酶可有效抑制肿瘤生长。
ABL-001(又名Asciminib，化学名为(R)-N-(4-(氯二氟甲氧基)苯基)-6-(3-羟基吡咯烷-1-基)-5-(1H-吡唑-5-基)烟酰胺，其具有以下结构式)是诺华制药公司研发的ABL1激酶变构抑制剂，靶向ABL1的肉豆蔻酰口袋而致其失活，与ATP竞争性BCR-ABL酪氨酸激酶的抑制剂联用可有效预防ATP抑制剂和/或变构抑制剂应用的抗药性的出现。已证明ABL-001与第二代BCR-ABL抑制剂尼洛替尼联用，在小鼠模型中可以起到根治CML的效果(Andrew A.Wylie等人(2017)Nature 543，733-737)。诺华正在开发ABL-001与多个ATP竞争性BCR-ABL抑制剂联用的临床治疗方案，包括伊马替尼、尼洛替尼和达沙替尼。
Figure PCTCN2018073338-appb-000001
因此，有必要进一步研发新的Bcr-Abl抑制剂。
发明内容
本发明提供了一种新的(杂)芳基酰胺类化合物及包含该化合物的组合物及其用途，其具有更好的Bcr-Abl激酶抑制活性(尤其对于T315I突变)、更低的副作用和/或更好的药效学/药代动力学性能，可用于治疗由Bcr-Abl激酶介导的疾病。
对此，本发明采用的技术方案如下：
本发明的第一方面中，提供了一种式(I)所示的(杂)芳基酰胺类化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000002
其中：
Y 1选自CR a或N；
Y独立地选自CR a或N；
R 1选自氢、卤素、腈基、硝基、C 1-6烷基或C 1-6卤代烷基，其中所述C 1-6烷基或C 1-6卤代烷基任选被R 1a基团取代；
R 2选自氢、C 1-6烷基或C 1-6卤代烷基，其中所述C 1-6烷基或C 1-6卤代烷基任选被R 2a基团取代；
Z为化学键、O、S(O) 0-2或NR b；
或者-Z-R 2一起表示-SF 5；
Ar为
Figure PCTCN2018073338-appb-000003
其中X 1选自O、S或NR b，X 2至X 8独立地选自CR或N；
并且当X 1为O或S时，X 2、X 3和X 4中的一个为与母核连接的C原子；当X 1为NR b时，X 2、X 3和X 4中的一个为与母核连接的C原子并且其中至少一个为N；
Het为
Figure PCTCN2018073338-appb-000004
其中X 9选自O、S、NR b或C(R) 2；
m为0、1或2；
n为0、1、2、3、4、5或6；
R a独立地选自氢、卤素、腈基、硝基、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
R b独立地选自氢、C 1-6烷基或C 1-6卤代烷基；
R 1a、R 2a和R独立地选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基；
或者相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。
在另一方面，本发明提供了包含本发明化合物，和其它治疗剂以及药学上可接受的载剂、佐剂或 媒剂的试剂盒。
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防Bcr-Abl导致的疾病的药物中的用途。
在另一个方面，本发明提供了在受试者中治疗和/或预防Bcr-Abl导致的疾病，包括向所述受试者给药本发明化合物或本发明组合物。
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防Bcr-Abl导致的疾病。
在具体实施方案中，所述疾病可选自：实体瘤、肉瘤、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病。
在具体实施方案中，所述Bcr-Abl导致的疾病是慢性粒细胞白血病、胃肠道间质瘤、急性粒细胞白血病、甲状腺癌、转移的浸润性癌或其组合。
在另一方面，本发明化合物可用于治疗和/或预防与野生型Abl的异常激活的激酶活性相关的疾病或障碍，所述疾病或障碍包括非恶性疾病或障碍、诸如CNS疾病、特别是神经变性疾病(例如阿尔茨海默病、帕金森病)、运动神经元病(肌萎缩侧索硬化)、肌营养不良、自身免疫疾病和炎症性疾病(糖尿病和肺纤维化)、病毒感染、朊病毒病。
在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。
由随后的具体实施方案、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-6烷基”包括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和C 5-6烷基。
应该理解，当本文描述时，任何下面所定义的部分可以被许多取代基取代，而且相应的定义在下面列出的它们的范围内，包括这种取代部分。除非另作说明，否则，术语“取代”如下面所定义。
“C 1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团，本文也称为“低级烷基”。在一些实施方案中，C 1-4烷基是特别优选的。所述烷基的实例包括但不限于：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)和正己基(C 6)。除非另作说明，否则，烷基的每个独立地任选被取代，即，未取代的(“未取代的烷基”)或被一个或多个取代基取代(“取代的烷基”)；例如，1至5个取代基、1至3个取代基或1个取代基。在一些实施方案中，烷基是未取代的C 1-6烷基(例如，-CH 3)。 在一些实施方案中，烷基是取代的C 1-6烷基。
“C 1-6烷氧基”是指基团-OR，其中，R为取代或未取代的C 1-6烷基。在一些实施方案中，C 1-4烷氧基是特别优选的。具体的所述烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中，卤素基团是F、Cl或Br。在一些实施方案中，卤素基团是Cl。在一些实施方案中，卤素基团是F。在一些实施方案中，卤素基团是Br。
因此，“C 1-6卤代烷基”是指上述“C 1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-4卤代烷基是特别优选的，更优选C 1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CClF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CF 2CClF 2、-CF 2CH 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。
“C 3-7环烷基”是指具有3至7个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C 3-6环烷基是特别优选的，更优选C 5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)、环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)，等等。除非另作说明，否则环烷基的每个独立地为任选取代的，即，未取代的(“未取代的环烷基”)或被一个或多个取代基取代(“取代的环烷基”)。在一些实施方案中，环烷基是未取代的C 3-7环烷基。在一些实施方案中，碳环基是取代的C 3-7环烷基。
“C 3-7杂环烷基”或是指具有环碳原子和1至4个环杂原子的3至7元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环烷基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，C 3-6杂环烷基是特别优选的，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；更优选C 5-6杂环烷基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。除非另作说明，否则，杂环烷基的每个独立地为任选取代的，即，未取代的(“未取代的杂环烷基”)或被一个或多个取代基取代(“取代的杂环烷基”)。在一些实施方案中，杂环烷基是未取代的C 3-7杂环烷基。在一些实施方案中，杂环烷基是取代的C 3-7杂环烷基。杂环烷基还包括其中上述杂环烷基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环烷基环上；且在这样的情况下，环成员的数目继续表示在杂环烷基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环烷基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环烷基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环烷基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环烷基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环烷基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包 含一个杂原子的6元杂环烷基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环烷基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环烷基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环烷基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C 6芳基环稠合的5元杂环烷基(在本文中也称作5,6-双环杂环烷基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C 6芳基环稠合的6元杂环烷基(本文还指的是6,6-双环杂环烷基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。
“C 6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环烷基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。除非另作说明，否则，芳基的每个独立地任选被取代，即，未取代(“未取代的芳基”)或被一个或多个取代基取代(“取代的芳基”)。在一些实施方案中，芳基是未取代的C 6-10芳基。在一些实施方案中，芳基是取代的C 6-10芳基。
“C 5-10杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环烷基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，C 5-6杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。除非另作说明，否则，杂芳基的每个独立地任选被取代的，即，未取代(“未取代的杂芳基”)或被一个或多个取代基取代(“取代的杂芳基”)。在一些实施方案中，杂芳基是未取代的5-10元杂芳基。在一些实施方案中，杂芳基是取代的5-10元杂芳基。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋 啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
“氰基”表示基团-CN。
“硝基”表示基团-NO 2。
其它定义
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适无机和有机酸和碱的盐。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其它疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“Bcr-Abl1”是指由裂点簇区(BCR)基因的N-端外显子和Abelson(Abl1)基因的主要的C-端部分(外显子2-11)形成的融合蛋白。最常见的融合转录物编码210-kDa蛋白质(p210Bcr-Abl1)，较罕见的转录物编码190-kDa蛋白质(p190Bcr-Abl1)和230-kDa蛋白质(p230Bcr-Abl1)。这些蛋白的Abl1序列包含在野生型蛋白质中严格调节、但在Bcr-Abl1融合蛋白中组成性激活的Abl1酪氨酸激酶域。该失调 的酪氨酸激酶与多种导致细胞转化和增殖失调的细胞细胞信号传导通路相互作用。
“Bcr-Abl1突变体”是指Bcr-Abl1中的众多单一位点突变，包括：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、His396→Pro、Phe311→Ile、His396→Arg、Phe311→Leu、Ser417→Tyr、Thr315→Ile、Glu459→Lys和Phe486→Ser。
“c-Abl”是指非-突变的野生型Abl1的全长基因产物。
具体实施方案
化合物
本文中，“本发明化合物”指的是以下的式(I)、式(Ia)和式(Ib)化合物、其药学上可接受的盐、立体异构体、溶剂合物或水合物。
在一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000005
其中：
Y 1选自CR a或N；
Y独立地选自CR a或N；
R 1选自氢、卤素、腈基、硝基、C 1-6烷基或C 1-6卤代烷基，其中所述C 1-6烷基或C 1-6卤代烷基任选被R 1a基团取代；
R 2选自氢、C 1-6烷基或C 1-6卤代烷基，其中所述C 1-6烷基或C 1-6卤代烷基任选被R 2a基团取代；
Z为化学键、O、S(O) 0-2或NR b；
或者-Z-R 2一起表示-SF 5；
Ar为
Figure PCTCN2018073338-appb-000006
其中X 1选自O、S或NR b，X 2至X 8独立地选自CR或N；
并且当X 1为O或S时，X 2、X 3和X 4中的一个为与母核连接的C原子；当X 1为NR b时，X 2、X 3和X 4中的一个为与母核连接的C原子并且其中至少一个为N；
Het为
Figure PCTCN2018073338-appb-000007
其中X 9选自O、S、NR b或C(R) 2；
m为0、1或2；
n为0、1、2、3、4、5或6；
R a独立地选自氢、卤素、腈基、硝基、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
R b独立地选自氢、C 1-6烷基或C 1-6卤代烷基；
R 1a、R 2a和R独立地选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基；
或者相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基。
在另一个实施方案中，本发明涉及上述化合物，其中
Ar为
Figure PCTCN2018073338-appb-000008
其中X 1为S，X 2至X 4独立地选自CR或N；并且X 2、X 3和X 4中的一个为与母核连接的C原子；
或者，Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000009
在另一个实施方案中，本发明涉及上述化合物，其为式(Ia)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000010
其中，Ar和Het如本文所定义。
在另一个实施方案中，本发明涉及上述化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Ar为
Figure PCTCN2018073338-appb-000011
其中，X 1至X 4如本文所定义；
或者，Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000012
Figure PCTCN2018073338-appb-000013
Figure PCTCN2018073338-appb-000014
其中，R和R b如本文所定义。
在另一个实施方案中，本发明涉及上述化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Ar为
Figure PCTCN2018073338-appb-000015
其中，X 5至X 8如本文所定义；
或者，Ar选自任选被R取代的以下基团：
Figure PCTCN2018073338-appb-000016
其中，R如本文所定义。
在另一个实施方案中，本发明涉及上述化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Het为
Figure PCTCN2018073338-appb-000017
其中，X 9为C(R) 2，并且m、n和R如本文所定义；
或者，Het选自任选被一个、两个、三个或更多个R取代的以下基团：
Figure PCTCN2018073338-appb-000018
其中R如本文所定义；
或者，Het选自以下基团：
Figure PCTCN2018073338-appb-000019
Figure PCTCN2018073338-appb-000020
在另一个实施方案中，本发明涉及上述化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Het为
Figure PCTCN2018073338-appb-000021
其中，其中一个X 9选自O、S或NR b，任选存在的其他X 9为C(R) 2，并且m、n、R和R b如本文所定义；
或者，Het选自以下基团：
Figure PCTCN2018073338-appb-000022
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000023
其中：
Ar为
Figure PCTCN2018073338-appb-000024
其中X 2至X 4独立地选自CR或N，并且X 2、X 3和X 4中的一个为与母核连接的C原子；
或者，Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000025
Figure PCTCN2018073338-appb-000026
R选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000027
其中：
Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000028
R选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000029
其中：
Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000030
R选自氢、羟基。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000031
其中：
Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000032
R选自氢、卤素、羟基。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000033
其中：
Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000034
R选自氢、羟基。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
Figure PCTCN2018073338-appb-000035
其中：
Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000036
R选自氢、卤素、羟基。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Figure PCTCN2018073338-appb-000037
其中：
Ar为
Figure PCTCN2018073338-appb-000038
其中X 2至X 4独立地选自CR或N，并且X 2、X 3和X 4中的一个为与母核连接的C原子并且其中至少一个为N；
或者，Ar选自任选被一个R取代的以下基团：
Figure PCTCN2018073338-appb-000039
R b选自氢、C 1-6烷基或C 1-6卤代烷基；
R选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ic)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Figure PCTCN2018073338-appb-000040
其中：
Ar选自任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000041
Figure PCTCN2018073338-appb-000042
R选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2。
在另一个实施方案中，本发明涉及上述化合物，其为式(Ic)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Figure PCTCN2018073338-appb-000043
其中：
Ar选自以下基团：
Figure PCTCN2018073338-appb-000044
在另一个实施方案中，本发明涉及上述化合物，其为式(Ic)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
Figure PCTCN2018073338-appb-000045
其中：
Ar选自以下基团：
Figure PCTCN2018073338-appb-000046
Y 1和Y
在一个具体实施方案中，Y 1为N；在另一个具体实施方案中，Y 1为CR a；在另一个具体实施方案中，Y 1为CH。
在一个具体实施方案中，Y为CR a；在另一个具体实施方案中，Y为N；在另一个具体实施方案中，Y为CH。
R 1
在一个具体实施方案中，R 1选自氢、卤素、腈基、硝基、C 1-6烷基或C 1-6卤代烷基；在另一个具体实施方案中，R 1选自氢、卤素、腈基、硝基或C 1-6烷基；在另一个具体实施方案中，R 1选自氢或卤素；在另一个具体实施方案中，R 1为氢；在另一个具体实施方案中，R 1为卤素(F、Cl、Br或I)；在另一个具体实施方案中，R 1为腈基；在另一个具体实施方案中，R 1为硝基；在另一个具体实施方案中，R 1为C 1-6烷基(甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基，等)；在另一个具体实施方案中，R 1为C 1-6卤代烷基(-CF 3、-CH 2F、-CHF 2、-CClF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CF 2CClF 2、-CF 2CH 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等)。
R 2和Z
在一个具体实施方案中，R 2选自氢、C 1-6烷基或C 1-6卤代烷基；在另一个具体实施方案中，R 2选自C 1-6烷基或C 1-6卤代烷基；在另一个具体实施方案中，R 2为氢；在另一个具体实施方案中，R 2为C 1-6烷基(甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、己基，等)；在另一个具体实施方案中，R 2为C 1-6卤代烷基(-CF 3、-CH 2F、-CHF 2、-CClF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CF 2CClF 2、-CF 2CH 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等)。
在一个具体实施方案中，Z为化学键；在另一个具体实施方案中，Z为O；在另一个具体实施方案中，Z为S(O) 0-2；在另一个具体实施方案中，Z为NR b；在另一个具体实施方案中，Z为NH。
在一个具体实施方案中，-Z-R 2一起表示-SF 5。
Ar和X 1至X 8
在一个具体实施方案中，Ar为
Figure PCTCN2018073338-appb-000047
其中X 1为O或S；在更具体的实施方案中，Ar为
Figure PCTCN2018073338-appb-000048
Figure PCTCN2018073338-appb-000049
在更具体的实施方案中，Ar为
Figure PCTCN2018073338-appb-000050
在上述关于Ar的具体实施方案中，X 2为CR；在另一个具体实施方案中，X 2为CH；在另一个具体实施方案中，X 2为N。在上述关于Ar的实施方案中，X 3为CR；在另一个具体实施方案中，X 3为CH；在另一个具体实施方案中，X 3为N。在上述关于Ar的具体实施方案中，X 4为CR；在另一个具体实施方案中，X 4为CH；在另一个具体实施方案中，X 4为N。
在上述实施方案中，X 2、X 3和X 4中的一个为与母核连接的C原子；在一个具体实施方案中，X 2为与母核连接的C原子；在另一个具体实施方案中，X 3为与母核连接的C原子；在另一个具体实施方案中，X 4为与母核连接的C原子。
在更具体的实施方案中，Ar为
Figure PCTCN2018073338-appb-000051
在上述关于Ar的具体实施方案中，X 2为CR；在另一个具体实施方案中，X 2为CH；在另一个具体实施方案中，X 2为N。在上述关于Ar的实施方案中，X 3为CR；在另一个具体实施方案中，X 3为CH；在另一个具体实施方案中，X 3为N。在上述关于Ar的具体实施方案中，X 4为CR；在另一个具体实施方案中，X 4为CH；在另一个具体实施方案中，X 4为N。
在上述实施方案中，X 2、X 3和X 4中的一个为与母核连接的C原子并且其中至少一个为N；在一个具体实施方案中，X 2为与母核连接的C原子，X 3为N；在另一个具体实施方案中，X 2为与母核连接的C原子，X 4为N；在另一个具体实施方案中，X 3为与母核连接的C原子，X 2为N；在另一个具体实施方案中，X 3为与母核连接的C原子，X 4为N；在另一个具体实施方案中，X 4为与母核连接的C原子，X 2为N；在另一个具体实施方案中，X 4为与母核连接的C原子，X 3为N。
在另一个具体实施方案中，Ar为
Figure PCTCN2018073338-appb-000052
在上述关于Ar的具体实施方案中，X 5为CR；在另一个具体实施方案中，X 5为CH；在另一个具体实施方案中，X 5为N。在上述关于Ar的具体实施方案中，X 6为CR；在另一个具体实施方案中，X 6为CH；在另一个具体实施方案中，X 6为N。在上述关于Ar的具体实施方案中，X 7为CR；在另一个具体实施方案中，X 7为CH；在另一个具体实施方案中，X 7为N。在上述关于Ar的具体实施方案中，X 8为CR；在另一个具体实施方案中，X 8为CH；在另一个具体实施方案中，X 8为N。
在更具体的实施方案中，Ar为任选被一个或两个R取代的以下基团：
Figure PCTCN2018073338-appb-000053
在更具体的实施方案中，Ar为任选被一个R取代的以下基团：
Figure PCTCN2018073338-appb-000054
在更具体的实施方案中，Ar为任选被R取代的以下基团：
Figure PCTCN2018073338-appb-000055
Het、X 9、m和n
在一个具体实施方案中，Het为
Figure PCTCN2018073338-appb-000056
在上述关于Het的具体实施方案中，X 9为O；在另一个具体实施方案中，X 9为S；在另一个具体实施方案中，X 9为NR b；在另一个具体实施方案中，X 9为C(R) 2。在上述关于Het的具体实施方案中，m为0；在另一个具体实施方案中，m为1；在另一个具体实施方案中，m为2。在上述关于Het的具体实施方案中，n为0；在另一个具体实施方案中，n为1；在另一个具体实施方案中，n为2；在另一个具体实施方案中，n为3；在另一个具体实施方案中，n为4；在另一个具体实施方案中，n为5；在另一个具体实施方案中，n为6。
在更具体的实施方案中，Het为
Figure PCTCN2018073338-appb-000057
其中，X 9为C(R) 2。在更具体的实施方案中，Het选自任选被一个、两个、三个或更多个R取代的以下基团：
Figure PCTCN2018073338-appb-000058
在更具体的实施方案中，Het选自以下基团：
Figure PCTCN2018073338-appb-000059
在更具体的实施方案中，Het为
Figure PCTCN2018073338-appb-000060
其中，其中一个X 9选自O、S或NR b，任选存在的其他X 9为C(R) 2，；在更具体的实施方案中，Het选自以下基团：
Figure PCTCN2018073338-appb-000061
R a、R b、R 1a、R 2a和R
在一个具体实施方案中，R a独立地选自氢、卤素、腈基、硝基、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；在另一个具体实施方案中，R a为氢；在另一个具体实施方案中，R a为卤素；在另一个具体实施方案中，R a为腈基；在另一个具体实施方案中，R a为硝基；在另一个具体实施方案中，R a为羟基；在另一个具体实施方案中，R a为-NH 2；在另一个具体实施方案中，R a为-NHC 1-6烷基；在另一个具体实施方案中，R a为-N(C 1-6烷基) 2；在另一个具体实施方案中，R a为C 1-6烷基；在另一个具体实施方案中，R a为C 1-6卤代烷基；在另一个具体实施方案中，R a为C 1-6烷氧基。
在一个具体实施方案中，R b独立地选自氢、C 1-6烷基或C 1-6卤代烷基；在另一个具体实施方案中，R b为氢；在另一个具体实施方案中，R b为C 1-6烷基；在另一个具体实施方案中，R b为C 1-6卤代烷基。
在一个具体实施方案中，R 1a、R 2a和R独立地选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基；在另一个具体实施方案中，R 1a、R 2a和R为氢；在另一个具体实施方案中，R 1a、R 2a和R为卤素；在另一个具体实施方案中，R 1a、R 2a和R为羟基；在另一个具体实施方案中，R 1a、R 2a和R为-NH 2；在另一个具体实施方案中，R 1a、R 2a和R为-NHC 1-6烷基；在另一个具体实施方案中，R 1a、R 2a和R为-N(C 1-6烷基) 2；在另一个具体实施方案中，R 1a、R 2a和R为C 1-6烷基；在另一个具体实施方案中，R 1a、R 2a和R为C 1-6卤代烷基；在另一个具体实施方案中，R 1a、R 2a和R为C 1-6烷氧基；在另一个具体实施方案中，R 1a、R 2a和R为C 3-7环烷基；在另一个具体实施方案中，R 1a、R 2a和R为C 3-7杂环烷基；在另一个具体实施方案中，R 1a、R 2a和R为C 6-10芳基；在另一个具体实施方案中，R 1a、R 2a和R为C 5-10杂芳基。
在一个具体实施方案中，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基；在另一个具体实施方案中，相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基；在另一个具体实施方案中，相同原子或相邻原子上的两个R基团可以一起形成C 3-7杂环烷基。在另一个具体实施方案中，相同原子或相邻原子上的两个R基团可以一起形成C 6-10芳基；在另一个具体实施方案中，相同原子或相邻原子上的两个R基团可以一起形成C 5-10杂芳基。
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，Y 1的任一技术方案或其任意组合，可以与Y、R 1、R 2、Z、Ar、X 1至X 9、Het、m、n、R a、R b、R 1a、R 2a和R的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。
在具体实施方案中，本发明化合物可选自下述化合物：
Figure PCTCN2018073338-appb-000062
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何 异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解，许多有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
药理和功效
本发明化合物尤其对依赖于Bcr-Abl1的活性的疾病或障碍显示治疗功效。特别地，本发明化合物抑制Bcr-Abl1的ATP结合位点(包括野生型Bcr-Abl1和/或其突变(包括T315I突变))。
癌细胞肿瘤侵袭和转移期间利用侵袭伪足(invapodia)降解细胞外基质。Abl激酶活性是Src-诱导的侵袭伪足形成所需要的，其调节侵袭伪足装配的不同阶段和功能。因此，作为Abl抑制剂的本发明化合物具有用作治疗转移的浸润性癌的治疗法的潜力。
c-Abl激酶的抑制剂可以用于治疗脑癌：包括为最常见和最具侵袭性的恶性原发性脑肿瘤的成胶质细胞瘤，其中在一个亚类的患者中可通过免疫组化技术检测到c-Abl的表达。因此，具有高脑暴露的新的c-Abl抑制剂代表了对成胶质细胞瘤和其他脑癌的固体治疗方法。
本发明化合物可以用于治疗病毒。例如，病毒感染可以由Abl1激酶活性介导，如在痘病毒类和埃博拉病毒的情况中。已显示伊马替尼和尼洛替尼在体外停止埃博拉病毒颗粒从受感染细胞的释放。因此能够预期抑制c-Abl激酶的本发明化合物可以用于降低病原体的复制能力。
帕金森病是第二普遍的慢性神经变性疾病，其具有最常见的由E3泛素蛋白连接酶(帕金蛋白(parkin))上的突变引起的家族性常染色体隐性形式。最新研究显示在散发性帕金森病患者的纹状体中发现激活的c-ABL。同时，帕金蛋白是酪氨酸-磷酸化的，引起其泛素蛋白连接酶和细胞保护活性的损失，如帕金蛋白底物的累积所示。
本发明化合物或组合物还用于治疗由Bcr-Abl激酶介导的下述疾病、障碍或病症：呼吸系统疾病、变态反应、类风湿性关节炎、骨关节炎、风湿性病症、银屑病、溃疡性结肠炎、局限性回肠炎、败血症性休克、增殖性病症、动脉粥样硬化、移植后的同种异体移植物排斥反应、糖尿病、中风、肥胖症或再狭窄、白血病、间质瘤、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成以及其他增生性或增殖性疾病、或其组合。
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
下列制剂实施例说明可根据本发明制备的代表性的药物组合物。然而，本发明不限于下列药物组合物。
示例性的制剂1-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为0.3-30mg片剂(每个片剂含有0.1-10mg活性化合物)。
示例性的制剂2-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为30-90mg片剂(每个片剂含有10-30mg活性化合物)。
示例性的制剂3-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为90-150mg片剂(每个片剂含有30-50mg活性化合物)。
示例性的制剂4-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为150-240mg片剂(每个片剂含有50-80mg活性化合物)。
示例性的制剂5-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为240-270mg片剂(每个片剂含有80-90mg活性化合物)。
示例性的制剂6-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为270-450mg片剂(每个片剂含 有90-150mg活性化合物)。
示例性的制剂7-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为450-900mg片剂(每个片剂含有150-300mg活性化合物)。
示例性的制剂8-胶囊剂：可以将干粉形式的本发明化合物与淀粉稀释剂以约1:1的重量比混合。将该混合物填充到250mg胶囊中(每个胶囊含有125mg活性化合物)。
示例性的制剂9-液体：可以将本发明化合物(125mg)与蔗糖(1.75g)和黄原胶(4mg)混合，且可将得到的混合物共混，通过No.10筛目美国筛，然后与预先制备的微晶纤维素和羧甲基纤维素钠(11:89，50mg)的水溶液混合。将苯甲酸钠(10mg)、调味剂和着色剂用水稀释，并在搅拌下加入。然后，可以加入充足的水，得到5mL的总体积。
示例性的制剂10-注射剂：可以将本发明化合物溶解或悬浮在缓冲无菌盐水可注射的水性介质中，达到约5mg/mL的浓度。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组 合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖；崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材 料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
治疗
本发明化合物还用于治疗由Bcr-Abl激酶介导的下述疾病、障碍或病症：呼吸系统疾病、变态反应、类风湿性关节炎、骨关节炎、风湿性病症、银屑病、溃疡性结肠炎、局限性回肠炎、败血症性休克、增殖性病症、动脉粥样硬化、移植后的同种异体移植物排斥反应、糖尿病、中风、肥胖症或再狭窄、白血病、间质瘤、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成以及其他增生性或增殖性疾病、或其组合。
本发明因此提供了用于在治疗中、特别是在治疗由不适当的Bcr-Abl活性介导的疾病和病况中使用的本发明化合物。
在本文中提及的不适当的Bcr-Abl活性是在特定哺乳动物对象中偏离预期的正常Bcr-Abl活性的任何Bcr-Abl活性。不适当的Bcr-Abl活性可以呈例如以下形式：活性异常增加，或者Bcr-Abl活性的时机和或控制的畸变。这种不适当的活性则可以由例如导致不适当或失控的活化的蛋白激酶的过表达或突变所导致。
在另一个实施方案中，本发明涉及为了预防和/或治疗与失调的或不适当的Bcr-Abl活性有关的病症而调节、调控或抑制Bcr-Abl的方法。
在另一个实施方案中，所述由Bcr-Abl活性介导的病症是呼吸系统疾病。在另一个实施方案中，所述病症是增殖性病症。在又一个实施方案中，所述病症是癌症。在另一个实施方案中，所述病症是白血病。
另一个实施方案中，本发明化合物还可以用于治疗神经变性。虽然在健康的成人脑中天然c-ABL酪氨酸激酶保持相对静止，但其在CNS疾病患者的脑中可以被激活，所述CNS疾病包括神经变性疾病、诸如阿尔茨海默病(AD)、帕金森病(AD)、额颞叶痴呆(frontotemporal dementia)(FTD)、皮克病、C型尼曼-皮克病(NPC)和其他退化性疾病、炎性疾病和自身免疫性疾病和老化。
本发明化合物的有效量通常在平均日剂量为0.01mg至50mg化合物/千克患者体重，优选0.1mg 至25mg化合物/千克患者体重，以单次或多次给药。通常，本发明化合物可向该有此治疗需要的患者以每位患者约1mg至约3500mg的日剂量范围给药，优选10mg至1000mg。例如，每位患者的日剂量可为10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、500、600、700、800、900或1000mg。可每天、每周(或间隔数天)或以间歇时间表，给药一次或多次。例如，可在每周的基础上(例如每周一)，每天给予所述化合物一次或多次，不定地或持续几周，例如4-10周。或者，可每天给药持续几天(例如2-10天)，然后几天(例如1-30天)不给药所述化合物，不定地重复该循环或重复给定的次数，例如4-10个循环。例如，本发明化合物可每天给药持续5天，然后间断9天，然后再每天给药持续5天，然后间断9天，以此类推，不定地重复该循环或共重复4-10次。
实施例
提供以下实施例以便为本领域技术人员提供如何实施、制备和评估本文请求保护的方法和化合物的完整公开和说明，旨在仅仅示例本发明而非限制本发明的范围。
合成方法
本发明化合物可按照本领域常规方法，并使用合适的试剂、原料和本领域技术人员已知的纯化方法制备。
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
通常，在制备中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)进行。反应时间通常为0.1小时-60小时，优选0.5-24小时。
实施例1 制备(R)-6-(3-羟基吡咯烷-1-基)-5-(异噻唑-3-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化 合物6)
Figure PCTCN2018073338-appb-000063
步骤1：6-氯-5-溴-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物2)的合成。
向反应瓶中加入6-氯-5-溴烟酸(1.17g，4.97mmol)，4-(氯二氟甲氧基)苯胺(0.8g，4.15mmol)，用20mL无水DMF溶解，加入2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU，2.1g，5.39mmol)和N，N-二异丙基乙胺(DIPEA，534mg，4.15mmol)，氮气保护下室温搅拌反应18小时，加入过量水稀释，乙酸乙酯萃取3-4遍，合并有机相，饱和食盐水洗涤，浓缩，柱层析纯化，真空干燥得产物1.18g，收率：69.5％。
步骤2：(R)-6-(3-羟基吡咯烷-1-基)-5-溴-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物4)的合成。
向反应瓶中加入化合物2(0.92g，2.0mmol)和(R)-3-羟基吡咯烷(209.1mg，2.4mmol)，加入2ml异丙醇，加入DIPEA(568.7mg，4.4mmol)，加热至140℃搅拌反应2小时，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到产物813mg，收率：88.2％。
步骤3：(R)-6-(3-羟基吡咯烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物5)的合成。
在反应瓶中加入化合物4(322.7mg，0.7mmol)，联硼酸频哪醇酯(711.03mg，2.8mmol)，乙酸钯(4.71mg，0.021mmol)，Xphos(25.0mg，0.053mmol)和磷酸钾(445.8mg，2.1mmol)，加入10mL无水二氧六环溶解，微波加热至60℃反应4小时，TLC检测原料未反应完全，补加联硼酸频哪醇酯(356mg，1.4mmol)后60℃反应过夜，TLC检测反应完毕，浓缩，硅胶柱层析纯化得到262mg产物，收率：73.5％。
步骤4：(R)-6-(3-羟基吡咯烷-1-基)-5-(异噻唑-3-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物6)的合成。
向反应瓶中加入化合物5(200mg，0.392mmol)、3-溴异噻唑(96mg，0.588mmol)、Pd(dppf)Cl 2(32mg，0.02mmol)和碳酸钠(126mg，1.18mmol)，加入2mL乙二醇二甲醚和0.4mL水，氮气鼓泡10分钟，微波加热至120℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到84mg产物，收率：46％。LC-MS(APCI):m/z＝467.3(M+1) +； 1H NMR(400MHz,DMSO)δ10.17(s,1H),9.04(s,1H),8.90(s,1H),8.76(d,J＝2.3Hz,1H),8.05(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.33(d,J＝8.8Hz,2H),4.86(d,J＝3.4Hz,1H),4.21(s,1H),3.41(dd,J＝17.0,9.3Hz,1H),3.29-3.18(m,2H),2.90(d,J＝11.1Hz,1H),1.89-1.80(m,1H),1.75(s,1H)。
实施例2 制备(R)-6-(3-羟基吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化 合物7)
Figure PCTCN2018073338-appb-000064
向反应瓶中加入化合物5(200mg，0.392mmol)、4-溴异噻唑(96mg，0.588mmol)、Pd(dppf)Cl 2(32mg，0.02mmol)和碳酸钠(126mg，1.18mmol)，加入2mL乙二醇二甲醚和0.4mL水，氮气鼓泡10分钟，微波加热至120℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到58mg产物，收率：31.7％。LC-MS(APCI):m/z＝467.3(M+1) +； 1H NMR(400MHz,DMSO)δ10.17(s,1H),9.04(s,1H),8.76(d,J＝2.3Hz,1H),8.70(s,1H),8.05(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.33(d,J＝8.8Hz,2H),4.86(d,J＝3.4Hz,1H),4.21(s,1H),3.41(dd,J＝17.0,9.3Hz,1H),3.29-3.18(m,2H),2.90(d,J＝11.1Hz,1H),1.89-1.80(m,1H),1.75(s,1H)。
实施例3 制备(R)-6-(3-羟基吡咯烷-1-基)-5-(异噻唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化 合物8)
Figure PCTCN2018073338-appb-000065
向反应瓶中加入化合物5(200mg，0.392mmol)、5-溴异噻唑(96mg，0.588mmol)、Pd(dppf)Cl 2(32mg，0.02mmol)和碳酸钠(126mg，1.18mmol)，加入2mL乙二醇二甲醚和0.4mL水，氮气鼓泡10分钟，微波加热至120℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到97mg产物，收率：53.1％。LC-MS(APCI):m/z＝467.3(M+1) +； 1H NMR(400MHz,DMSO)δ10.17(s,1H),9.04(s,1H),8.90(s,1H),8.76(d,J＝2.3Hz,1H),8.35(d,J＝2.3Hz,1H),7.86(d,J＝9.1Hz,2H),7.33(d,J＝8.8Hz,2H),4.86(d,J＝3.4Hz,1H),4.21(s,1H),3.41(dd,J＝17.0,9.3Hz,1H),3.29-3.18(m,2H),2.90(d,J＝11.1Hz,1H),1.89-1.80(m,1H),1.75(s,1H)。
实施例4 制备(R)-6-(3-羟基吡咯烷-1-基)-5-(1H-1,2,3-三唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰 胺(化合物12)
Figure PCTCN2018073338-appb-000066
步骤1：6-氯-5-(2-三甲基硅基乙炔-1-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物9)的合成。
向反应瓶中加入化合物2(400mg，0.97mmol)、三甲基硅基乙炔(143.4mg，1.46mmol)、Pd(PPh 3) 2Cl 2(34mg，0.048mmol)、碘化亚铜(18.4mg，0.096mmol)和DIPEA(377mg，2.92mmol)，加入10mL无水四氢呋喃溶解，氮气保护下微波加热至120℃反应1小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到产物250mg，收率：60.2％。
步骤2：6-氯-5-乙炔基-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物10)的合成。
向反应瓶中加入化合物9(250mg，0.58mmol)，加入10mL无水四氢呋喃溶解，加入1M四丁基氟化胺的四氢呋喃溶液(1.17mL，1.17mmol)，氮气保护下室温反应20分钟，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到产物194.5mg，收率：94.2％。
步骤3：6-氯-5-(1H-1,2,3-三唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物11)的合成。
向反应瓶中加入化合物10(127mg，0.357mmol)和三甲基硅基叠氮化物(82.2mg，0.713mmol)，加入2mL无水甲苯溶解，氮气保护下加热至120℃反应48小时，浓缩，硅胶柱层析纯化得到产物45mg，收率：31.6％。
步骤4：(R)-6-(3-羟基吡咯烷-1-基)-5-(1H-1,2,3-三唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合 物12)的合成。
向反应瓶中加入化合物11(30mg，0.075mmol)和(R)-3-羟基吡咯烷(7.86mg，0.09mmol)，加入2mL异丙醇，加入DIPEA(21.32mg，0.165mmol)，加热至140℃搅拌反应2小时，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到产物27.3mg，收率：81％。LC-MS(APCI):m/z＝451.5(M+1) +； 1H NMR(400MHz,DMSO)δ10.22(s,1H),8.75(d,J＝2.4Hz,1H),8.25(s,1H),8.07(d,J＝2.3Hz,1H),7.89(d,J＝9.1Hz,2H),7.31(d,J＝8.9Hz,2H),4.81(s,1H),4.14(s,1H),3.50-3.42(m,1H),3.23-3.14(m,2H),2.80(d,J＝11.8Hz,1H),1.79(dd,J＝8.9,4.4Hz,1H),1.73-1.63(m,1H)。
实施例5 制备(R)-6-(3-羟基吡咯烷-1-基)-5-(1H-1,2,3,4-四唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟 酰胺(化合物16)
Figure PCTCN2018073338-appb-000067
步骤1：(R)-6-(3-叔丁基二甲基硅氧基吡咯烷-1-基)-5-溴-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物13)的合成。
向反应瓶中加入化合物4(200mg，0.434mmol)、叔丁基二甲基氯硅烷(100mg，0.65mmol)和咪唑(100mg，1.47mmol)，加入5mL无水DMF，室温搅拌反应1小时，TLC检测反应完毕，加入水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到产物248mg，收率：99％。
步骤2：(R)-6-(3-叔丁基二甲基硅氧基吡咯烷-1-基)-5-氰基-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物14)的合成。
向反应瓶中加入化合物13(317mg，0.551mmol)、氰化锌(65mg，0.551mmol)和四(三苯基膦)钯(19mg，0.0165mmol)，加入5mL无水DMF，微波加热至150℃反应10分钟，TLC检测反应完毕，加入水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到产物209mg，收率：93％。
步骤3：(R)-6-(3-叔丁基二甲基硅氧基吡咯烷-1-基)-5-(1H-1,2,3,4-四唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物15)的合成。
向反应瓶中加入化合物14(209mg，0.4mmol)、叠氮化钠(312mg，4.8mmol)和氯化铵(254mg，4.8mmol)，加入5mL无水DMF，加热至150℃反应过夜，加入水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到产物102mg，收率：45.1％。
步骤4：(R)-6-(3-羟基吡咯烷-1-基)-5-(1H-1,2,3,4-四唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物16)的合成。
向反应瓶中加入化合物15(102mg，0.18mmol)，加入3mL甲醇溶解，加入4N的氯化氢甲醇溶 液(0.225ml，0.9mmol)，室温搅拌反应0.5小时，浓缩后硅胶柱层析纯化得到产物67.4mg，收率：83％。LC-MS(APCI):m/z＝452.4(M+1) +； 1H NMR(400MHz,DMSO)δ10.22(s,1H),8.75(d,J＝2.4Hz,1H),8.07(d,J＝2.3Hz,1H),7.89(d,J＝9.1Hz,2H),7.31(d,J＝8.9Hz,2H),4.81(s,1H),4.14(s,1H),3.50-3.42(m,1H),3.23-3.14(m,2H),2.80(d,J＝11.8Hz,1H),1.79(dd,J＝8.9,4.4Hz,1H),1.73-1.63(m,1H)。
实施例6 制备(R)-6-(3-羟基吡咯烷-1-基)-5-(1,2,4-噻二唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰 胺(化合物20)
Figure PCTCN2018073338-appb-000068
步骤1：(R)-6-(3-羟基吡咯烷-1-基)-5-氰基-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物17)的合成。
向反应瓶中加入化合物4(92.2mg，0.2mmol)、氰化锌(23.5mg，0.2mmol)和四(三苯基膦)钯(7mg，0.006mmol)，加入2mL无水DMF，微波加热至150℃反应10分钟，TLC检测反应完毕，加入水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到产物77.5mg，收率：95％。
步骤2：(R)-6-(3-羟基吡咯烷-1-基)-5-氨基硫代甲酰基-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物18)的合成。
向反应瓶中加入化合物17(250mg，0.612mmol)和五硫化二磷(117mg，1.838mmol)，加入10mL乙醇，加热至90℃反应18小时，浓缩除去溶剂后，硅胶柱层析纯化得到产物75mg，收率：27.7％。
步骤3：(R)-6-(3-羟基吡咯烷-1-基)-5-((二甲氨基)亚甲基氨基硫代甲酰基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物19)的合成。
向反应瓶中加入化合物18(75mg，0.178mmol)和N,N-二甲基甲酰胺二甲基缩醛(64mg，0.534mmol)，加入5mL无水DMF，室温搅拌反应10分钟，TLC检测反应完毕，加入水稀释，用乙酸乙酯萃取3-4次，合并有机相，饱和食盐水洗涤，浓缩后硅胶柱层析纯化得到产物40mg，收率：45.2％。
步骤4：(R)-6-(3-羟基吡咯烷-1-基)-5-(1,2,4-噻二唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物20)的合成。
向反应瓶中加入化合物19(40mg，0.08mmol)和吡啶(12.6mg，0.16mmol)，加入2.5mL乙醇溶解，缓慢滴加羟基磺酸(10mg，0.088mmol)的1.5mL甲醇溶液，加毕，室温搅拌反应1小时，TLC检测反应完毕，浓缩除去溶剂，硅胶柱层析纯化得到产物21mg，收率：56.1％。LC-MS(APCI):m/z＝468.6(M+1) +； 1H NMR(400MHz,DMSO)δ10.31(s,1H),9.01(s,1H),8.88(d,J＝2.3Hz,1H),8.33(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),5.32(t,J＝4.8Hz,1H),4.27(s,1H),3.56 (d,J＝7.4Hz,1H),3.28(dd,J＝13.2,5.3Hz,2H),2.93(d,J＝12.0Hz,1H),1.92-1.85(m,1H),1.80(dt,J＝15.9,6.5Hz,1H。
实施例7 (R)-6-(3-氟吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物23)
Figure PCTCN2018073338-appb-000069
步骤1：(R)-6-(3-氟吡咯烷-1-基)-5-溴-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物21)的合成。
向反应瓶中加入化合物2(0.90g，2.19mmol)和(R)-3-氟吡咯烷盐酸盐(330mg，2.63mmol)，加入15mL异丙醇，加入DIPEA(621mg，4.82mmol)，加热至140℃搅拌反应2小时，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到产物841mg，收率：83％。
步骤2：(R)-6-(3-氟吡咯烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物22)的合成。
在反应瓶中加入化合物21(628mg，1.35mmol)，联硼酸频哪醇酯(1.03g，4.06mmol)，乙酸钯(10mg，0.041mmol)，Xphos(50mg，0.101mmol)和磷酸钾(861mg，4.06mmol)，加入20mL无水二氧六环溶解，微波加热至60℃反应4小时，TLC检测原料未反应完全，补加联硼酸频哪醇酯(1.03g，4.06mmol)后60℃反应过夜，TLC检测反应完毕，浓缩，硅胶柱层析纯化得到514.3mg产物，收率：75％。
步骤3：(R)-6-(3-氟吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物23)的合成。
向反应瓶中加入化合物22(100mg，0.195mmol)、4-溴异噻唑(50mg，0.293mmol)、Pd(dppf)Cl 2(5mg，0.006mmol)和碳酸钠(60mg，0.558mmol)，加入5mL乙二醇二甲醚和0.9mL水，氮气鼓泡10分钟，微波加热至100℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到42mg产物，收率：46％。LC-MS(APCI):m/z＝469.5(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.69(d,J＝2.4Hz,1H),8.58(d,J＝9.6Hz,2H),7.94(d,J＝2.4Hz,1H),7.74(s,1H),7.67(d,J＝9.0Hz,2H),7.23(s,1H),5.21(d,J＝52.0Hz,1H),3.56(d,J＝3.1Hz,1H),3.52–3.44(m,2H),3.30(t,J＝9.7Hz,1H),2.26–2.19(m,1H),2.03–1.97(m,1H).
实施例8 (R)-6-(3-氟吡咯烷-1-基)-5-(异噻唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物24)
Figure PCTCN2018073338-appb-000070
向反应瓶中加入化合物22(100mg，0.195mmol)、5-溴异噻唑(50mg，0.293mmol)、Pd(dppf)Cl 2(5mg，0.006mmol)和碳酸钠(60mg，0.558mmol)，加入5mL乙二醇二甲醚和0.9mL水，氮气鼓泡10分钟，微波加热至100℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到45mg产物，收率：48％。LC-MS(APCI):m/z＝469.5(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.73(d,J＝2.3Hz,1H),8.49(d,J＝1.4Hz,1H),7.97(d,J＝2.3Hz,1H),7.90(s,1H),7.66(d,J＝9.0Hz,2H),7.24(s,1H),7.23–7.20(m,2H),5.30(s,1H),3.66(dd,J＝13.6,3.2Hz,1H),3.60–3.53(m,2H),3.36(t,J＝9.8Hz,1H),2.29–2.18(m,1H),2.10–1.94(m,1H).
实施例9 (R)-6-(3-氟吡咯烷-1-基)-5-(1,2,4-噻二唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合 物28)
Figure PCTCN2018073338-appb-000071
按照与前述实施例相同的操作，最终得到目标产物化合物28。LC-MS(APCI):m/z＝470.8(M+1) +。 1H NMR(400MHz,DMSO)δ10.31(s,1H),9.01(s,1H),8.88(d,J＝2.3Hz,1H),8.33(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝8.9Hz,2H),5.32(t,J＝4.8Hz,1H),4.27(s,1H),3.56(d,J＝7.4Hz,1H),3.28(dd,J＝13.2,5.3Hz,2H),2.93(d,J＝12.0Hz,1H),1.92–1.85(m,1H),1.80(dt,J＝15.9,6.5Hz,1H).
实施例10 (R)-6-(3-二甲氨基吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化 合物31)
Figure PCTCN2018073338-appb-000072
步骤1：(R)-6-(3-二甲氨基吡咯烷-1-基)-5-溴-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物29)的合成。
向反应瓶中加入化合物2(0.90g，2.19mmol)和(R)-3-二甲氨基吡咯烷盐酸盐(300mg，2.63mmol)， 加入15mL异丙醇，加入DIPEA(621mg，4.82mmol)，加热至140℃搅拌反应2小时，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到产物1.06g，收率：99％。
步骤2：(R)-6-(3-二甲氨基吡咯烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物30)的合成。
在反应瓶中加入化合物29(633mg，1.3mmol)，联硼酸频哪醇酯(0.98g，3.89mmol)，乙酸钯(25mg，0.039mmol)，Xphos(50mg，0.1mmol)和磷酸钾(826mg，3.9mmol)，加入20mL无水二氧六环溶解，微波加热至60℃反应4小时，TLC检测原料未反应完全，补加联硼酸频哪醇酯(0.98g，3.89mmol)后60℃反应过夜，TLC检测反应完毕，浓缩，硅胶柱层析纯化得到564mg产物，收率：81％。
步骤3：(R)-6-(3-二甲氨基吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物31)的合成。
向反应瓶中加入化合物30(100mg，0.186mmol)、4-溴异噻唑(50mg，0.279mmol)、Pd(dppf)Cl 2(5mg，0.006mmol)和碳酸钠(60mg，0.558mmol)，加入5mL乙二醇二甲醚和0.9mL水，氮气鼓泡10分钟，微波加热至100℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到78mg产物，收率：85％。LC-MS(APCI):m/z＝494.7(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.54(d,J＝4.3Hz,2H),7.96(s,1H),7.91(s,1H),7.67(d,J＝8.8Hz,2H),7.22(d,J＝8.6Hz,2H),3.43–3.34(m,1H),3.34–3.21(m,2H),3.18(dd,J＝17.9,9.0Hz,1H),2.67(s,1H),2.23(s,6H),2.05(d,J＝6.5Hz,1H),1.76(dd,J＝20.3,10.0Hz,1H).
实施例11 (R)-6-(3-二甲氨基吡咯烷-1-基)-5-(异噻唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化 合物32)
Figure PCTCN2018073338-appb-000073
向反应瓶中加入化合物30(100mg，0.186mmol)、5-溴异噻唑(50mg，0.279mmol)、Pd(dppf)Cl 2(5mg，0.006mmol)和碳酸钠(60mg，0.558mmol)，加入5mL乙二醇二甲醚和0.9mL水，氮气鼓泡10分钟，微波加热至100℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到54mg产物，收率：58.8％。LC-MS(APCI):m/z＝494.7(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.72(d,J＝2.3Hz,1H),8.46(d,J＝1.5Hz,1H),8.40(s,1H),8.01(d,J＝2.3Hz,1H),7.72(d,J＝9.0Hz,2H),7.24–7.17(m,3H),3.50(dd,J＝10.8,7.1Hz,1H),3.42(t,J＝9.6Hz,1H),3.32(dd,J＝9.3,4.4Hz,2H),2.91–2.84(m,1H),2.35(s,6H),2.10(dd,J＝11.6,6.0Hz,1H),1.91(dd,J＝20.5,10.4Hz,1H).
实施例12 (R)-6-(3-二甲氨基吡咯烷-1-基)-5-(1,2,4-噻二唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰 胺(化合物36)
Figure PCTCN2018073338-appb-000074
按照与前述实施例相同的操作，最终得到目标产物化合物36。LC-MS(APCI):m/z＝495.0(M+1) +。 1H NMR(400MHz,DMSO)δ10.34(s,1H),9.02(s,1H),8.88(d,J＝2.3Hz,1H),8.36(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.35(d,J＝9.0Hz,2H).3.50(dd,J＝10.8,7.1Hz,1H),3.42(t,J＝9.6Hz,1H),3.32(dd,J＝9.3,4.4Hz,2H),2.91–2.84(m,1H),2.35(s,6H),2.10(dd,J＝11.6,6.0Hz,1H),1.91(dd,J＝20.5,10.4Hz,1H).
实施例13 6-(3-羟基-4-氟吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物 42)
Figure PCTCN2018073338-appb-000075
步骤1：3-羟基-4-氟-N-叔丁氧羰基吡咯烷(化合物38)的合成。
向反应瓶中加入3-叔丁氧羰基-6-氧杂-3-氮杂二环[3.1.0]己烷(1.11g，6.0mmol)和三乙胺氢氟酸盐(967.3mg，7.2mmol)，加热至100℃搅拌反应过夜，降至室温，硅胶柱层析纯化得到产物881mg，收率：71.6％。
步骤2：3-羟基-4-氟吡咯烷(化合物39)的合成。
向反应瓶中加入化合物38(881mg，4.29mmol)和4M氯化氢二氧六环溶液(27ml，107.4mmol)，室温搅拌反应3-4小时，TLC检测反应完毕后，浓缩除去溶剂，不需纯化直接投入下一步。
步骤3：6-(3-羟基-4-氟吡咯烷-1-基)-5-溴-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物40)的合成。
向反应瓶中加入化合物2(883mg，2.15mmol)和化合物39(276.1mg，2.63mmol)，加入15mL异丙醇，加入DIPEA(610mg，4.73mmol)，加热至140℃搅拌反应2小时，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到产物896mg，收率：87％。
步骤4：6-(3-羟基-4-氟吡咯烷-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物41)的合成。
在反应瓶中加入化合物40(650mg，1.35mmol)，联硼酸频哪醇酯(1.03g，4.06mmol)，乙酸钯(10 mg，0.045mmol)，Xphos(50mg，0.1mmol)和磷酸钾(861mg，4.06mmol)，加入20mL无水二氧六环溶解，微波加热至60℃反应4小时，TLC检测原料未反应完全，补加联硼酸频哪醇酯(1.03g，4.06mmol)后60℃反应过夜，TLC检测反应完毕，浓缩，硅胶柱层析纯化得到664mg产物，收率：93.4％。
步骤5：6-(3-羟基-4-氟吡咯烷-1-基)-5-(异噻唑-4-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物42)的合成。
向反应瓶中加入化合物41(100mg，0.19mmol)、4-溴异噻唑(50mg，0.27mmol)、Pd(dppf)Cl 2(5mg，0.006mmol)和碳酸钠(60mg，0.558mmol)，加入5mL乙二醇二甲醚和0.9mL水，氮气鼓泡10分钟，微波加热至100℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到58mg产物，收率：63％。LC-MS(APCI):m/z＝485.3(M+1) +。 1H NMR(400MHz,CDCl 3)δ10.23(s,1H),9.09(s,1H),8.77(d,J＝2.0Hz,1H),8.72(s,1H),8.10(d,J＝2.0Hz,1H),7.87(d,J＝9.0Hz,2H),7.34(d,J＝8.7Hz,2H),5.47(d,J＝3.5Hz,1H),4.94(d,J＝51.5Hz,1H),4.18(s,1H),3.64(ddd,J＝41.8,13.5,3.1Hz,1H),3.43–3.38(m,1H),3.02(d,J＝11.9Hz,1H).
实施例14 6-(3-羟基-4-氟吡咯烷-1-基)-5-(异噻唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化合物 43)
Figure PCTCN2018073338-appb-000076
向反应瓶中加入化合物41(100mg，0.19mmol)、5-溴异噻唑(50mg，0.27mmol)、Pd(dppf)Cl 2(5mg，0.006mmol)和碳酸钠(60mg，0.558mmol)，加入5mL乙二醇二甲醚和0.9mL水，氮气鼓泡10分钟，微波加热至100℃反应半小时，TLC检测反应完毕后浓缩，硅胶柱层析纯化得到29mg产物，收率：31.5％。LC-MS(APCI):m/z＝485.3(M+1) +。 1H NMR(400MHz,DMSO)δ10.29(s,1H),8.82(d,J＝2.3Hz,1H),8.65(d,J＝1.6Hz,1H),8.15(d,J＝2.3Hz,1H),7.87(d,J＝9.1Hz,2H),7.50(d,J＝1.6Hz,1H),7.34(d,J＝9.0Hz,2H),5.50(d,J＝2.8Hz,1H),4.97(d,J＝52.1Hz,1H),4.21(s,1H),3.75(ddd,J＝41.8,13.6,3.3Hz,1H),3.51(d,J＝12.1Hz,1H),3.46–3.36(m,1H),3.08(d,J＝11.9Hz,1H).
实施例15 6-(3-羟基-4-氟吡咯烷-1-基)-5-(1,2,4-噻二唑-5-基)-N-(4-(氯二氟甲氧基)苯基)烟酰胺(化 合物47)
Figure PCTCN2018073338-appb-000077
按照与前述实施例相同的操作，最终得到目标产物化合物47。LC-MS(APCI):m/z＝486.8(M+1) +。 1H NMR(400MHz,DMSO)δ10.35(s,1H),9.04(s,1H),8.90(d,J＝2.3Hz,1H),8.37(d,J＝2.3Hz,1H),7.86(t,J＝6.0Hz,2H),7.35(d,J＝8.9Hz,2H),5.54(d,J＝3.3Hz,1H),5.00(d,J＝52.8Hz,1H),4.25(s,1H),3.91–3.77(m,1H),3.61(d,J＝12.1Hz,1H),3.46–3.38(m,1H),3.02(d,J＝12.2Hz,1H).
生物活性测试
实施例16：细胞毒性实验
检测实施例化合物对Ba/F 3亲本细胞，Ba/F 3Bcr-Abl T315I细胞活性的抑制效应。
耗材及试剂：RPMI-1640培养基(GIBCO，目录号A10491-01)、胎牛血清(GIBCO，目录号10099141)、抗生素(青霉素-链霉素)，IL-3(PeproTech)，嘌呤霉素；细胞系：Ba/F 3亲本细胞，Ba/F 3Bcr-Abl T315I(购自美国标准生物品收藏中心，ATCC)，活细胞检测试剂盒CellTiter-Glo4(Promega，目录号G7572)，96孔黑壁透明平底细胞培养板(Corning，目录号3340)。
实验方法：
1.制备细胞板：将Ba/F 3亲本细胞，Ba/F 3Bcr-Abl T315I细胞分别种于96孔板中，并在Ba/F 3亲本细胞中加入8ng/ml IL-3，细胞板置于二氧化碳培养箱中过夜培养。
2.制备被测化合物：用DMSO溶解被测化合物并进行3.16倍梯度稀释，9个化合物浓度，设置三复孔实验，化合物起始浓度为10μM。
3.化合物处理细胞：将各浓度的化合物转移到细胞板中。细胞板置于二氧化碳培养箱中培养3天。
4.检测：向细胞板中加入CellTiter-Glo4试剂，室温孵育30分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
实施例中对细胞的体外增殖的抑制作用的结果归纳于下表1，其中A表示IC 50≤100nM，B表示100nM<IC 50≤500nM，C表示500nM<IC 50≤1000nM，D表示IC 50>1000nM。
表1实施例化合物的细胞毒性作用
实施例编号 Ba/F 3亲本细胞IC 50 Ba/F 3Bcr-Abl1 T315IIC 50
实施例1 D B
实施例2 D A
实施例3 D A
实施例4 D C
实施例5 D D
实施例6 D B
实验结果表明，本发明化合物对与药物副作用相关的Ba/F 3细胞表现出相对低的抑制活性(IC 50大于1000nM)，而对Ba/F 3Bcr-Abl T315I突变体的细胞表现出优良的抑制活性(最佳的IC 50≤100nM)，因此本发明化合物可作为Bcr-Abl抑制剂，用于对现有酪氨酸激酶抑制剂(TKI)治疗耐药或抵抗的肿瘤患者，例如对慢性粒细胞白血病(CML)慢性期、急变期、加速期患者以及费城染色体阳性(Ph +)的慢性粒细胞白血病和急性淋巴细胞白血病患者具有好的前景。
此外，本发明化合物还具有极佳的治疗指数(由Ba/F 3亲本细胞的IC 50除以Ba/F 3Bcr-Abl T315I的IC 50得到)，例如实施例2的化合物具有高于180的治疗指数，实施例3的化合物具有高于90的治疗指数。
实施例17：大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉(静脉2mg/kg)或口服单个剂量的化合物(口服20mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃ 5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
本实验使用ABL-001作为阳性对照，实验结果如下表2。
表2实施例化合物的大鼠的PK参数
Figure PCTCN2018073338-appb-000078
该实验结果表明，本发明化合物具有更好的药代动力学性质。例如，实施例2的化合物与ABL-001同时口服给药大鼠后，发现实施例2化合物具有更好的代谢参数——最大血浆暴露浓度(C max)、血浆暴露量(AUC last)和口服利用度(F％)。
实施例18：BA/F3(BCR-ABL T315I)皮下肿瘤模型中的药效学评价
实验动物：NOD/SCID小鼠，雌性，7-8周(肿瘤细胞接种时的小鼠周龄)，平均体重21.8g，32只，购自北京华阜康生物技术有限公司，动物合格证编号：11401300068166。饲养环境：SPF级。
实验动物饲养室的环境条件：实验动物均饲养于恒温恒湿的独立通风盒内，饲养室温度22.3-24.5℃，湿度51-58％，10-20次/小时换气，昼夜明暗交替时间12h/12h；持续供给钴60放射灭菌鼠全价颗粒饲料，不限量自由摄取，饮用自来水(高压蒸汽灭菌后使用)，饮水瓶不间断供水，自由摄取。 饲养鼠盒是聚砜鼠盒，高压灭菌后使用，规格为325mm×210mm×180mm；垫料是高压灭菌玉米芯，每盒4只动物，笼卡上标明IACUC批准号、实验编号、实验开始时间、课题负责人、实验人员、动物来源、组别和动物号等；实验动物打耳号进行标记。
方法：每只NOD/SCID小鼠于右侧背部皮下接种5×10 6BA/F3(BCR-ABL T315I)细胞，细胞重悬在PBS(0.1ml/只)中，建立皮下肿瘤模型。试验分为溶媒对照组，阳性对照ABL001 15mg/kg组，化合物实施例2 15mg/kg组；每组6只小鼠，每天给药2次，溶媒对照组给药15天，阳性对照ABL00115mg/kg组给药19天，化合物实施例2 15mg/kg组给药19天。根据相对肿瘤抑制率(TGI)进行疗效评价，根据动物体重变化和死亡情况进行安全性评价。
本实验过程中动物实验的实验方案均通过CrownBio IACUC委员会审核并批准通过。实验过程中，动物实验操作均根据AAALAC的要求。肿瘤接种后，常规监测包括了肿瘤生长及治疗对动物正常行为的影响，具体内容有实验动物的活动性，摄食和饮水情况，体重增加或降低情况，眼睛、被毛及其它异常情况。实验过程中观察到的异常临床症状均记录在原始数据中。实验过程中每周测量并记录三次小鼠体重和肿瘤大小。每次给药前称量小鼠重量，根据小鼠重量进行给药。
相对肿瘤抑制率TGI(％)：TGI％＝(1-T/C)×100％。T/C％为相对肿瘤增值率，即在某一时间点，治疗组和对照组相对肿瘤体积或瘤重的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)或瘤重(TW)。
统计分析：所有实验结果以平均值±标准误
Figure PCTCN2018073338-appb-000079
表示，对照组与各治疗组之间用单因素方差分析(one-way ANOVA)比较分组后12天时肿瘤体积有无显著性差异，随后用Games-Howell(数据方差不齐)比较对照组与各治疗组之间或各治疗组之间肿瘤体积的显著性差异，p<0.05为差异显著。
实验结果：
在BA/F 3(BCR-ABL T315I)皮下肿瘤模型中，本发明化合物具有更好的抗肿瘤作用和更好的安全性。例如，与ABL-001相比，实施例2化合物的相对肿瘤抑制率(TGI)高出至少20％；实验过程中，ABL-001组小鼠的平均体重下降了5％，而实施例2化合物组小鼠平均体重有所增加，从小鼠的体重的变化可以得出：实施例2化合物的安全性比ABL-001高。
应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围，实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (13)

  1. 式(I)化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
    Figure PCTCN2018073338-appb-100001
    其中：
    Y 1选自CR a或N；
    Y独立地选自CR a或N；
    R 1选自氢、卤素、腈基、硝基、C 1-6烷基或C 1-6卤代烷基，其中所述C 1-6烷基或C 1-6卤代烷基任选被R 1a基团取代；
    R 2选自氢、C 1-6烷基或C 1-6卤代烷基，其中所述C 1-6烷基或C 1-6卤代烷基任选被R 2a基团取代；
    Z为化学键、O、S(O) 0-2或NR b；
    或者-Z-R 2一起表示-SF 5；
    Ar为
    Figure PCTCN2018073338-appb-100002
    其中X 1为S，X 2至X 4独立地选自CR或N；并且X 2、X 3和X 4中的一个为与母核连接的C原子；Het为
    Figure PCTCN2018073338-appb-100003
    其中X 9选自O、S、NR b或C(R) 2；
    m为0、1或2；
    n为0、1、2、3、4、5或6；
    R a独立地选自氢、卤素、腈基、硝基、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基或C 1-6烷氧基；
    R b独立地选自氢、C 1-6烷基或C 1-6卤代烷基；
    R 1a、R 2a和R独立地选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基、-N(C 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基；
    或者相同原子或相邻原子上的两个R基团可以一起形成C 3-7环烷基、C 3-7杂环烷基、C 6-10芳基或C 5-10杂芳基。
  2. 根据权利要求1所述的化合物，其为式(Ia)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
    Figure PCTCN2018073338-appb-100004
    其中，Ar和Het如权利要求1所定义。
  3. 根据权利要求1-2中任一项所述的化合物，或其药学上可接受的盐、立体异构体、溶剂合物或水合物，其中：
    Het为
    Figure PCTCN2018073338-appb-100005
    其中，X 9为C(R) 2，并且m、n和R如权利要求1所定义；
    或者，Het选自任选被一个、两个、三个或更多个R取代的以下基团：
    Figure PCTCN2018073338-appb-100006
    其中R如权利要求1所定义；
    或者，Het选自以下基团：
    Figure PCTCN2018073338-appb-100007
  4. 根据权利要求1-3中任一项所述的化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
    Figure PCTCN2018073338-appb-100008
    其中：
    Ar选自任选被一个或两个R取代的以下基团：
    Figure PCTCN2018073338-appb-100009
    R选自氢、卤素、羟基、-NH 2、-NHC 1-6烷基或-N(C 1-6烷基) 2。
  5. 根据权利要求1-3中任一项所述的化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
    Figure PCTCN2018073338-appb-100010
    其中：
    Ar选自任选被一个或两个R取代的以下基团：
    Figure PCTCN2018073338-appb-100011
    R选自氢或羟基。
  6. 根据权利要求1-3中任一项所述的化合物，其为式(Ib)，或其药学上可接受的盐、立体异构体、溶剂合物或水合物：
    Figure PCTCN2018073338-appb-100012
    其中：
    Ar选自任选被一个或两个R取代的以下基团：
    Figure PCTCN2018073338-appb-100013
    R选自氢或羟基。
  7. 化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物，所述化合物选自：
    Figure PCTCN2018073338-appb-100014
  8. 药物组合物，其含有权利要求1-7中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物，和药学上可接受的赋形剂。
  9. 试剂盒，其包括
    第一容器，其中含有权利要求1-7中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物；和任选地，第二容器，其中含有其它治疗剂；和任选地，第三容器，其中含有用于稀释或悬浮所述化合物和/或其它治疗剂的药用赋形剂。
  10. 权利要求1-7中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物在制备用于治疗和/或预防Bcr-Abl导致的疾病的药物中的用途。
  11. 一种在受试者中治疗和/或预防Bcr-Abl导致的疾病的方法，所述方法包括向所述受试者给药权利要求1-7中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物或权利要求8的药物组合物。
  12. 权利要求1-7中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物或水合物或权利要求8的药物组合物，其用于治疗和/或预防Bcr-Abl导致的疾病。
  13. 根据权利要求10的用途、权利要求11的方法或权利要求12的化合物的用途，其中所述Bcr-Abl导致的疾病为增殖性疾病，其选自：实体瘤、肉瘤、急性淋巴细胞白血病、急性髓细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、胃肠道间质瘤、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病；或者所述Bcr-Abl导致的疾病为转移的浸润性癌、病毒感染或CNS障碍。
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